Beneficial effects of erythropoietin on airway histology in a murine model of chronic asthma

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Fuiano, S. Fusilli, C. Incorvaia" "autores" => array:3 [ 0 => array:2 [ "nombre" => "N." "apellidos" => "Fuiano" ] 1 => array:2 [ "nombre" => "S." "apellidos" => "Fusilli" ] 2 => array:2 [ "nombre" => "C." "apellidos" => "Incorvaia" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054611001649?idApp=UINPBA00004N" "url" => "/03010546/0000004000000002/v1_201304101104/S0301054611001649/v1_201304101104/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Beneficial effects of erythropoietin on airway histology in a murine model of chronic asthma" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "75" "paginaFinal" => "80" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M. Karaman, F. Firinci, M. Kiray, T. Tuncel, A. Bagriyanik, O. Yilmaz, N. Uzuner, O. Karaman" "autores" => array:8 [ 0 => array:3 [ "nombre" => "M." "apellidos" => "Karaman" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:4 [ "nombre" => "F." "apellidos" => "Firinci" "email" => array:2 [ 0 => "fatih.firinci@deu.edu.tr" 1 => "fatihfirinci@yahoo.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] 2 => array:3 [ "nombre" => "M." "apellidos" => "Kiray" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "T." "apellidos" => "Tuncel" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "A." "apellidos" => "Bagriyanik" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 5 => array:3 [ "nombre" => "O." "apellidos" => "Yilmaz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "N." "apellidos" => "Uzuner" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 7 => array:3 [ "nombre" => "O." "apellidos" => "Karaman" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Multidisciplinary Laboratory, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Histology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "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" => 764 "Ancho" => 2354 "Tamanyo" => 100628 ] ] "descripcion" => array:1 [ "en" => "Murine model of airway inflammation and treatment with EPO." ] ] ] "textoCompleto" => "IntroductionAsthma is a chronic disease characterised by reversible airway obstruction, airway inflammation, and remodelling.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Current strategies for the management of asthma focus on suppressing airway inflammation, the key factor in the pathogenesis of asthma.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Airway remodelling, a potentially important consequence of asthma, comprises progressive structural changes in the composition, content, and organisation of the cellular and molecular constituents of the airway wall, as well as enhanced turnover of extracellular matrix components.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> It includes goblet cell hyperplasia, basement membrane thickening, subepithelial fibrosis, airway smooth muscle hypertrophy/hyperplasia, and angiogenesis.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Airway remodelling is poorly responsive to current anti-inflammatory asthma therapies, including inhaled corticosteroids and antileukotrienes.<a class="elsevierStyleCrossRefs" href="#bib0025">5,6</a> Thus, new therapeutic options are required.Erythropoietin (EPO), a 30.4-kD glycoprotein that regulates the rate of red blood cell production through binding to its specific cell surface receptors, has been used for many years for the treatment of anaemia.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> EPO has pleiotropic actions including antioxidant, anti-apoptotic, anti-inflammatory and angiogenic effects. Antioxidant effect of EPO is via decreasing plasma iron concentration and increasing the capability of plasma in inhibition of lipid peroxidation.<a class="elsevierStyleCrossRefs" href="#bib0035">7–10</a> EPO also inhibits the synthesis of IL-4, IL-5.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Thus, given the abovementioned effects, EPO may have a role in the treatment of asthma. However, the accurate benefits of EPO in asthma treatment have not been investigated yet. Therefore, in this study our aim is to investigate the efficacy of EPO on lung histopathology in a murine model of chronic asthma.Materials and methodsExperimental animalsSpecific pathogen-free, 6- to 8-week-old, female BALB/c mice, weighting 18–20g, were maintained in a pathogen-free laboratory of Dokuz Eylul University. They were kept in hygienic macrolene cages in air-conditioned rooms and allowed ad libitum with food and water on a 12-h light/12-h dark cycle. All experimental procedures complied with the requirements of the Animal Care and Ethics Committee of the Dokuz Eylul University. Thirty-five BALB/c mice were divided into five groups: I, II, III, IV, and control group, each group included seven mice.Sensitisation and inhalational exposureBALB/c mice are high responders to ovalbumin.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> The mice in study groups I, II, III, and IV were sensitised via two intraperitoneal injections, on days 0 and 14 of the experiment, of 10μg/0.1mL chicken egg albumin (ovalbumin, grade V, ≥98% pure; Sigma, St. Louis, MO, USA) with alum as an adjuvant. The mice in study groups I, II, III, and IV were then exposed to aerosolised ovalbumin for 30min per day on three days of a week for eight weeks, beginning from the 21st day of the study (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Exposures were carried out in a whole body inhalation exposure system. Temperature and relative humidity were maintained between 20–25°C and 40–60%, respectively. A solution of 2.5% ovalbumin in normal saline was delivered by aerosolisation via compressed air to a sidestream jet nebuliser 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.<a class="elsevierStyleCrossRef" href="#bib0065">13</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>The mice in the control group were administered normal saline with alum via intraperitoneally on the 0 and 14th days of the experiment and exposed aerosolised saline for 30min per day on three days of the week for eight weeks, beginning from the 21st day of the study.<a class="elsevierStyleCrossRefs" href="#bib0060">12,13</a>Study drugsMice in Group I received saline; Group II received EPO at dose of 500IU/kg; Group III received EPO at dose of 1000IU/kg; and Group IV dexamethasone at dose of 1mg/kg intraperitoneally once a day in the last five days of the challenge period. Intraperitoneal doses of human recombinant EPO (Epoetin alpha, Eprex, Roche) and dexamethasone 1mg/kg were chosen from other studies also conducted with BALB/c mice.