Beneficial effects of arginase inhibition and inhaled l-arginine administration on airway histology in a murine model of chronic asthma

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Feurle, J. Petersen, M. Uder, H.G. Schwelberger" "autores" => array:5 [ 0 => array:2 [ "nombre" => "M.A." "apellidos" => "Kuefner" ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Feurle" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "Petersen" ] 3 => array:2 [ "nombre" => "M." "apellidos" => "Uder" ] 4 => array:2 [ "nombre" => "H.G." "apellidos" => "Schwelberger" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054613000505?idApp=UINPBA00004N" "url" => "/03010546/0000004200000004/v1_201407030035/S0301054613000505/v1_201407030035/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0301054613001109" "issn" => "03010546" "doi" => "10.1016/j.aller.2013.02.010" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "aid" => "509" "copyright" => "SEICAP" "documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "Allergol Immunopathol (Madr). 2014;42:307-15" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 989 "formatos" => array:3 [ "EPUB" => 9 "HTML" => 541 "PDF" => 439 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Overuse of bronchodilators and steroids in bronchiolitis of different severity" "subtitulo" => "Bronchiolitis-study of variability, appropriateness, and adequacy" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "307" "paginaFinal" => "315" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 833 "Ancho" => 2313 "Tamanyo" => 166879 ] ] "descripcion" => array:1 [ "en" => "Use of bronchodilators, adrenaline, and corticosteroids in each health care setting (percentages)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "C. Ochoa Sangrador, J. González de Dios" "autores" => array:3 [ 0 => array:2 [ "nombre" => "C." "apellidos" => "Ochoa Sangrador" ] 1 => array:2 [ "nombre" => "J." "apellidos" => "González de Dios" ] 2 => array:1 [ "colaborador" => "Research Group of the aBREVIADo Project" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054613001109?idApp=UINPBA00004N" "url" => "/03010546/0000004200000004/v1_201407030035/S0301054613001109/v1_201407030035/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Beneficial effects of arginase inhibition and inhaled l-arginine administration on airway histology in a murine model of chronic asthma" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "316" "paginaFinal" => "323" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Z. Arıkan-Ayyıldız, M. Karaman, T. Tuncel, M. Kiray, A. Bağrıyanık, O. Yilmaz, N. Uzuner, Ö. Karaman" "autores" => array:8 [ 0 => array:4 [ "nombre" => "Z." "apellidos" => "Arıkan-Ayyıldız" "email" => array:1 [ 0 => "zeynep.ayyildiz@deu.edu.tr" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] 1 => array:4 [ "nombre" => "M." "apellidos" => "Karaman" "email" => array:1 [ 0 => "meral.karaman@deu.edu.tr" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:4 [ "nombre" => "T." "apellidos" => "Tuncel" "email" => array:1 [ 0 => "tuba.tuncel@deu.edu.tr" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:4 [ "nombre" => "M." "apellidos" => "Kiray" "email" => array:1 [ 0 => "muge.kiray@deu.edu.tr" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 4 => array:4 [ "nombre" => "A." "apellidos" => "Bağrıyanık" "email" => array:1 [ 0 => "alper.bagriyanik@deu.edu.tr" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 5 => array:4 [ "nombre" => "O." "apellidos" => "Yilmaz" "email" => array:1 [ 0 => "osman.yilmaz@deu.edu.tr" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 6 => array:4 [ "nombre" => "N." "apellidos" => "Uzuner" "email" => array:1 [ 0 => "nevin.uzuner@deu.edu.tr" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 7 => array:4 [ "nombre" => "Ö." "apellidos" => "Karaman" "email" => array:1 [ 0 => "ozkan.karaman@deu.edu.tr" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Department of Pediatric Allergy, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Experimental Animal Laboratory, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Physiology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Histology and Embriology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1115 "Ancho" => 1900 "Tamanyo" => 493111 ] ] "descripcion" => array:1 [ "en" => "(a) Light and electron microscopic findings of study groups: (I) control (n: 7); (II) placebo (n: 7); (III) l-arginine (n: 7); (IV) nor-NOHA (n: 7); (V) l-arginine+nor-NOHA (n: 7); (VI) budesonide (n: 6). (A) H&E; (B) PAS; (C) Toluidine staining. (A) Two-headed arrow: subepithelial smooth muscle thickening; (*) peribronchial mononuclear cell infiltration. (B) Arrows: goblet cells; (C) arrows: mast cells. (D) Electron microscopic views. Increased goblet cells in placebo group (Gc), basal membrane thickening (*). C: cilia. (B) Masson Trichrome staining. Masson Trichrome staining (blue colour) showed minimal peribronchial and perivascular collagen accumulating in control (I) and budesonide (VI) groups. Increased collagen deposition was seen with Trichrome staining in the OVA-induced asthma mice (II), as compared to normal tissue. Collagen deposition was reduced in groups III, IV and V. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)" ] ] ] "textoCompleto" => "IntroductionBronchial asthma is characterised by airway hyperresponsiveness, remodelling and inflammation. Lung inflammation in allergic asthma is mediated by a cascade of reactions involving various mediators including nitric oxide (NO). Nitric oxide is thought to have an important role in smooth muscle relaxation, bronchodilation and neurotransmission besides participating in inflammation.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Nitric oxide is formed by the metabolism of l-arginine by nitric oxide synthase (NOS). Three NOS mammalian isoenzymes have been identified: NOS-1, NOS-2 and NOS-3. Neuronal NOS or NOS-1 and endothelial NOS (NOS-3, eNOS) are expressed in airway epithelium and involved in neurotransmission and smooth muscle relaxation and bronchodilation, respectively. Their activity is regulated by calcium and they produce small amount of NO. Inducible NOS (NOS 2, iNOS) is also expressed in airway epithelium but regulated by pro-inflammatory stimuli with the ability of producing large amounts of NO over hours.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Deficiency of eNOS derived NO is involved in inflammatory response during asthmatic reaction. Thus it has been shown that e-NOS derived NO inhibits airway inflammation by suppressing expression of inflammatory cytokines and iNOS.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> In inflamed asthmatic airways, expression of iNOS is increased in airway epithelium by cytokines like TNF-α and IFN-γ and levels of exhaled nitric oxide are increased in patients with persistent asthma.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> iNOS-derived NO is shown to be associated with epithelial damage, infiltration of inflammatory cells, stimulation of TH2-mediated response, mucus hypersecretion and vascular permeability but it is suggested that formation of peroxynitrite from iNOS-derived NO contributes to airway hyperresponsiveness rather than NO itself.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2,5</a> It is thought that increased formation of peroxynitrite is the result of decreased bioavailability of l-arginine to NOS. Increasing the l-arginine concentration in macrophages is found to stimulate NO production and inhibit the formation of peroxynitrite.<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a>l-Arginine is metabolised by arginase which has also gained an important role in regulating endogenous NO production. Arginase is an urea cycle enzyme that hydrolyses l-arginine to urea and l-ornithine. Two isoforms of arginase (arginase I and II) are expressed in airways and arginase reduces the bioavailability of l-arginine for NOS and therefore affects NO production. l-Ornithine is also involved in synthesis of polyamines and l-proline which are involved in promotion of cell growth and repair and collagen synthesis, respectively. Experimental models of asthma have demonstrated that arginase activity is induced following challenge with allergens.<a class="elsevierStyleCrossRefs" href="#bib0040">8,9</a> Studies in human asthma also confirm the importance of arginase in the pathogenesis of experimental asthma.<a class="elsevierStyleCrossRefs" href="#bib0050">10,11</a> The lung function of severe asthmatics correlates directly with l-arginine bioavailability and inversely with serum arginase activity, indicating that serum arginase activity reduces circulating l-arginine levels which contribute to NO deficiency within airways.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>Increased understanding of the role of arginase in the pathogenesis of asthma represents a drug target that opens novel therapeutic perspectives for the treatment of asthma. In this study we determined the effects of l-arginine, arginase inhibitor Nω-hydroxy-nor-l-arginine (nor-NOHA) and co-treatment of these on airway inflammation in a murine model of asthma.Materials and methodsAnimalsForty-two male, conventionally raised, 6–8-week-old, BALB/c mice weighing 18–20g were used in the experiment. The animals were fed a commercial diet ad libitum and housed in an air-conditioned facility on a 12-h light/12-h dark cycle. The studies adhered to the National Institutes of Health guidelines for the experimental use of animals. The Institutional Animal Care and Use Committee granted approval for the study.Experimental protocolMice were sensitised by an intraperitoneal (ip) injection of ovalbumin (10μg/0.1ml, 2 weeks apart, i.e. on Day 0 and Day 14) consisting of chicken egg albumin (ovalbumin, grade V, ≥98 pure, Sigma, St. Louis, MO, USA) with alum adjuvant as described by Temelkovski et al.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Mice in study groups II, III, IV, V and VI were then challenged with an aerosol of 5ml 2.5% ovalbumin (OVA) in saline for 30min per day on 3 days of the week for 8 weeks beginning from the 21st day of the study. The mice in the control group (Group I) received normal saline with alum intraperitoneally on Days 0 and 14 of the experiment and aerosolised saline without alum for 30min per day on 3 days of the week for 8 weeks beginning from the 21st day of the study. Exposures were carried out in a whole body inhalation exposure system in a plexiglass chamber with 40×60×120 diameters designed for the placement of cages. Temperature and relative humidity were maintained at 20–25°C and 40–60%, respectively. A solution of 2.5% ovalbumin in normal saline was aerosolised by delivery of compressed air to a sidestream jet nebuliser with a flow rate of 6L/min (Medicair, UK) and injected into a chamber. The aerosol generated by this nebuliser comprised >80% particles with a diameter of <4μm. Particle concentration was maintained in the range of 10–20mg/mm3 in the chamber.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>Study drugsMice in Group III received nebulised l-arginine 1M (174mg/ml),<a class="elsevierStyleCrossRef" href="#bib0070">14</a> Group IV received nebulised nor-NOHA 20μM (3.5μg/ml),<a class="elsevierStyleCrossRef" href="#bib0075">15</a> Group V received both l-arginine and nor-NOHA, Group VI received nebulised budesonide 0.5mg/2ml,<a class="elsevierStyleCrossRef" href="#bib0080">16</a>, and Group II received nebulised saline once a day for the last 7 days of the challenge period. l-Arginine was obtained from Sigma–Aldrich (St. Louis, MO, USA) and nor-NOHA from Cayman Chemical (Ann Arbor, MI, USA). Experimental protocol and study drugs are presented in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Preparations of lung homogenatesAnimals were sacrificed by an overdose of ketamine 24h after the last drug administration. Lungs were removed and washed with cold PBS three times in order to remove blood. Lung tissues were taken into 2ml microcentrifuge tubes and stored at −80°C until analysis. On the study day, frozen lungs were thawed, weighed (60–80mg), transferred into different tubes on ice containing 5ml of stainless beads, 0.1% SDS, protease inhibitor cocktail (Sigma–Aldrich, St. Louis, MO, USA) and 0.1mg/ml phenylmethanesulfonyl fluoride (PMSF) in PBS. Microcentrifuge tubes were transferred to pre-cooled Tissuelyser LT racks and placed into TissueLyser (Qiagen, Germany) homogenisator. Frequency and time were set to 50 and 5min, respectively. The homogenates were then centrifuged at 15,000×g for 1h at 4°C. The supernatants were stored at −80°C.Measurement of cytokinesLevels of IL-4 and IL-5 were quantified in the supernatants of the lung tissue by standard ELISA protocols using commercial mouse IL-4 and IL-5 (Bender MedSystems, MedSystems Diagnostics GmbH, Vienna, Austria). Detection levels were 2.0pg/ml for IL-4 and 3.3pg/ml for IL-5.Measurement of l-arginine in lung tissue supernatantsL-Arginine content of lung homogenates was assessed by the method described by Frank et al.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> In brief, airway homogenate aliquots of 100μl were added to 5% HClO4 and centrifuged at 15,000×g for 15min. 100μl of supernatant was mixed with the equal amount of OPA and after 30min, 10μl was analysed with HPLC.Bronchoalveolar lavageBronchoalveolar lavage fluid (BAL) was immediately collected from euthanised mice by instillation and recovery of 1ml 0.99% NaCl through the tracheal cannula. BAL was centrifuged at 3000×g for 10min and supernatant was removed and stored at −80°C until assay of NO. Histological smear samples were prepared. A differential cell count was performed using May-Grünwald Giemsa staining and classified as eosinophils, neutrophils, and lymphocytes on the basis of morphological criteria and staining characteristics. Differential cell counts were performed in a blinded fashion by counting at least 200 cells per slide under light microscopy.Determination of NONO levels in BAL samples were measured by a Griess reaction.