<a class="elsevierStyleCrossRefs" href="#bib0065">13–15</a>Histopathological analysisAnimals were sacrificed by an overdose of ketamine 24h after the last drug administration. Two investigators who were blinded to the treatment groups interpreted the histopathology. 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 obtained from adjacent regions were stocked in 2.5% gluteraldehyde for electron microscopic evaluation. After fixation, samples were embedded in paraffin for light microscopic evaluation and serial sections of 5-μm thickness were prepared. After choosing the first section randomly, 10 sections in each mouse were selected by skipping over 10 sections and proceeded to staining process. For light microscopic evaluation, three 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 12o’clock. Considering that each section contained approximately two to three airways, around 20 or more airways were evaluated for each mouse.Photomicrographs were taken by JVC TK-890-E camera (Japan), which was adapted on Olympus BH-2 RFCA model microscope (Olympus Optical, Tokyo, Japan). The histological analysis was carried out with UTHSCSA Image Tool for Windows Version 3.00 software.The consecutive 10 sections were stained with toluidine blue and the other 10 sections with periodic acid-Schiff (PAS). 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 eight 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 one hundred.Tissues were embedded in EPON after follow-up process of electron microscopic evaluation. Airways were marked from the semithin sections by light microscope. Ultrathin sections were obtained and stained with uraniyl acetate and lead citrate. Libra 120 Carl Zeiss EFTEM electron microscope (Oberkochen, Germany) was used for this evaluation. For each mouse, five to seven ultrathin sections were achieved from each two blocks for evaluation of epithelium of the airway, the surrounding structures, and the intercellular connections.For each mouse, eight to ten areas were photographed by Trondle (2048×2048 pixel) digital camera, attached to the electron microscope. Thicknesses of the basement membrane of the respiratory epithelium were measured from 20 points of preparations at equal distances to each other and the data were recorded in sequence.Statistical analysisSPSS 11 package program was used for the statistical analysis. Data were presented as mean±standard deviation (SD) (minimum–maximum) of seven animals in each group. The comparisons between all groups were conducted by using Kruskal–Wallis method. When differences were statistically significant, Mann–Whitney U test was used for group comparisons. p<0.05 was considered statistically significant.ResultsThe light and electron microscopic examinations revealed normal findings in the control group (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>-I). In the chronic asthma group (placebo), the numbers of mast cells and goblet cells as well as the thicknesses of basement membrane, epithelium, and subepithelial smooth muscle layer were significantly higher when compared to the control group (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Additionally, <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>-II demonstrates that characteristic asthmatic changes were successfully established in the group treated with saline (Group I).<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>In Group II (EPO 500IU/kg), basement membrane thickness and number of mast cells were significantly lower compared with regard to the group treated with saline (Group I). Both the thicknesses of epithelium and subepithelial muscle layer and the number of goblet cells were similar to that of the group treated with saline (Group I). Additionally, respiratory tract epithelium and ciliary structures were similar to normal airway findings (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>-III).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>When EPO was administered at a dose of 1000IU/kg (Group III), significant improvement occurred in all histological parameters compared with the group treated with saline (Group I). This improvement was similar to dexamethasone, the gold standard treatment of asthma (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Parenchymal structures and respiratory epithelium were normal (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>-IV).In Group IV (dexamethasone 1mg/kg), all histological parameters were significantly better compared to the group treated with saline (Group I). Electron microscopic findings demonstrated regular basement membrane and normal ciliary epithelium (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>-V).When low and high dosages of EPO were compared to each other; all histological parameters were found to be significantly better in the group treated with high dose of EPO (Group III) (p<0.05) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). When EPO groups were compared with dexamethasone group, among all the histological variables, the only significant difference was lower mast cell counts in the group treated with high dose of EPO (Group III) (p<0.05) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).DiscussionAirway inflammation in asthma causes subsequent structural changes called as remodelling.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Structural changes in asthmatic airways occur as a result of an injury/repair process. Currently, drugs used for the treatment of asthma have little effect on airway remodelling.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> EPO has uncertain value in the treatment of asthma. Although the anti-inflammatory properties of EPO have been reported many times, their effects on remodelling have rarely been evaluated. Thus, we aimed to investigate the efficacy of EPO on lung histological changes and especially on remodelling in a murine model of chronic asthma.Chronic inflammation in asthma is thought to initiate and perpetuate tissue injury and repair.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> In our study, the structural changes observed in the asthmatic group revealed that the model was well established. It seems very important to prevent airway remodelling in the chronic management of asthma,<a class="elsevierStyleCrossRef" href="#bib0015">3</a> because once formed, remodelling is resistant to asthma therapy.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Inhalation of corticosteroids and administration of β2 agonists, antileukotrienes, and theophylline are poorly responsive to these structural changes. Inhaled corticosteroids may be effective in reducing reticular basement membrane thickness when used for a long period of time and at high doses.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> In our study, dexamethasone and high dose of EPO significantly ameliorated all the structural changes of chronic asthma. This finding is very important because reticular basement membrane thickness is considered a hallmark for airway remodelling in asthma.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>EPO is a hormone which maintains erythrocyte mass. The major mechanism for increasing in erythrocyte mass is the prevention of apoptosis of late erythroid progenitor cells.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> In the haematopoietic system, the principal function of EPO is the regulation of red blood cell production, mediated by its specific cell surface receptor. Recombinant EPO forms EPO alfa, EPO beta, and long-acting analogue darbepoetin alfa have been widely used for treatment of anaemia in chronic kidney disease and chemotherapy-induced anaemia in cancer patients.<a class="elsevierStyleCrossRef" href="#bib0105">21</a>Recent studies showed that EPO protects various tissues through antiapoptotic effects. EPO protects the developing brain against N-methylaspartate receptor antagonist induced neuronal cell apoptosis,<a class="elsevierStyleCrossRef" href="#bib0110">22</a> and inhibits spinal neuronal apoptosis and pain following nerve root crush.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> EPO also markedly reduced apoptosis of adult rat cardiomyocytes subjected to hypoxia in vitro, and reduced cardiomyocyte loss by 50%.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> In addition, EPO protected tubular epithelial cells against apoptosis induced by ischemic acute renal injury.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>EPO is a complex anti-inflammatory agent which exerts a wide variety of immunosuppressive effects targeting epithelial cells, neutrophils, T and B lymphocytes, mast cells, natural killer cells, and endothelial cells. Additionally, EPO has an inhibiting effect on the synthesis of some inflammatory cytokines such as IL-4, IL-5.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> IL-4, IL-5 are important mediators in pathogenesis of asthma. We considered that EPO, especially at a higher dose, showed beneficial results owing to its anti-inflammatory and anti-reactive oxygen species effects. Due to the delayed expression of EPO gene after the injury and the suppression of EPO production by inflammatory cytokines, just exogenous EPO can be protective against the inflammation.<a class="elsevierStyleCrossRef" href="#bib0130">26</a>NF-κB is a family of DNA-binding protein factors that have an important role for the transcription of pro-inflammatory molecules.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> So, NF-κB can be a basic mediator in the pathogenesis of asthma. The inhibition of NF-κB causes the reduction of allergic lung inflammation and airway hyperresponsiveness.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> NF-κB-binding activity in bronchial mucosa biopsy samples of asthmatic patients was reduced with inhaled budesonide treatment.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Consequently the inhibition of NF-κB has an important role for the control of pulmonary inflammation.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> In recent studies, it was demonstrated that EPO reduces the production of NF-κB-inducible immune mediators.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> In our study, EPO may reduce the inflammation with the helping of inhibited NF-κB.The basic mediators of injury are reactive free radicals produced by cellular metabolism under hypoxic condition. Hypoxia leads to synthesis of the hypoxia inducible factor family protein genes, including EPO.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> Cuzzocrea et al. previously demonstrated that EPO reduced arthritis caused by type II collagen in mice, partly by decreasing free radical production.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> EPO significantly reduced the ultrastructural pathological changes and levels of lipid peroxidation in lung tissues after traumatic brain injury. Reactive oxygen species and nitric oxide have been demonstrated to be involved in the pathogenesis of bleomycin-induced pulmonary fibrosis in rodents.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> EPO may therefore also be beneficial against lung injury and fibrosis as an antioxidant agent.There were some limitations of our study, such as the fact that cytokine levels could not be evaluated and the results found in our study may not translate to positive findings in human clinical trials. Here, to determine the effect of EPO in the treatment of chronic asthma, we evaluated only histopathological changes. Most of the asthma models are devoid of the chronic histopathological changes seen in human asthma because of short term exposure to inhaled antigen. Temelkovski et al. suggested that this experimental model replicated many features of human asthma.