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> The colorimetric kit (Sigma–Aldrich Co., USA) was used according to the manufacturer's manual. Results are determined spectrophotometrically on 540nm (BioTek Synergy HT, USA).Histological evaluationExaminations were conducted in a blind fashion by two of the investigators. Tissue specimens were obtained from the mid-zone of the left lung of mice. Samples were fixed in 10% formalin for light microscopic evaluation. Some tissue samples of 1–2mm3 taken from adjacent regions were stocked in 2% gluteraldehyte for electron microscopic evaluation. After fixation, samples were embedded in paraffin for light microscopic evaluation. Paraffin blocks were placed in Leica RM2125 rotary microtome (Germany) and serial sections of 5μm thickness were obtained. After choosing the first section randomly, 10 sections in each mouse were selected by skipping over 10 sections and proceeding to staining process. For light microscopic evaluation, four different staining processes were used. The first 10 samples were stained with haematoxylin and eosin (H&E). In these samples, general tissue features were examined and thicknesses of epithelium and subepithelial smooth muscle layers of the medium and small airways were measured. In order to evaluate the thicknesses of epithelium and subepithelial smooth muscle layers, measurements were performed from four points of each airway at levels of 3, 6, 9, and 12 o’clock. Considering that each section contained two to three airways, nearly 20 or more airways were evaluated in each mouse.Photomicrographs were taken by Olympus DP25 (Japan) camera, which was adapted on Olympus CX-41 model microscope (Olympus Optical, Tokyo, Japan). The histological analysis was carried out with a computer-assisted image analyser system (DP2-BSW).The 10 consecutive sections were stained with Toluidine Blue and the other 10 sections with periodic acid–Schiff (PAS). Last sections were stained with Masson Trichrome stain for demonstration of collagen deposition. Photomicrographs were taken randomly from five fields of each section which were stained with Toluidine Blue. For mast cell enumeration, a standard transparent counting frame representing an area of 20,000μm2 was used manually and 10 fields in each photograph were examined for each mouse. Goblet cells stained with PAS were enumerated in 10 sections of each mouse. In each section, three to five randomly selected airways were photographed. Circumferences of all airways were measured and goblet cell numbers in these areas were recorded. For standardisation, goblet cell numbers in 100μm were analysed by division of total goblet cell number to the total length of airway circumferences and multiplying the result by 100.For ultrastructural investigations, the tissues were postfixed with osmium tetroxide (OsO4), dehydrated in a graded series of alcohol, and then embedded in Araldite® CY212. The thin (60–90nm) sections were obtained with ultra-microtome (Leica) and stained with uranyl acetate and lead citrate, examined on a transmission electron microscope (Carl Zeiss Libra 120 EFTEM, Germany), and digitally photographed. In each mouse, five to seven ultrathin sections were taken from each two blocks and epithelium of the airway, the surrounding structures, and the intercellular connections were evaluated. Thicknesses of the basement membrane of the respiratory epithelium were measured from 20 points that were at equal distances to each other and the data were recorded.Statistical analysisThe SPSS 15.0 package program was used in the statistical analysis. Data were presented as mean±standard deviation (SD) in each group. All data were analysed by Kruskal–Wallis and then Mann–Whitney test for dual comparisons. p<0.05 was considered statistically significant.ResultsWe set out to determine if nebulised arginase inhibitor nor-NOHA was effective in vivo. In order to answer this question, we compared the concentration of l-arginine in lung homogenates in nor-NOHA treated and untreated Balb/c mice. In the mice treated with nor-NOHA, the concentration of l-arginine was significantly higher compared to the mice receiving OVA alone (mean: 4.39±1.38 and 1.68±1.38mol/L, respectively; p=0.024). So it was concluded that the dose and the route of nor-NOHA treatment were effective in raising the concentration of l-arginine in the lung of mice receiving this arginase inhibitor.Every group consisted of seven mice at the beginning of the experiment, and one mouse died in Group VI during the study. We compared the histopathological features of the control group with the placebo in order to show that the model of asthma was established. In the chronic asthma group (placebo), thickness of basal membrane, epithelium and subepithelial smooth muscle layer as well as the number of mast cells and goblet cells were significantly higher than the control group (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>a). These results showed that the chronic asthma model was established.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia>In Group III (L-arginine), subepithelial smooth muscle thickness, epithelial thickness, basal membrane thickness, number of mast and goblet cells were significantly lower compared to placebo group and no difference was noted in histological parameters with regard to gold standard budesonide treated group except epithelial thickness (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>a).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>In Group IV (nor-NOHA), all histological parameters except the number of mast cells were significantly better compared to placebo and improvement was similar to budesonide in all parameters except epithelial thickness (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>a).In Group V in which the study drugs were l-arginine and nor-NOHA combination, all histological parameters were improved compared to the placebo group but this combination did not add any improvement on administration of l-arginine and nor-NOHA alone (p>0.05).In Masson Trichrome staining, increased subepithelial and perivascular deposition of collagen was seen in OVA-induced asthma mice (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>b, II). Control and budesonide groups showed a thin collagen accumulating in peribronchiolar subepithelial and perivascular regions (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>b, I and VI). Collagen deposition in these regions was reduced in groups receiving l-arginine, nor-NOHA and Larginine and nor-NOHA combination.Interleukin 4 and 5 levels were significantly higher in the placebo group compared to the control group as expected. But significant decreases of interleukins were not detected in study groups except nor-NOHA treated group in which the levels of IL-4 decreased (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>The number of eosinophils in BAL fluid was significantly reduced in groups receiving l-arginine and nor-NOHA when compared with placebo. The number of neutrophils was also reduced in study groups but this was not statistically significant (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Mean bronchoalveolar NO levels were 0.064, 0.056, 0.054 and 0.060μM in groups III, IV, V and VI, respectively. There was no statistically significant difference in NO levels between groups receiving both l-arginine and nor-NOHA when compared to other study groups (p>0.05).Discussionl-Arginine and arginase inhibitors have been studied in experimental models of asthma in various studies but the effect of cotreatment is firstly investigated in our study. Using a histologically well established murine model of asthma, we demonstrated that l-arginine and nor-NOHA were effective in reversing abnormal histological findings of asthma. We hypothesized that both arginase inhibition and l-arginine administration will increase l-arginine bioavailability and increase production of NO much more but cotreatment did not have any additive effect and NO levels did not increase as expected.l-Arginine has been used as a potential therapy in various disease states including asthma.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> Since l-arginine bioavailability is shown to be reduced in asthma, it has been hypothesized that exogenous administration of l-arginine may increase the bronchodilation effect by constitutive forms of NO. Oral, inhaled and intraperitoneal routes were chosen for l-arginine administration in animal studies<a class="elsevierStyleCrossRefs" href="#bib0070">14,20,21</a> and oral and inhaled routes were used for humans.<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</a> In an asthma model, delivery of dietary l-arginine increased eosinophilia and levels of IL-5 production in the study by Takano et al.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> and intraperitoneal l-arginine treatment also increased eosinophils and neutrophils in bronchoalveolar lavage and increased airway responsiveness to inhaled methacholine in another study.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> Inhaled l-arginine is used in two studies involving healthy and asthmatic subjects and effect of l-arginine on exhaled NO is studied.<a class="elsevierStyleCrossRefs" href="#bib0115">23,24</a> These studies showed different results: one suggesting that l-arginine increases the formation of endogenous NO, and the other ignoring the rise in exhaled NO. In a guinea pig model of asthma using perfused tracheal preparations ex vivo, it was demonstrated that inhaled l-arginine reversed airway hyperresponsiveness.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> In another study it was found that l-arginine administration restored mitochondrial dysfunction and reduced airway injury in murine allergic inflammation.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> These different results can be explained with the species of animals used, methodology of the studies and the dosage of l-arginine, as suggested by Mabalirajan et al.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> They state that low doses of l-arginine may not be sufficient to increase the substrate availability of eNOS and the high dose of l-arginine administered orally in their study enhanced eNOS expression, downregulated both iNOS and arginase and these resulted in reduction of airway inflammation and airway hyperresponsiveness. We chose to use inhaled l-arginine administration in order to reach higher concentrations in airways and bypass the systemic effects of other routes. Our study was mainly based on histological outcome of l-arginine treatment and we noted improvement in most of the parameters similar to gold standard budesonide.It is thought that chronic administration of l-arginine would increase the activity of the arginase leading to enhanced formation of downstream products of l-ornithine that are involved in airway remodelling, and prolonged treatment of asthma with l-arginine may be contraindicated.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> Then the interest has been focused on arginase and arginase inhibitors. Arginase plays a role in airway remodelling and fibrosis by decreasing NO production through competition for l-arginine and reducing anti-fibrotic and anti-proliferative effects of NO. However, contradictory effects of arginase inhibition have been reported in animal studies.<a class="elsevierStyleCrossRefs" href="#bib0070">14,27,28</a> In a guinea pig model of asthma, specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) administration reduced airway sensitivity to inhaled allergen and protected against early and late asthmatic reactions including airway hyperresponsiveness and airway inflammation.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> Nor-NOHA, another arginase inhibitor reduced total inflammatory cell content of lung lavage fluid in C57BL/6 mice exposed to OVA. This study also showed that NOS2−/− strain mice treated with nor-NOHA did not show a reduction in eosinophilic influx, indicating that when l-arginine concentrations were increased by arginase inhibition eosinophilic inflammation is decreased directly or indirectly through NOS2.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> In mice sensitised to ovalbumin, another arginase inhibitor S-(2-boronoethyl)-1-cysteine (BEC) given orally, increased the peribronchial and perivascular inflammation in association with increases in protein S-nitrosylation and tyrosine nitration.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> The results of our study were consistent with the former two studies as we found improvement of histological parameters and decrease in Th2 cytokines in nor-NOHA treated group. Differences among studies can be seen because of the different species of study animals and type of arginase inhibitors and their route of administration.We originally hypothesized that arginase inhibition with l-arginine administration will lead to a better histological outcome. We may speculate that hyperargininaemia occurring from these treatments limited the rate of NO production by NOS or led to systemic effects apart from local effects on lungs and had no benefit over l-arginine or nor-NOHA alone. These complex interactions should be highlighted in studies investigating arginase and NOS expressions in models treated with l-arginine and arginase inhibitor combination. In order to confirm the effects of study drugs on NO production we planned to measure NO in BAL supernatants, but the results were similar in study groups indicating that this hypothesis was not valid.In conclusion, inhaled administration of l-arginine and arginase inhibitor nor-NOHA alleviated airway inflammation and remodelling in murine model of asthma but combination therapy did not have additive effects. Arginine and arginase represent drug targets that have potentials to open new therapeutic perspectives. However, specific and off-target effects and mechanisms should be elucidated in oncoming studies of inhaled l-arginine and arginase inhibitors.Conflict of interestNone of the authors have conflict of interest to declare.ContributorsZAA and NU contributed in the design of the study, OY and MK (M. Karaman) participated in animal study of the work, MK (M. Karaman) was involved in determination of NO and cytokine levels, MK (M. Kiray) carried out conventional histological work, AB carried out electron microscopy, TT performed statistical analysis, OK participated in design and coordination of the work. ZAA wrote the manuscript; all authors read and approved the manuscript.Ethical disclosuresProtection of human subjects and animals in researchWe declare that the procedures followed were in accordance with the regulations of the responsible Animal Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration.Patients’ data protectionWe declare that no patient data appears in this article.Right to privacy and informed consentWe declare that no patient data appears in this article." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres349802" "titulo" => array:5 [ 0 => "Abstract" 1 => "Background" 2 => "Methods" 3 => "Results" 4 => "Conclusion" ] ] 1 => array:2 [ "identificador" => "xpalclavsec331465" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Animals" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Experimental protocol" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Study drugs" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Preparations of lung homogenates" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Measurement of cytokines" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Measurement of l-arginine in lung tissue supernatants" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Bronchoalveolar lavage" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Determination of NO" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Histological evaluation" ] ] ] 4 => array:2 [ "identificador" => "sec0060" "titulo" => "Statistical analysis" ] 5 => array:2 [ "identificador" => "sec0065" "titulo" => "Results" ] 6 => array:2 [ "identificador" => "sec0070" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflict of interest" ] 8 => array:2 [ "identificador" => "sec0080" "titulo" => "Contributors" ] 9 => array:3 [ "identificador" => "sec0085" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0090" "titulo" => "Protection of human subjects and animals in research" ] 1 => array:2 [ "identificador" => "sec0095" "titulo" => "Patients’ data protection" ] 2 => array:2 [ "identificador" => "sec0100" "titulo" => "Right to privacy and informed consent" ] ] ] 10 => array:2 [ "identificador" => "xack86225" "titulo" => "Acknowledgement" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-11-16" "fechaAceptado" => "2013-01-19" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec331465" "palabras" => array:5 [ 0 => "Asthma" 1 => "Murine model" 2 => "l-Arginine" 3 => "Arginase inhibition" 4 => "nor-NOHA" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "BackgroundIncreased arginase activity in the airways induces reduced bioavailability of l-arginine and cause deficiency of bronchodilatating and anti-inflammatory nitric oxide (NO). Therefore, arginine and arginase inhibitors may have therapeutic potential in the treatment of asthma. Using a murine model of asthma, we aimed to investigate the effects of inhaled l-arginine and arginase inhibitor Nω-hydroxy-nor-l-arginine (nor-NOHA) and co-treatment on airway histology of asthmatic lung tissue. MethodsForty-two BALB/c mice were divided into six groups: I (control), II (placebo), III, IV, V and VI. All mice except for control group were sensitised by an intraperitoneal injection of ovalbumin with alum adjuvant and then challenged with an aerosol of ovalbumin on three days of the week for eight weeks beginning from the 21st day of the study. Lung histology and bronchoalveolar lavage cell (BAL) counts were evaluated after treatment with inhaled l-arginine, nor-NOHA, l-arginine-nor-NOHA combination, budesonide and placebo. Interleukin(IL)-4 and IL-5 levels are determined in lung homogenates with ELISA. Resultsl-Arginine group was similar to budesonide group in lowering all histological parameters. Results of groups treated with nor-NOHA were also similar to budesonide group except for epithelial thickness. The number of eosinophils in BAL decreased significantly in groups receiving study drugs. Decrease was only noted in IL-4 levels in group receiving nor-NOHA. ConclusionWe demonstrated that inhaled l-arginine administration alleviated all histological parameters similar to budesonide and treatment with arginase inhibitor improved not all but some of the pathological changes in chronic asthma. Combination therapy had no additive effect on either treatment." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1669 "Ancho" => 1985 "Tamanyo" => 185928 ] ] "descripcion" => array:1 [ "en" => "Schematic presentation for murine model of airway inflammation and study drugs." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1115 "Ancho" => 1900 "Tamanyo" => 493111 ] ] "descripcion" => array:1 [ "en" => "(a) Light and electron microscopic findings of study groups: (I) control (n: 7); (II) placebo (n: 7); (III) l-arginine (n: 7); (IV) nor-NOHA (n: 7); (V) l-arginine+nor-NOHA (n: 7); (VI) budesonide (n: 6). (A) H&E; (B) PAS; (C) Toluidine staining. (A) Two-headed arrow: subepithelial smooth muscle thickening; (*) peribronchial mononuclear cell infiltration. (B) Arrows: goblet cells; (C) arrows: mast cells. (D) Electron microscopic views. Increased goblet cells in placebo group (Gc), basal membrane thickening (*). C: cilia. (B) Masson Trichrome staining. Masson Trichrome staining (blue colour) showed minimal peribronchial and perivascular collagen accumulating in control (I) and budesonide (VI) groups. Increased collagen deposition was seen with Trichrome staining in the OVA-induced asthma mice (II), as compared to normal tissue. Collagen deposition was reduced in groups III, IV and V. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)" ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Control (n: 7)(mean±SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Placebo (n: 7)(mean±SD) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subepithelial smooth muscle thickness (μm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.41±0.44<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.68±0.81 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epithelial thickness (μm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10.86±0.64<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30.94±2.44 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number of goblet cells/100 (μm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.44±0.12<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.30±0.40 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number of mast cells/16,400 (μm2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.76±0.27<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.14±0.53 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Basal membrane thickness (μm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">341.1±14.48<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">684.3±18.28 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab522882.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "p<0.05." ] ] ] "descripcion" => array:1 [ "en" => "Histological comparison of the placebo and the control group." ] ] 3 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "n: 7 in each group except Group VI which includes 6 mice." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">PlaceboGroup II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">l-ArginineGroup III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">nor-NOHAGroup IV(mean±SD) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">l-Arginine and nor-NOHAGroup V \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">BudesonideGroup VI \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subepithelial smooth muscle thickness (μm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.68±0.81<a class="elsevierStyleCrossRef" href="#tblfn0015">¥</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.36±0.18<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.51±0.67<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.59±0.23<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.85±0.54<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epithelial thickness (μm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30.94±2.44<a class="elsevierStyleCrossRef" href="#tblfn0015">¥</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15.12±0.35<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a>,<a class="elsevierStyleCrossRef" href="#tblfn0015">¥</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16.76±0.96<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a>,<a class="elsevierStyleCrossRef" href="#tblfn0015">¥</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14.74±0.67<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a>,<a class="elsevierStyleCrossRef" href="#tblfn0015">¥</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.18±0.38<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number of goblet cells/100 (μm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.30±0.40<a class="elsevierStyleCrossRef" href="#tblfn0015">¥</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.77±0.19<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.51±0.44<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.94±0.23<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.29±0.21<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number of mast cells/16,400 (μm2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.14±0.53<a class="elsevierStyleCrossRef" href="#tblfn0015">¥</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.07±0.19<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.19±0.59 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.38±0.30<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.05±0.10<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Basal membrane thickness (μm) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">684.3±18.28<a class="elsevierStyleCrossRef" href="#tblfn0015">¥</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">515.6±13.37<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">546±11.32<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">558.6±14.65<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">391.5±8.43<a class="elsevierStyleCrossRef" href="#tblfn0010">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab522884.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "*" "nota" => "p<0.05 compared with placebo." ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "¥" "nota" => "p<0.05 compared with budesonide." ] ] ] "descripcion" => array:1 [ "en" => "Histological comparison of the study groups." ] ] 4 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "n: 7 in each group." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Groups \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">IL-4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">IL-5 \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">63.04±27.36<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43.74±34.86<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">127.82±74.99 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">174.50±91.93 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">l-Arginine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">108.95±46.61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">323.16±16 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nor-NOHA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41.93±31.79<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">116.63±68.79 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">l-Arginine/nor-NOHA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">92.36±46.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">281.73±93.64 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab522883.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "*" "nota" => "p<0.05 when compared with placebo." ] ] ] "descripcion" => array:1 [ "en" => "Comparison of IL-4 and IL-5 between study groups." ] ] 5 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "n: 5 in each group." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">% cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Group IControl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Group IIPlacebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Group IIIl-Arginine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Group IVnor-NOHA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Group VCombination \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Group VIBudesonide \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Eosinophils \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.0±0.27<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48.2±2.43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21.8±1.82<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.8±1.77<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24.4±0.50<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21.6±2.42<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutrophils \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.4±0.70<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.8±2.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.6±1.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.6±1.88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.0±0.31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.0±2.77 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lymphocytes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16.0±0.70<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24.2±1.31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19.0±1.09<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18.2±0.96<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18.8±0.58<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19.2±1.15<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab522885.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "*" "nota" => "p<0.05 when compared to placebo." ] ] ] "descripcion" => array:1 [ "en" => "Differential cell counts of bronchoalveolar fluid in study groups." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ 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Original article

Z. Arıkan-Ayyıldıza,

Corresponding author

zeynep.ayyildiz@deu.edu.tr

Corresponding author.

, M. Karamanb, T. Tuncela, M. Kirayc, A. Bağrıyanıkd, O. Yilmazb, N. Uzunera, Ö. Karamana

a Department of Pediatric Allergy, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey

b Department of Experimental Animal Laboratory, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey

c Department of Physiology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey

d Department of Histology and Embriology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey

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            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
          2 => array:3 [
            "entidad" => "Department of Physiology&#44; Dokuz Eylul University&#44; Faculty of Medicine&#44; Izmir&#44; Turkey"
            "etiqueta" => "c"
            "identificador" => "aff0015"
          ]
          3 => array:3 [
            "entidad" => "Department of Histology and Embriology&#44; Dokuz Eylul University&#44; Faculty of Medicine&#44; Izmir&#44; Turkey"
            "etiqueta" => "d"
            "identificador" => "aff0020"
          ]
        ]
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            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">&#40;a&#41; Light and electron microscopic findings of study groups&#58; &#40;I&#41; control &#40;<span class="elsevierStyleItalic">n</span>&#58; 7&#41;&#59; &#40;II&#41; placebo &#40;<span class="elsevierStyleItalic">n</span>&#58; 7&#41;&#59; &#40;III&#41; <span class="elsevierStyleSmallCaps">l</span>-arginine &#40;<span class="elsevierStyleItalic">n</span>&#58; 7&#41;&#59; &#40;IV&#41; nor-NOHA &#40;<span class="elsevierStyleItalic">n</span>&#58; 7&#41;&#59; &#40;V&#41; <span class="elsevierStyleSmallCaps">l</span>-arginine<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>nor-NOHA &#40;<span class="elsevierStyleItalic">n</span>&#58; 7&#41;&#59; &#40;VI&#41; budesonide &#40;<span class="elsevierStyleItalic">n</span>&#58; 6&#41;&#46; &#40;A&#41; H&#38;E&#59; &#40;B&#41; PAS&#59; &#40;C&#41; Toluidine staining&#46; &#40;A&#41; Two-headed arrow&#58; subepithelial smooth muscle thickening&#59; &#40;&#42;&#41; peribronchial mononuclear cell infiltration&#46; &#40;B&#41; Arrows&#58; goblet cells&#59; &#40;C&#41; arrows&#58; mast cells&#46; &#40;D&#41; Electron microscopic views&#46; Increased goblet cells in placebo group &#40;Gc&#41;&#44; basal membrane thickening &#40;&#42;&#41;&#46; C&#58; cilia&#46; &#40;B&#41; Masson Trichrome staining&#46; Masson Trichrome staining &#40;blue colour&#41; showed minimal peribronchial and perivascular collagen accumulating in control &#40;I&#41; and budesonide &#40;VI&#41; groups&#46; Increased collagen deposition was seen with Trichrome staining in the OVA-induced asthma mice &#40;II&#41;&#44; as compared to normal tissue&#46; Collagen deposition was reduced in groups III&#44; IV and V&#46; &#40;For interpretation of the references to color in this figure legend&#44; the reader is referred to the web version of the article&#46;&#41;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Bronchial asthma is characterised by airway hyperresponsiveness&#44; remodelling and inflammation&#46; Lung inflammation in allergic asthma is mediated by a cascade of reactions involving various mediators including nitric oxide &#40;NO&#41;&#46; Nitric oxide is thought to have an important role in smooth muscle relaxation&#44; bronchodilation and neurotransmission besides participating in inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Nitric oxide is formed by the metabolism of <span class="elsevierStyleSmallCaps">l</span>-arginine by nitric oxide synthase &#40;NOS&#41;&#46; Three NOS mammalian isoenzymes have been identified&#58; NOS-1&#44; NOS-2 and NOS-3&#46; Neuronal NOS or NOS-1 and endothelial NOS &#40;NOS-3&#44; eNOS&#41; are expressed in airway epithelium and involved in neurotransmission and smooth muscle relaxation and bronchodilation&#44; respectively&#46; Their activity is regulated by calcium and they produce small amount of NO&#46; Inducible NOS &#40;NOS 2&#44; iNOS&#41; is also expressed in airway epithelium but regulated by pro-inflammatory stimuli with the ability of producing large amounts of NO over hours&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Deficiency of eNOS derived NO is involved in inflammatory response during asthmatic reaction&#46; Thus it has been shown that e-NOS derived NO inhibits airway inflammation by suppressing expression of inflammatory cytokines and iNOS&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In inflamed asthmatic airways&#44; expression of iNOS is increased in airway epithelium by cytokines like TNF-&#945; and IFN-&#947; and levels of exhaled nitric oxide are increased in patients with persistent asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> iNOS-derived NO is shown to be associated with epithelial damage&#44; infiltration of inflammatory cells&#44; stimulation of TH2-mediated response&#44; mucus hypersecretion and vascular permeability but it is suggested that formation of peroxynitrite from iNOS-derived NO contributes to airway hyperresponsiveness rather than NO itself&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;5</span></a> It is thought that increased formation of peroxynitrite is the result of decreased bioavailability of <span class="elsevierStyleSmallCaps">l</span>-arginine to NOS&#46; Increasing the <span class="elsevierStyleSmallCaps">l</span>-arginine concentration in macrophages is found to stimulate NO production and inhibit the formation of peroxynitrite&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSmallCaps">l</span>-Arginine is metabolised by arginase which has also gained an important role in regulating endogenous NO production&#46; Arginase is an urea cycle enzyme that hydrolyses <span class="elsevierStyleSmallCaps">l</span>-arginine to urea and <span class="elsevierStyleSmallCaps">l</span>-ornithine&#46; Two isoforms of arginase &#40;arginase I and II&#41; are expressed in airways and arginase reduces the bioavailability of <span class="elsevierStyleSmallCaps">l</span>-arginine for NOS and therefore affects NO production&#46; <span class="elsevierStyleSmallCaps">l</span>-Ornithine is also involved in synthesis of polyamines and <span class="elsevierStyleSmallCaps">l</span>-proline which are involved in promotion of cell growth and repair and collagen synthesis&#44; respectively&#46; Experimental models of asthma have demonstrated that arginase activity is induced following challenge with allergens&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> Studies in human asthma also confirm the importance of arginase in the pathogenesis of experimental asthma&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> The lung function of severe asthmatics correlates directly with <span class="elsevierStyleSmallCaps">l</span>-arginine bioavailability and inversely with serum arginase activity&#44; indicating that serum arginase activity reduces circulating <span class="elsevierStyleSmallCaps">l</span>-arginine levels which contribute to NO deficiency within airways&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Increased understanding of the role of arginase in the pathogenesis of asthma represents a drug target that opens novel therapeutic perspectives for the treatment of asthma&#46; In this study we determined the effects of <span class="elsevierStyleSmallCaps">l</span>-arginine&#44; arginase inhibitor N&#969;-hydroxy-nor-<span class="elsevierStyleSmallCaps">l</span>-arginine &#40;nor-NOHA&#41; and co-treatment of these on airway inflammation in a murine model of asthma&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Animals</span><p id="par0020" class="elsevierStylePara elsevierViewall">Forty-two male&#44; conventionally raised&#44; 6&#8211;8-week-old&#44; BALB&#47;c mice weighing 18&#8211;20<span class="elsevierStyleHsp" style=""></span>g were used in the experiment&#46; The animals were fed a commercial diet ad libitum and housed in an air-conditioned facility on a 12-h light&#47;12-h dark cycle&#46; The studies adhered to the National Institutes of Health guidelines for the experimental use of animals&#46; The Institutional Animal Care and Use Committee granted approval for the study&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Experimental protocol</span><p id="par0025" class="elsevierStylePara elsevierViewall">Mice were sensitised by an intraperitoneal &#40;ip&#41; injection of ovalbumin &#40;10<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;0&#46;1<span class="elsevierStyleHsp" style=""></span>ml&#44; 2 weeks apart&#44; i&#46;e&#46; on Day 0 and Day 14&#41; consisting of chicken egg albumin &#40;ovalbumin&#44; grade V&#44; &#8805;98 pure&#44; Sigma&#44; St&#46; Louis&#44; MO&#44; USA&#41; with alum adjuvant as described by Temelkovski et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Mice in study groups II&#44; III&#44; IV&#44; V and VI were then challenged with an aerosol of 5<span class="elsevierStyleHsp" style=""></span>ml 2&#46;5&#37; ovalbumin &#40;OVA&#41; in saline for 30<span class="elsevierStyleHsp" style=""></span>min per day on 3 days of the week for 8 weeks beginning from the 21st day of the study&#46; The mice in the control group &#40;Group I&#41; received normal saline with alum intraperitoneally on Days 0 and 14 of the experiment and aerosolised saline without alum for 30<span class="elsevierStyleHsp" style=""></span>min per day on 3 days of the week for 8 weeks beginning from the 21st day of the study&#46; Exposures were carried out in a whole body inhalation exposure system in a plexiglass chamber with 40<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>60<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>120 diameters designed for the placement of cages&#46; Temperature and relative humidity were maintained at 20&#8211;25<span class="elsevierStyleHsp" style=""></span>&#176;C and 40&#8211;60&#37;&#44; respectively&#46; A solution of 2&#46;5&#37; ovalbumin in normal saline was aerosolised by delivery of compressed air to a sidestream jet nebuliser with a flow rate of 6<span class="elsevierStyleHsp" style=""></span>L&#47;min &#40;Medicair&#44; UK&#41; and injected into a chamber&#46; The aerosol generated by this nebuliser comprised &#62;80&#37; particles with a diameter of &#60;4<span class="elsevierStyleHsp" style=""></span>&#956;m&#46; Particle concentration was maintained in the range of 10&#8211;20<span class="elsevierStyleHsp" style=""></span>mg&#47;mm<span class="elsevierStyleSup">3</span> in the chamber&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Study drugs</span><p id="par0030" class="elsevierStylePara elsevierViewall">Mice in Group III received nebulised <span class="elsevierStyleSmallCaps">l</span>-arginine 1<span class="elsevierStyleHsp" style=""></span>M &#40;174<span class="elsevierStyleHsp" style=""></span>mg&#47;ml&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Group IV received nebulised nor-NOHA 20<span class="elsevierStyleHsp" style=""></span>&#956;M &#40;3&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Group V received both <span class="elsevierStyleSmallCaps">l</span>-arginine and nor-NOHA&#44; Group VI received nebulised budesonide 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;2<span class="elsevierStyleHsp" style=""></span>ml&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#44; and Group II received nebulised saline once a day for the last 7 days of the challenge period&#46; <span class="elsevierStyleSmallCaps">l</span>-Arginine was obtained from Sigma&#8211;Aldrich &#40;St&#46; Louis&#44; MO&#44; USA&#41; and nor-NOHA from Cayman Chemical &#40;Ann Arbor&#44; MI&#44; USA&#41;&#46; Experimental protocol and study drugs are presented in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Preparations of lung homogenates</span><p id="par0035" class="elsevierStylePara elsevierViewall">Animals were sacrificed by an overdose of ketamine 24<span class="elsevierStyleHsp" style=""></span>h after the last drug administration&#46; Lungs were removed and washed with cold PBS three times in order to remove blood&#46; Lung tissues were taken into 2<span class="elsevierStyleHsp" style=""></span>ml microcentrifuge tubes and stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C until analysis&#46; On the study day&#44; frozen lungs were thawed&#44; weighed &#40;60&#8211;80<span class="elsevierStyleHsp" style=""></span>mg&#41;&#44; transferred into different tubes on ice containing 5<span class="elsevierStyleHsp" style=""></span>ml of stainless beads&#44; 0&#46;1&#37; SDS&#44; protease inhibitor cocktail &#40;Sigma&#8211;Aldrich&#44; St&#46; Louis&#44; MO&#44; USA&#41; and 0&#46;1<span