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> By the same model, a progressive inflammatory response was developed in the airways of mice characterised by the presence of intraepithelial eosinophils and by infiltration of the lamina propria with lymphoid, mononuclear cells. Goblet cell hyperplasia, epithelial thickening, and subepithelial fibrosis were also evident. Although we could only evaluate the histopathological changes of asthma, the validity of our method increases the value of our study.In conclusion, the current study has shown that administration of EPO is effective in resolving the established chronic histopathological changes of lungs in a murine model of asthma. Further studies with long-term treatments which evaluate the effects of EPO on lung inflammation and remodelling are needed and especially the cytokine response for the EPO treatment in asthma should be investigated.Conflict of interestThe authors have no conflict of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:2 [ "identificador" => "xres86085" "titulo" => array:5 [ 0 => "Summary" 1 => "Background" 2 => "Methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec74248" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Experimental animals" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Sensitisation and inhalational exposure" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Study drugs" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Histopathological analysis" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical analysis" ] ] ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Results" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflict of interest" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-01-03" "fechaAceptado" => "2011-02-14" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec74248" "palabras" => array:4 [ 0 => "Chronic asthma" 1 => "Erythropoietin" 2 => "Mouse" 3 => "Treatment" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Summary" "resumen" => "BackgroundErythropoietin (EPO) is originally defined as a haematopoietic growth factor, but also has anti-inflammatory effects through cytokine modulation. This anti-inflammatory and cytokine modulating effect has not been investigated for the treatment of asthma. We aimed to determine the beneficial effects of erythropoietin on lung histology of murine model of chronic asthma. MethodsThirty-five BALB/c mice were divided into five groups: I; II; III; IV; and control group. All groups except control group were sensitised and challenged with ovalbumin. Mice with experimentally induced asthma in Group I received saline; Group II EPO 500IU/kg; Group III EPO 1000IU/kg; and Group IV dexamethasone 1mg/kg intraperitoneally once a day in the last five days of the challenge period. Animals were sacrificed 24h after the last administration of study drugs. Histological findings of airways were evaluated by light and electron microscopic examination. ResultsAll histological parameters of asthma in the group treated with a high dose of EPO (Group III) were significantly ameliorated when compared with the group treated with saline (Group I). In comparison to the group treated with low dose of EPO (Group II) and the group treated with saline (Group I), basement membrane thicknesses and number of mast cells were significantly lower in the group treated with low dose of EPO (Group II). All histological parameters were similar between the group treated with high dose of EPO (Group III) and the group treated with dexamethasone (Group IV) except higher number of mast cells in the group treated with high dose of EPO (Group III). Additionally, the results of all histological parameters in the group treated with high dose of EPO (Group III) were significantly better when compared with the group treated with low dose of EPO (Group II). ConclusionsWe found that EPO ameliorated histological changes of chronic murine model of asthma. Further studies are needed to evaluate the efficacy of EPO in the treatment of asthma." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 764 "Ancho" => 2354 "Tamanyo" => 100628 ] ] "descripcion" => array:1 [ "en" => "Murine model of airway inflammation and treatment with EPO." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2090 "Ancho" => 3347 "Tamanyo" => 1083536 ] ] "descripcion" => array:1 [ "en" => "Light and electron microscopic findings of Groups. I; control, II; asthma, III; EPO (500IU/kg), IV; EPO (1000IU/kg), V; Dexa group. In representative histological images, lung tissues were stained with H&E (a; 1st row), PAS (b; 2nd row) and toluidine blue (c; 3rd row). In control group; light microscopic findings (Ia) revealed a regular respiratory epithelium and airways (Av), a thin, regular subepithelial smooth muscle layer (arrow with two heads), and normal PAS-stained parenchymal structures (Ib). Parenchymal structures with toluidine blue staining were regular (Ic). Electron microscopy (Id) revealed goblet cells (Gc), and healthy epithelial cells with cilia (C). The basement membrane was thin and regular (*), and there were two to three layers of subepithelial smooth muscle cells (Sm). In asthma group; H&E staining (IIa) revealed thickened epithelium, thickened subepithelial smooth muscle (arrow with two heads), and peribronchial mononuclear infiltration (*). High numbers of goblet cells (Gc) were seen with PAS-staining (IIb), and mast cells with toluidine blue staining (IIc). In dexa group; no difference in light microscopic findings was found compared with control rats (Va, Vb, Vc and Vd), In EPO (500IU/kg) and EPO (1000IU/kg) groups; the pathological changes, cellular infiltration around airways, goblet cell hyperplasia and number of mast cells, were significantly less than in asthma group. Electron microscopic findings revealed a thickened basement membrane (*) and smooth muscle cells (Sm) in asthma group (IId). Healthy respiratory epithelium with cilia (C) and goblet cells (Gc) in EPO (500IU/kg) (IIId), EPO (1000IU/kg) (IVd) and dexa (Vd) groups." ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "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 (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">Asthma (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">p \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">Basement membrane thickness (nm) \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">272.61±19.14 \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">662.05±33.17 \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"><0.05 \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">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">4.67±0.40 \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">11.27±0.64 \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"><0.05 \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">Epithelium 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">38.91±2.99 \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">50.96±1.61 \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"><0.05 \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">0.32±0.12 \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">2.75±1.20 \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"><0.05 \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 (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">0.72±0.14 \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">1.99±0.40 \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"><0.05 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab165431.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Comparison between asthma (Group I) and control groups." ] ] 3 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "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">Erythropoietin (500IU/kg)Group II (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">Erythropoietin (1000IU/kg)Group III (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">Dexamethasone (1mg/kg)Group 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">AsthmaGroup I (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">Basement membrane thickness (nm) \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">580.56±10.53<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">503.96±12.68<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a>,<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">518.29±30.18<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">662.05±33.17 \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">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">10.90±0.42<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">8.10±0.50<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">7.49±0.14<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">11.27±0.64 \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">Epithelium 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">48.82±2.66<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">43.10±0.58<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">41.07±3.09<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">50.96±1.61 \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">0.92±0.21<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">0.63±0.22<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a>,<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">0.92±0.17<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">2.75±1.20 \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 (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">1.51±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">1.11±0.01<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a>,<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">1.12±0.17<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">1.99±0.40 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab165432.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "*" "nota" => "p<0.05 in groups versus placebo (asthma)." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "**" "nota" => "p<0.05 in groups versus dexamethasone." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "***" "nota" => "p<0.05 in groups treated with two different doses of EPO." ] ] ] "descripcion" => array:1 [ "en" => "Comparison between study groups." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:31 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Novel drugs for treating asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "T.T. 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M. Karamana, F. Firincib,

Corresponding author

fatih.firinci@deu.edu.tr
fatihfirinci@yahoo.com

Corresponding author.

, M. Kirayc, T. Tuncelb, A. Bagriyanikc, O. Yilmaza, N. Uzunerb, O. Karamanb

a Multidisciplinary Laboratory, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey

b Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey

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

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6- to 8-week-old&#44; female BALB&#47;c mice&#44; weighting 18&#8211;20<span class="elsevierStyleHsp" style=""></span>g&#44; were maintained in a pathogen-free laboratory of Dokuz Eylul University&#46; They were kept in hygienic macrolene cages in air-conditioned rooms and allowed ad libitum with food and water on a 12-h light&#47;12-h dark cycle&#46; All experimental procedures complied with the requirements of the Animal Care and Ethics Committee of the Dokuz Eylul University&#46; Thirty-five BALB&#47;c mice were divided into five groups&#58; I&#44; II&#44; III&#44; IV&#44; and control group&#44; each group included seven mice&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Sensitisation and inhalational exposure</span><p id="par0020" class="elsevierStylePara elsevierViewall">BALB&#47;c mice are high responders to ovalbumin&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The mice in study groups I&#44; II&#44; III&#44; and IV were sensitised via two intraperitoneal injections&#44; on days 0 and 14 of the experiment&#44; of 10<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;0&#46;1<span class="elsevierStyleHsp" style=""></span>mL chicken egg albumin &#40;ovalbumin&#44; grade V&#44; &#8805;98&#37; pure&#59; Sigma&#44; St&#46; Louis&#44; MO&#44; USA&#41; with alum as an adjuvant&#46; The mice in study groups I&#44; II&#44; III&#44; and IV were then exposed to aerosolised ovalbumin for 30<span class="elsevierStyleHsp" style=""></span>min per day on three days of a week for eight weeks&#44; beginning from the 21st day of the study &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Exposures were carried out in a whole body inhalation exposure system&#46; Temperature and relative humidity were maintained between 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 delivered by aerosolisation via compressed air to a sidestream jet nebuliser 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>&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The mice in the control group were administered normal saline with alum via intraperitoneally on the 0 and 14th days of the experiment and exposed aerosolised saline for 30<span class="elsevierStyleHsp" style=""></span>min per day on three days of the week for eight weeks&#44; beginning from the 21st day of the study&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;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 I received saline&#59; Group II received EPO at dose of 500<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#59; Group III received EPO at dose of 1000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#59; and Group IV dexamethasone at dose of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg intraperitoneally once a day in the last five days of the challenge period&#46; Intraperitoneal doses of human recombinant EPO &#40;Epoetin