class="elsevierStyleHsp" style=""></span>mg&#47;ml phenylmethanesulfonyl fluoride &#40;PMSF&#41; in PBS&#46; Microcentrifuge tubes were transferred to pre-cooled Tissuelyser LT racks and placed into TissueLyser &#40;Qiagen&#44; Germany&#41; homogenisator&#46; Frequency and time were set to 50 and 5<span class="elsevierStyleHsp" style=""></span>min&#44; respectively&#46; The homogenates were then centrifuged at 15&#44;000<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> for 1<span class="elsevierStyleHsp" style=""></span>h at 4<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; The supernatants were stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Measurement of cytokines</span><p id="par0040" class="elsevierStylePara elsevierViewall">Levels of IL-4 and IL-5 were quantified in the supernatants of the lung tissue by standard ELISA protocols using commercial mouse IL-4 and IL-5 &#40;Bender MedSystems&#44; MedSystems Diagnostics GmbH&#44; Vienna&#44; Austria&#41;&#46; Detection levels were 2&#46;0<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for IL-4 and 3&#46;3<span class="elsevierStyleHsp" style=""></span>pg&#47;ml for IL-5&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Measurement of <span class="elsevierStyleSmallCaps">l</span>-arginine in lung tissue supernatants</span><p id="par0045" class="elsevierStylePara elsevierViewall">L-Arginine content of lung homogenates was assessed by the method described by Frank et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In brief&#44; airway homogenate aliquots of 100<span class="elsevierStyleHsp" style=""></span>&#956;l were added to 5&#37; HClO<span class="elsevierStyleInf">4</span> and centrifuged at 15&#44;000<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> for 15<span class="elsevierStyleHsp" style=""></span>min&#46; 100<span class="elsevierStyleHsp" style=""></span>&#956;l of supernatant was mixed with the equal amount of OPA and after 30<span class="elsevierStyleHsp" style=""></span>min&#44; 10<span class="elsevierStyleHsp" style=""></span>&#956;l was analysed with HPLC&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Bronchoalveolar lavage</span><p id="par0050" class="elsevierStylePara elsevierViewall">Bronchoalveolar lavage fluid &#40;BAL&#41; was immediately collected from euthanised mice by instillation and recovery of 1<span class="elsevierStyleHsp" style=""></span>ml 0&#46;99&#37; NaCl through the tracheal cannula&#46; BAL was centrifuged at 3000<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">g</span> for 10<span class="elsevierStyleHsp" style=""></span>min and supernatant was removed and stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C until assay of NO&#46; Histological smear samples were prepared&#46; A differential cell count was performed using May-Gr&#252;nwald Giemsa staining and classified as eosinophils&#44; neutrophils&#44; and lymphocytes on the basis of morphological criteria and staining characteristics&#46; Differential cell counts were performed in a blinded fashion by counting at least 200 cells per slide under light microscopy&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Determination of NO</span><p id="par0055" class="elsevierStylePara elsevierViewall">NO levels in BAL samples were measured by a Griess reaction&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> The colorimetric kit &#40;Sigma&#8211;Aldrich Co&#46;&#44; USA&#41; was used according to the manufacturer&#39;s manual&#46; Results are determined spectrophotometrically on 540<span class="elsevierStyleHsp" style=""></span>nm &#40;BioTek Synergy HT&#44; USA&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Histological evaluation</span><p id="par0060" class="elsevierStylePara elsevierViewall">Examinations were conducted in a blind fashion by two of the investigators&#46; Tissue specimens were obtained from the mid-zone of the left lung of mice&#46; Samples were fixed in 10&#37; formalin for light microscopic evaluation&#46; Some tissue samples of 1&#8211;2<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">3</span> taken from adjacent regions were stocked in 2&#37; gluteraldehyte for electron microscopic evaluation&#46; After fixation&#44; samples were embedded in paraffin for light microscopic evaluation&#46; Paraffin blocks were placed in Leica RM2125 rotary microtome &#40;Germany&#41; and serial sections of 5<span class="elsevierStyleHsp" style=""></span>&#956;m thickness were obtained&#46; After choosing the first section randomly&#44; 10 sections in each mouse were selected by skipping over 10 sections and proceeding to staining process&#46; For light microscopic evaluation&#44; four different staining processes were used&#46; The first 10 samples were stained with haematoxylin and eosin &#40;H&#38;E&#41;&#46; In these samples&#44; general tissue features were examined and thicknesses of epithelium and subepithelial smooth muscle layers of the medium and small airways were measured&#46; In order to evaluate the thicknesses of epithelium and subepithelial smooth muscle layers&#44; measurements were performed from four points of each airway at levels of 3&#44; 6&#44; 9&#44; and 12 o&#8217;clock&#46; Considering that each section contained two to three airways&#44; nearly 20 or more airways were evaluated in each mouse&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Photomicrographs were taken by Olympus DP25 &#40;Japan&#41; camera&#44; which was adapted on Olympus CX-41 model microscope &#40;Olympus Optical&#44; Tokyo&#44; Japan&#41;&#46; The histological analysis was carried out with a computer-assisted image analyser system &#40;DP2-BSW&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The 10 consecutive sections were stained with Toluidine Blue and the other 10 sections with periodic acid&#8211;Schiff &#40;PAS&#41;&#46; Last sections were stained with Masson Trichrome stain for demonstration of collagen deposition&#46; Photomicrographs were taken randomly from five fields of each section which were stained with Toluidine Blue&#46; For mast cell enumeration&#44; a standard transparent counting frame representing an area of 20&#44;000<span class="elsevierStyleHsp" style=""></span>&#956;m<span class="elsevierStyleSup">2</span> was used manually and 10 fields in each photograph were examined for each mouse&#46; Goblet cells stained with PAS were enumerated in 10 sections of each mouse&#46; In each section&#44; three to five randomly selected airways were photographed&#46; Circumferences of all airways were measured and goblet cell numbers in these areas were recorded&#46; For standardisation&#44; goblet cell numbers in 100<span class="elsevierStyleHsp" style=""></span>&#956;m were analysed by division of total goblet cell number to the total length of airway circumferences and multiplying the result by 100&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">For ultrastructural investigations&#44; the tissues were postfixed with osmium tetroxide &#40;OsO<span class="elsevierStyleInf">4</span>&#41;&#44; dehydrated in a graded series of alcohol&#44; and then embedded in Araldite<span class="elsevierStyleSup">&#174;</span> CY212&#46; The thin &#40;60&#8211;90<span class="elsevierStyleHsp" style=""></span>nm&#41; sections were obtained with ultra-microtome &#40;Leica&#41; and stained with uranyl acetate and lead citrate&#44; examined on a transmission electron microscope &#40;Carl Zeiss Libra 120 EFTEM&#44; Germany&#41;&#44; and digitally photographed&#46; In each mouse&#44; five to seven ultrathin sections were taken from each two blocks and epithelium of the airway&#44; the surrounding structures&#44; and the intercellular connections were evaluated&#46; Thicknesses of the basement membrane of the respiratory epithelium were measured from 20 points that were at equal distances to each other and the data were recorded&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical analysis</span><p id="par0080" class="elsevierStylePara elsevierViewall">The SPSS 15&#46;0 package program was used in the statistical analysis&#46; Data were presented as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation &#40;SD&#41; in each group&#46; All data were analysed by Kruskal&#8211;Wallis and then Mann&#8211;Whitney test for dual comparisons&#46; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 was considered statistically significant&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><p id="par0085" class="elsevierStylePara elsevierViewall">We set out to determine if nebulised arginase inhibitor nor-NOHA was effective in vivo&#46; In order to answer this question&#44; we compared the concentration of <span class="elsevierStyleSmallCaps">l</span>-arginine in lung homogenates in nor-NOHA treated and untreated Balb&#47;c mice&#46; In the mice treated with nor-NOHA&#44; the concentration of <span class="elsevierStyleSmallCaps">l</span>-arginine was significantly higher compared to the mice receiving OVA alone &#40;mean&#58; 4&#46;39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;38 and 1&#46;68<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;38<span class="elsevierStyleHsp" style=""></span>mol&#47;L&#44; respectively&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;024&#41;&#46; So it was concluded that the dose and the route of nor-NOHA treatment were effective in raising the concentration of <span class="elsevierStyleSmallCaps">l</span>-arginine in the lung of mice receiving this arginase inhibitor&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Every group consisted of seven mice at the beginning of the experiment&#44; and one mouse died in Group VI during the study&#46; We compared the histopathological features of the control group with the placebo in order to show that the model of asthma was established&#46; In the chronic asthma group &#40;placebo&#41;&#44; thickness of basal membrane&#44; epithelium and subepithelial smooth muscle layer as well as the number of mast cells and goblet cells were significantly higher than the control group &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>a&#41;&#46; These results showed that the chronic asthma model was established&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">In Group III &#40;L-arginine&#41;&#44; subepithelial smooth muscle thickness&#44; epithelial thickness&#44; basal membrane thickness&#44; number of mast and goblet cells were significantly lower compared to placebo group and no difference was noted in histological parameters with regard to gold standard budesonide treated group except epithelial thickness &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>a&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">In Group IV &#40;nor-NOHA&#41;&#44; all histological parameters except the number of mast cells were significantly better compared to placebo and improvement was similar to budesonide in all parameters except epithelial thickness &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>a&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">In Group V in which the study drugs were <span class="elsevierStyleSmallCaps">l</span>-arginine and nor-NOHA combination&#44; all histological parameters were improved compared to the placebo group but this combination did not add any improvement on administration of <span class="elsevierStyleSmallCaps">l</span>-arginine and nor-NOHA alone &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In Masson Trichrome staining&#44; increased subepithelial and perivascular deposition of collagen was seen in OVA-induced asthma mice &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>b&#44; II&#41;&#46; Control and budesonide groups showed a thin collagen accumulating in peribronchiolar subepithelial and perivascular regions &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>b&#44; I and VI&#41;&#46; Collagen deposition in these regions was reduced in groups receiving <span class="elsevierStyleSmallCaps">l</span>-arginine&#44; nor-NOHA and Larginine and nor-NOHA combination&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Interleukin 4 and 5 levels were significantly higher in the placebo group compared to the control group as expected&#46; But significant decreases of interleukins were not detected in study groups except nor-NOHA treated group in which the levels of IL-4 decreased &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">The number of eosinophils in BAL fluid was significantly reduced in groups receiving <span class="elsevierStyleSmallCaps">l</span>-arginine and nor-NOHA when compared with placebo&#46; The number of neutrophils was also reduced in study groups but this was not statistically significant &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">Mean bronchoalveolar NO levels were 0&#46;064&#44; 0&#46;056&#44; 0&#46;054 and 0&#46;060<span class="elsevierStyleHsp" style=""></span>&#956;M in groups III&#44; IV&#44; V and VI&#44; respectively&#46; There was no statistically significant difference in NO levels between groups receiving both <span class="elsevierStyleSmallCaps">l</span>-arginine and nor-NOHA when compared to other study groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSmallCaps">l</span>-Arginine and arginase inhibitors have been studied in experimental models of asthma in various studies but the effect of cotreatment is firstly investigated in our study&#46; Using a histologically well established murine model of asthma&#44; we demonstrated that <span class="elsevierStyleSmallCaps">l</span>-arginine and nor-NOHA were effective in reversing abnormal histological findings of asthma&#46; We hypothesized that both arginase inhibition and <span class="elsevierStyleSmallCaps">l</span>-arginine administration will increase <span class="elsevierStyleSmallCaps">l</span>-arginine bioavailability and increase production of NO much more but cotreatment did not have any additive effect and NO levels did not increase as expected&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSmallCaps">l</span>-Arginine has been used as a potential therapy in various disease states including asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Since <span class="elsevierStyleSmallCaps">l</span>-arginine bioavailability is shown to be reduced in asthma&#44; it has been hypothesized that exogenous administration of <span class="elsevierStyleSmallCaps">l</span>-arginine may increase the bronchodilation effect by constitutive forms of NO&#46; Oral&#44; inhaled and intraperitoneal routes were chosen for <span class="elsevierStyleSmallCaps">l</span>-arginine administration in animal studies<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;20&#44;21</span></a> and oral and inhaled routes were used for humans&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> In an asthma model&#44; delivery of dietary <span class="elsevierStyleSmallCaps">l</span>-arginine increased eosinophilia and levels of IL-5 production in the study by Takano et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> and intraperitoneal <span class="elsevierStyleSmallCaps">l</span>-arginine treatment also increased eosinophils and neutrophils in bronchoalveolar lavage and increased airway responsiveness to inhaled methacholine in another study&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Inhaled <span class="elsevierStyleSmallCaps">l</span>-arginine is used in two studies involving healthy and asthmatic subjects and effect of <span class="elsevierStyleSmallCaps">l</span>-arginine on exhaled NO is studied&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a> These studies showed different results&#58; one suggesting that <span class="elsevierStyleSmallCaps">l</span>-arginine increases the formation of endogenous NO&#44; and the other ignoring the rise in exhaled NO&#46; In a guinea pig model of asthma using perfused tracheal preparations ex vivo&#44; it was demonstrated that inhaled <span class="elsevierStyleSmallCaps">l</span>-arginine reversed airway hyperresponsiveness&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In another study it was found that <span class="elsevierStyleSmallCaps">l</span>-arginine administration restored mitochondrial dysfunction and reduced airway injury in murine allergic inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> These different results can be explained with the species of animals used&#44; methodology of the studies and the dosage of <span class="elsevierStyleSmallCaps">l</span>-arginine&#44; as suggested by Mabalirajan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> They state that low doses of <span class="elsevierStyleSmallCaps">l</span>-arginine may not be sufficient to increase the substrate availability of eNOS and the high dose of <span class="elsevierStyleSmallCaps">l</span>-arginine administered orally in their study enhanced eNOS expression&#44; downregulated both iNOS and arginase and these resulted in reduction of airway inflammation and airway hyperresponsiveness&#46; We chose to use inhaled <span class="elsevierStyleSmallCaps">l</span>-arginine administration in order to reach higher concentrations in airways and bypass the systemic effects of other routes&#46; Our study was mainly based on histological outcome of <span class="elsevierStyleSmallCaps">l</span>-arginine treatment and we noted improvement in most of the parameters similar to gold standard budesonide&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">It is thought that chronic administration of <span class="elsevierStyleSmallCaps">l</span>-arginine would increase the activity of the arginase leading to enhanced formation of downstream products of <span class="elsevierStyleSmallCaps">l</span>-ornithine that are involved in airway remodelling&#44; and prolonged treatment of asthma with <span class="elsevierStyleSmallCaps">l</span>-arginine may be contraindicated&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Then the interest has been focused on arginase and arginase inhibitors&#46; Arginase plays a role in airway remodelling and fibrosis by decreasing NO production through competition for <span class="elsevierStyleSmallCaps">l</span>-arginine and reducing anti-fibrotic and anti-proliferative effects of NO&#46; However&#44; contradictory effects of arginase inhibition have been reported in animal studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;27&#44;28</span></a> In a guinea pig model of asthma&#44; specific arginase inhibitor 2&#40;S&#41;-amino-6-boronohexanoic acid &#40;ABH&#41; administration reduced airway sensitivity to inhaled allergen and protected against early and late asthmatic reactions including airway hyperresponsiveness and airway inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Nor-NOHA&#44; another arginase inhibitor reduced total inflammatory cell content of lung lavage fluid in C57BL&#47;6 mice exposed to OVA&#46; This study also showed that NOS2&#8722;&#47;&#8722; strain mice treated with nor-NOHA did not show a reduction in eosinophilic influx&#44; indicating that when <span class="elsevierStyleSmallCaps">l</span>-arginine concentrations were increased by arginase inhibition eosinophilic inflammation is decreased directly or indirectly through NOS2&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> In mice sensitised to ovalbumin&#44; another arginase inhibitor S-&#40;2-boronoethyl&#41;-1-cysteine &#40;BEC&#41; given orally&#44; increased the peribronchial and perivascular inflammation in association with increases in protein S-nitrosylation and tyrosine nitration&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> The results of our study were consistent with the former two studies as we found improvement of histological parameters and decrease in Th2 cytokines in nor-NOHA treated group&#46; Differences among studies can be seen because of the different species of study animals and type of arginase inhibitors and their route of administration&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">We originally hypothesized that arginase inhibition with <span class="elsevierStyleSmallCaps">l</span>-arginine administration will lead to a better histological outcome&#46; We may speculate that hyperargininaemia occurring from these treatments limited the rate of NO production by NOS or led to systemic effects apart from local effects on lungs and had no benefit over <span class="elsevierStyleSmallCaps">l</span>-arginine or nor-NOHA alone&#46; These complex interactions should be highlighted in studies investigating arginase and NOS expressions in models treated with <span class="elsevierStyleSmallCaps">l</span>-arginine and arginase inhibitor combination&#46; In order to confirm the effects of study drugs on NO production we planned to measure NO in BAL supernatants&#44; but the results were similar in study groups indicating that this hypothesis was not valid&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">In conclusion&#44; inhaled administration of <span class="elsevierStyleSmallCaps">l</span>-arginine and arginase inhibitor nor-NOHA alleviated airway inflammation and remodelling in murine model of asthma but combination therapy did not have additive effects&#46; Arginine and arginase represent drug targets that have potentials to open new therapeutic perspectives&#46; However&#44; specific and off-target effects and mechanisms should be elucidated in oncoming studies of inhaled <span class="elsevierStyleSmallCaps">l</span>-arginine and arginase inhibitors&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">None of the authors have conflict of interest to declare&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Contributors</span><p id="par0160" class="elsevierStylePara elsevierViewall">ZAA and NU contributed in the design of the study&#44; OY and MK &#40;M&#46; Karaman&#41; participated in animal study of the work&#44; MK &#40;M&#46; Karaman&#41; was involved in determination of NO and cytokine levels&#44; MK &#40;M&#46; Kiray&#41; carried out conventional histological work&#44; AB carried out electron microscopy&#44; TT performed statistical analysis&#44; OK participated in design and coordination of the work&#46; ZAA wrote the manuscript&#59; all authors read and approved the manuscript&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Ethical disclosures</span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Protection of human subjects and animals in research</span><p id="par0165" class="elsevierStylePara elsevierViewall">We declare that the procedures followed were in accordance with the regulations of the responsible Animal Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Patients&#8217; data protection</span><p id="par0170" class="elsevierStylePara elsevierViewall">We declare that no patient data appears in this article&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Right to privacy and informed consent</span><p id="par0175" class="elsevierStylePara elsevierViewall">We declare that no patient data appears in this article&#46;</p></span></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Materials and methods"
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              "titulo" => "Preparations of lung homogenates"
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              "titulo" => "Measurement of cytokines"
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              "titulo" => "Measurement of l-arginine in lung tissue supernatants"
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              "identificador" => "sec0045"
              "titulo" => "Bronchoalveolar lavage"
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              "titulo" => "Determination of NO"
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              "titulo" => "Protection of human subjects and animals in research"
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              "titulo" => "Patients&#8217; data protection"
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          "titulo" => "Acknowledgement"
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    "fechaRecibido" => "2012-11-16"
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            1 => "Murine model"
            2 => "<span class="elsevierStyleSmallCaps">l</span>-Arginine"