alpha&#44; Eprex&#44; Roche&#41; and dexamethasone 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg were chosen from other studies also conducted with BALB&#47;c mice&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#8211;15</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Histopathological analysis</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; Two investigators who were blinded to the treatment groups interpreted the histopathology&#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> obtained from adjacent regions were stocked in 2&#46;5&#37; gluteraldehyde for electron microscopic evaluation&#46; After fixation&#44; samples were embedded in paraffin for light microscopic evaluation and serial sections of 5-&#956;m thickness were prepared&#46; After choosing the first section randomly&#44; 10 sections in each mouse were selected by skipping over 10 sections and proceeded to staining process&#46; For light microscopic evaluation&#44; three 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<span class="elsevierStyleHsp" style=""></span>o&#8217;clock&#46; Considering that each section contained approximately two to three airways&#44; around 20 or more airways were evaluated for each mouse&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Photomicrographs were taken by JVC TK-890-E camera &#40;Japan&#41;&#44; which was adapted on Olympus BH-2 RFCA model microscope &#40;Olympus Optical&#44; Tokyo&#44; Japan&#41;&#46; The histological analysis was carried out with UTHSCSA Image Tool for Windows Version 3&#46;00 software&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The consecutive 10 sections were stained with toluidine blue and the other 10 sections with periodic acid-Schiff &#40;PAS&#41;&#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 eight 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 one hundred&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Tissues were embedded in EPON after follow-up process of electron microscopic evaluation&#46; Airways were marked from the semithin sections by light microscope&#46; Ultrathin sections were obtained and stained with uraniyl acetate and lead citrate&#46; Libra 120 Carl Zeiss EFTEM electron microscope &#40;Oberkochen&#44; Germany&#41; was used for this evaluation&#46; For each mouse&#44; five to seven ultrathin sections were achieved from each two blocks for evaluation of epithelium of the airway&#44; the surrounding structures&#44; and the intercellular connections&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">For each mouse&#44; eight to ten areas were photographed by Trondle &#40;2048<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2048 pixel&#41; digital camera&#44; attached to the electron microscope&#46; Thicknesses of the basement membrane of the respiratory epithelium were measured from 20 points of preparations at equal distances to each other and the data were recorded in sequence&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">SPSS 11 package program was used for 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; &#40;minimum&#8211;maximum&#41; of seven animals in each group&#46; The comparisons between all groups were conducted by using Kruskal&#8211;Wallis method&#46; When differences were statistically significant&#44; Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test was used for group 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><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><p id="par0065" class="elsevierStylePara elsevierViewall">The light and electron microscopic examinations revealed normal findings in the control group &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>-I&#41;&#46; In the chronic asthma group &#40;placebo&#41;&#44; the numbers of mast cells and goblet cells as well as the thicknesses of basement membrane&#44; epithelium&#44; and subepithelial smooth muscle layer were significantly higher when compared to the control group &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Additionally&#44; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>-II demonstrates that characteristic asthmatic changes were successfully established in the group treated with saline &#40;Group I&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">In Group II &#40;EPO 500<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#41;&#44; basement membrane thickness and number of mast cells were significantly lower compared with regard to the group treated with saline &#40;Group I&#41;&#46; Both the thicknesses of epithelium and subepithelial muscle layer and the number of goblet cells were similar to that of the group treated with saline &#40;Group I&#41;&#46; Additionally&#44; respiratory tract epithelium and ciliary structures were similar to normal airway findings &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>-III&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">When EPO was administered at a dose of 1000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg &#40;Group III&#41;&#44; significant improvement occurred in all histological parameters compared with the group treated with saline &#40;Group I&#41;&#46; This improvement was similar to dexamethasone&#44; the gold standard treatment of asthma &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Parenchymal structures and respiratory epithelium were normal &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>-IV&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">In Group IV &#40;dexamethasone 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#44; all histological parameters were significantly better compared to the group treated with saline &#40;Group I&#41;&#46; Electron microscopic findings demonstrated regular basement membrane and normal ciliary epithelium &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>-V&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">When low and high dosages of EPO were compared to each other&#59; all histological parameters were found to be significantly better in the group treated with high dose of EPO &#40;Group III&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; When EPO groups were compared with dexamethasone group&#44; among all the histological variables&#44; the only significant difference was lower mast cell counts in the group treated with high dose of EPO &#40;Group III&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">Airway inflammation in asthma causes subsequent structural changes called as remodelling&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Structural changes in asthmatic airways occur as a result of an injury&#47;repair process&#46; Currently&#44; drugs used for the treatment of asthma have little effect on airway remodelling&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> EPO has uncertain value in the treatment of asthma&#46; Although the anti-inflammatory properties of EPO have been reported many times&#44; their effects on remodelling have rarely been evaluated&#46; Thus&#44; we aimed to investigate the efficacy of EPO on lung histological changes and especially on remodelling in a murine model of chronic asthma&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Chronic inflammation in asthma is thought to initiate and perpetuate tissue injury and repair&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In our study&#44; the structural changes observed in the asthmatic group revealed that the model was well established&#46; It seems very important to prevent airway remodelling in the chronic management of asthma&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> because once formed&#44; remodelling is resistant to asthma therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Inhalation of corticosteroids and administration of &#946;<span class="elsevierStyleInf">2</span> agonists&#44; antileukotrienes&#44; and theophylline are poorly responsive to these structural changes&#46; Inhaled corticosteroids may be effective in reducing reticular basement membrane thickness when used for a long period of time and at high doses&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In our study&#44; dexamethasone and high dose of EPO significantly ameliorated all the structural changes of chronic asthma&#46; This finding is very important because reticular basement membrane thickness is considered a hallmark for airway remodelling in asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">EPO is a hormone which maintains erythrocyte mass&#46; The major mechanism for increasing in erythrocyte mass is the prevention of apoptosis of late erythroid progenitor cells&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> In the haematopoietic system&#44; the principal function of EPO is the regulation of red blood cell production&#44; mediated by its specific cell surface receptor&#46; Recombinant EPO forms EPO alfa&#44; EPO beta&#44; and long-acting analogue darbepoetin alfa have been widely used for treatment of anaemia in chronic kidney disease and chemotherapy-induced anaemia in cancer patients&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Recent studies showed that EPO protects various tissues through antiapoptotic effects&#46; EPO protects the developing brain against N-methylaspartate receptor antagonist induced neuronal cell apoptosis&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> and inhibits spinal neuronal apoptosis and pain following nerve root crush&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> EPO also markedly reduced apoptosis of adult rat cardiomyocytes subjected to hypoxia in vitro&#44; and reduced cardiomyocyte loss by 50&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> In addition&#44; EPO protected tubular epithelial cells against apoptosis induced by ischemic acute renal injury&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">EPO is a complex anti-inflammatory agent which exerts a wide variety of immunosuppressive effects targeting epithelial cells&#44; neutrophils&#44; T and B lymphocytes&#44; mast cells&#44; natural killer cells&#44; and endothelial cells&#46; Additionally&#44; EPO has an inhibiting effect on the synthesis of some inflammatory cytokines such as IL-4&#44; IL-5&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> IL-4&#44; IL-5 are important mediators in pathogenesis of asthma&#46; We considered that EPO&#44; especially at a higher dose&#44; showed beneficial results owing to its anti-inflammatory and anti-reactive oxygen species effects&#46; Due to the delayed expression of EPO gene after the injury and the suppression of EPO production by inflammatory cytokines&#44; just exogenous EPO can be protective against the inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">NF-&#954;B is a family of DNA-binding protein factors that have an important role for the transcription of pro-inflammatory molecules&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> So&#44; NF-&#954;B can be a basic mediator in the pathogenesis of asthma&#46; The inhibition of NF-&#954;B causes the reduction of allergic lung inflammation and airway hyperresponsiveness&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> NF-&#954;B-binding activity in bronchial mucosa biopsy samples of asthmatic patients was reduced with inhaled budesonide treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Consequently the inhibition of NF-&#954;B has an important role for the control of pulmonary inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> In recent studies&#44; it was demonstrated that EPO reduces the production of NF-&#954;B-inducible immune mediators&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In our study&#44; EPO may reduce the inflammation with the helping of inhibited NF-&#954;B&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The basic mediators of injury are reactive free radicals produced by cellular metabolism under hypoxic condition&#46; Hypoxia leads to synthesis of the hypoxia inducible factor family protein genes&#44; including EPO&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Cuzzocrea et al&#46; previously demonstrated that EPO reduced arthritis caused by type II collagen in mice&#44; partly by decreasing free radical production&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> EPO significantly reduced the ultrastructural pathological changes and levels of lipid peroxidation in lung tissues after traumatic brain injury&#46; Reactive oxygen species and nitric oxide have been demonstrated to be involved in the pathogenesis of bleomycin-induced pulmonary fibrosis in rodents&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> EPO may therefore also be beneficial against lung injury and fibrosis as an antioxidant agent&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">There were some limitations of our study&#44; such as the fact that cytokine levels could not be evaluated and the results found in our study may not translate