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            4 => "nor-NOHA"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Increased arginase activity in the airways induces reduced bioavailability of <span class="elsevierStyleSmallCaps">l</span>-arginine and cause deficiency of bronchodilatating and anti-inflammatory nitric oxide &#40;NO&#41;&#46; Therefore&#44; arginine and arginase inhibitors may have therapeutic potential in the treatment of asthma&#46; Using a murine model of asthma&#44; we aimed to investigate the effects of inhaled <span class="elsevierStyleSmallCaps">l</span>-arginine and arginase inhibitor N&#969;-hydroxy-nor-<span class="elsevierStyleSmallCaps">l</span>-arginine &#40;nor-NOHA&#41; and co-treatment on airway histology of asthmatic lung tissue&#46;</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Forty-two BALB&#47;c mice were divided into six groups&#58; I &#40;control&#41;&#44; II &#40;placebo&#41;&#44; III&#44; IV&#44; V and VI&#46; All mice except for control group were sensitised by an intraperitoneal injection of ovalbumin with alum adjuvant and then challenged with an aerosol of ovalbumin on three days of the week for eight weeks beginning from the 21st day of the study&#46; Lung histology and bronchoalveolar lavage cell &#40;BAL&#41; counts were evaluated after treatment with inhaled <span class="elsevierStyleSmallCaps">l</span>-arginine&#44; nor-NOHA&#44; <span class="elsevierStyleSmallCaps">l</span>-arginine-nor-NOHA combination&#44; budesonide and placebo&#46; Interleukin&#40;IL&#41;-4 and IL-5 levels are determined in lung homogenates with ELISA&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSmallCaps">l</span>-Arginine group was similar to budesonide group in lowering all histological parameters&#46; Results of groups treated with nor-NOHA were also similar to budesonide group except for epithelial thickness&#46; The number of eosinophils in BAL decreased significantly in groups receiving study drugs&#46; Decrease was only noted in IL-4 levels in group receiving nor-NOHA&#46;</p> <span class="elsevierStyleSectionTitle">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We demonstrated that inhaled <span class="elsevierStyleSmallCaps">l</span>-arginine administration alleviated all histological parameters similar to budesonide and treatment with arginase inhibitor improved not all but some of the pathological changes in chronic asthma&#46; Combination therapy had no additive effect on either treatment&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">&#40;a&#41; Light and electron microscopic findings of study groups&#58; &#40;I&#41; control &#40;<span class="elsevierStyleItalic">n</span>&#58; 7&#41;&#59; &#40;II&#41; placebo &#40;<span class="elsevierStyleItalic">n</span>&#58; 7&#41;&#59; &#40;III&#41; <span class="elsevierStyleSmallCaps">l</span>-arginine &#40;<span class="elsevierStyleItalic">n</span>&#58; 7&#41;&#59; &#40;IV&#41; nor-NOHA &#40;<span class="elsevierStyleItalic">n</span>&#58; 7&#41;&#59; &#40;V&#41; <span class="elsevierStyleSmallCaps">l</span>-arginine<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>nor-NOHA &#40;<span class="elsevierStyleItalic">n</span>&#58; 7&#41;&#59; &#40;VI&#41; budesonide &#40;<span class="elsevierStyleItalic">n</span>&#58; 6&#41;&#46; &#40;A&#41; H&#38;E&#59; &#40;B&#41; PAS&#59; &#40;C&#41; Toluidine staining&#46; &#40;A&#41; Two-headed arrow&#58; subepithelial smooth muscle thickening&#59; &#40;&#42;&#41; peribronchial mononuclear cell infiltration&#46; &#40;B&#41; Arrows&#58; goblet cells&#59; &#40;C&#41; arrows&#58; mast cells&#46; &#40;D&#41; Electron microscopic views&#46; Increased goblet cells in placebo group &#40;Gc&#41;&#44; basal membrane thickening &#40;&#42;&#41;&#46; C&#58; cilia&#46; &#40;B&#41; Masson Trichrome staining&#46; Masson Trichrome staining &#40;blue colour&#41; showed minimal peribronchial and perivascular collagen accumulating in control &#40;I&#41; and budesonide &#40;VI&#41; groups&#46; Increased collagen deposition was seen with Trichrome staining in the OVA-induced asthma mice &#40;II&#41;&#44; as compared to normal tissue&#46; Collagen deposition was reduced in groups III&#44; IV and V&#46; &#40;For interpretation of the references to color in this figure legend&#44; the reader is referred to the web version of the article&#46;&#41;</p>"
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                  \t\t\t\t" style="border-bottom: 2px solid black">Control &#40;<span class="elsevierStyleItalic">n</span>&#58; 7&#41;&#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Subepithelial smooth muscle thickness &#40;&#956;m&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3&#46;41<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;44<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">11&#46;68<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;81&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Epithelial thickness &#40;&#956;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;86<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;64<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#46;94<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Number of goblet cells&#47;100 &#40;&#956;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;44<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;12<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&#46;30<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;40&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Number of mast cells&#47;16&#44;400 &#40;&#956;m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;76<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;27<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Basal membrane thickness &#40;&#956;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">341&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#46;48<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">684&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>18&#46;28&nbsp;\t\t\t\t\t\t\n
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">n</span>&#58; 7 in each group except Group VI which includes 6 mice&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">PlaceboGroup II&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleSmallCaps">l</span>-ArginineGroup III&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">nor-NOHAGroup IV&#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleSmallCaps">l</span>-Arginine and nor-NOHAGroup V&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">BudesonideGroup VI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Subepithelial smooth muscle thickness &#40;&#956;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">11&#46;68<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;81<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#165;</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">4&#46;36<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;18<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">4&#46;51<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;67<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">5&#46;59<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;23<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">4&#46;85<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;54<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epithelial thickness &#40;&#956;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#46;94<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;44<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#165;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;12<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;35<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#165;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;76<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;96<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#165;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#46;74<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;67<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#165;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">11&#46;18<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;38<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Number of goblet cells&#47;100 &#40;&#956;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;30<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;40<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#165;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;77<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;19<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;51<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;44<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;94<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;23<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&#46;29<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;21<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Number of mast cells&#47;16&#44;400 &#40;&#956;m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;53<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#165;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;07<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;19<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;19<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;38<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;30<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;05<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;10<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Basal membrane thickness &#40;&#956;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">684&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>18&#46;28<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#165;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">515&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#46;37<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">546<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;32<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">558&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#46;65<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">391&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;43<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Histological comparison of the study groups&#46;</p>"
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        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
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        "mostrarFloat" => true
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">n</span>&#58; 7 in each group&#46;</p>"
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            0 => array:2 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Groups&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">IL-4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">IL-5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#46;04<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>27&#46;36<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">43&#46;74<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>34&#46;86<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">127&#46;82<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>74&#46;99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">174&#46;50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>91&#46;93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSmallCaps">l</span>-Arginine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">108&#46;95<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>46&#46;61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">323&#46;16<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nor-NOHA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&#46;93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>31&#46;79<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">116&#46;63<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>68&#46;79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleSmallCaps">l</span>-Arginine&#47;nor-NOHA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&#46;36<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>46&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">281&#46;73<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>93&#46;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Comparison of IL-4 and IL-5 between study groups&#46;</p>"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">n</span>&#58; 5 in each group&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&#37; cells&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Group IControl&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Group IIPlacebo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Group IVnor-NOHA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Group VCombination&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Group VIBudesonide&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Eosinophils&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;27<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">48&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;82<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;77<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;50<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;42<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neutrophils&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;70<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;77&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lymphocytes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;70<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;09<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;96<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;58<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">19&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;15<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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Article information

ISSN: 03010546
Original language: English

DOI:10.1016/j.aller.2013.01.001

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	1	3	4
2024 October	29	14	43
2024 September	25	18	43
2024 August	32	23	55
2024 July	36	12	48
2024 June	26	8	34
2024 May	33	12	45
2024 April	34	5	39
2024 March	44	5	49
2024 February	44	11	55
2024 January	38	12	50
2023 December	69	14	83
2023 November	48	20	68
2023 October	54	12	66
2023 September	32	10	42
2023 August	42	15	57
2023 July	36	12	48
2023 June	45	10	55
2023 May	57	7	64
2023 April	65	6	71
2023 March	39	4	43
2023 February	22	4	26
2023 January	51	8	59
2022 December	36	4	40
2022 November	38	15	53
2022 October	40	12	52
2022 September	23	21	44
2022 August	19	9	28
2022 July	16	14	30
2022 June	14	10	24
2022 May	16	15	31
2022 April	25	15	40
2022 March	28	13	41
2022 February	29	23	52
2022 January	65	7	72
2021 December	33	11	44
2021 November	35	14	49
2021 October	57	38	95
2021 September	55	24	79
2021 August	61	12	73
2021 July	31	13	44
2021 June	27	9	36
2021 May	44	14	58
2021 April	49	13	62
2021 March	20	9	29
2021 February	43	13	56
2021 January	41	14	55
2020 December	4	5	9
2020 November	0	3	3
2020 October	0	3	3
2020 September	0	2	2
2020 July	0	4	4
2020 June	0	1	1
2020 May	0	4	4
2020 April	0	4	4
2020 March	0	8	8
2020 February	0	10	10
2020 January	0	12	12
2019 December	0	10	10
2019 November	0	6	6
2019 October	0	6	6
2019 September	0	6	6
2019 August	0	10	10
2019 July	0	13	13
2019 June	0	14	14
2019 May	0	43	43
2019 April	0	32	32
2019 February	0	5	5
2019 January	0	3	3
2018 December	0	5	5
2018 June	0	1	1
2018 April	0	3	3
2018 March	0	1	1
2018 February	7	9	16
2018 January	13	4	17
2017 December	3	4	7
2017 November	9	5	14
2017 October	7	2	9
2017 September	11	14	25
2017 August	13	2	15
2017 July	13	1	14
2017 June	17	8	25
2017 May	27	4	31
2017 April	14	5	19
2017 March	19	7	26
2017 February	16	27	43
2017 January	14	4	18
2016 December	15	5	20
2016 November	21	5	26
2016 October	27	10	37
2016 September	22	14	36
2016 August	19	14	33
2016 July	13	2	15
2016 June	24	13	37
2016 May	7	14	21
2016 April	14	15	29
2016 March	16	10	26
2016 February	17	20	37
2016 January	10	16	26
2015 December	10	7	17
2015 November	4	4	8
2015 October	19	11	30
2015 September	9	4	13
2015 August	9	10	19
2015 July	5	5	10
2015 June	1	1	2
2015 May	2	1	3
2015 April	12	3	15
2015 March	1	2	3
2015 February	1	1	2
2015 January	2	4	6
2014 December	0	2	2
2014 November	0	1	1
2014 October	3	3	6
2014 September	1	3	4
2014 August	1	6	7
2014 July	3	6	9

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Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

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Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

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