to positive findings in human clinical trials&#46; Here&#44; to determine the effect of EPO in the treatment of chronic asthma&#44; we evaluated only histopathological changes&#46; Most of the asthma models are devoid of the chronic histopathological changes seen in human asthma because of short term exposure to inhaled antigen&#46; Temelkovski et al&#46; suggested that this experimental model replicated many features of human asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> By the same model&#44; a progressive inflammatory response was developed in the airways of mice characterised by the presence of intraepithelial eosinophils and by infiltration of the lamina propria with lymphoid&#44; mononuclear cells&#46; Goblet cell hyperplasia&#44; epithelial thickening&#44; and subepithelial fibrosis were also evident&#46; Although we could only evaluate the histopathological changes of asthma&#44; the validity of our method increases the value of our study&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">In conclusion&#44; the current study has shown that administration of EPO is effective in resolving the established chronic histopathological changes of lungs in a murine model of asthma&#46; Further studies with long-term treatments which evaluate the effects of EPO on lung inflammation and remodelling are needed and especially the cytokine response for the EPO treatment in asthma should be investigated&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interest</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare&#46;</p></span></span>"
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          "identificador" => "xres86085"
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            4 => "Conclusions"
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          "titulo" => "Introduction"
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          "titulo" => "Materials and methods"
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              "titulo" => "Experimental animals"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Sensitisation and inhalational exposure"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Study drugs"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Histopathological analysis"
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              "titulo" => "Statistical analysis"
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        4 => array:2 [
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          "titulo" => "Results"
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        5 => array:2 [
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          "titulo" => "Discussion"
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          "titulo" => "Conflict of interest"
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    "fechaRecibido" => "2011-01-03"
    "fechaAceptado" => "2011-02-14"
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          "palabras" => array:4 [
            0 => "Chronic asthma"
            1 => "Erythropoietin"
            2 => "Mouse"
            3 => "Treatment"
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        "titulo" => "Summary"
        "resumen" => "<span class="elsevierStyleSectionTitle">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Erythropoietin &#40;EPO&#41; is originally defined as a haematopoietic growth factor&#44; but also has anti-inflammatory effects through cytokine modulation&#46; This anti-inflammatory and cytokine modulating effect has not been investigated for the treatment of asthma&#46; We aimed to determine the beneficial effects of erythropoietin on lung histology of murine model of chronic asthma&#46;</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Thirty-five BALB&#47;c mice were divided into five groups&#58; I&#59; II&#59; III&#59; IV&#59; and control group&#46; All groups except control group were sensitised and challenged with ovalbumin&#46; Mice with experimentally induced asthma in Group I received saline&#59; Group II EPO 500<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#59; Group III EPO 1000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#59; and Group IV dexamethasone 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg intraperitoneally once a day in the last five days of the challenge period&#46; Animals were sacrificed 24<span class="elsevierStyleHsp" style=""></span>h after the last administration of study drugs&#46; Histological findings of airways were evaluated by light and electron microscopic examination&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">All histological parameters of asthma in the group treated with a high dose of EPO &#40;Group III&#41; were significantly ameliorated when compared with the group treated with saline &#40;Group I&#41;&#46; In comparison to the group treated with low dose of EPO &#40;Group II&#41; and the group treated with saline &#40;Group I&#41;&#44; basement membrane thicknesses and number of mast cells were significantly lower in the group treated with low dose of EPO &#40;Group II&#41;&#46; All histological parameters were similar between the group treated with high dose of EPO &#40;Group III&#41; and the group treated with dexamethasone &#40;Group IV&#41; except higher number of mast cells in the group treated with high dose of EPO &#40;Group III&#41;&#46; Additionally&#44; the results of all histological parameters in the group treated with high dose of EPO &#40;Group III&#41; were significantly better when compared with the group treated with low dose of EPO &#40;Group II&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We found that EPO ameliorated histological changes of chronic murine model of asthma&#46; Further studies are needed to evaluate the efficacy of EPO in the treatment of asthma&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Light and electron microscopic findings of Groups&#46; I&#59; control&#44; II&#59; asthma&#44; III&#59; EPO &#40;500<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#41;&#44; IV&#59; EPO &#40;1000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#41;&#44; V&#59; Dexa group&#46; In representative histological images&#44; lung tissues were stained with H&#38;E &#40;a&#59; 1st row&#41;&#44; PAS &#40;b&#59; 2nd row&#41; and toluidine blue &#40;c&#59; 3rd row&#41;&#46; In control group&#59; light microscopic findings &#40;Ia&#41; revealed a regular respiratory epithelium and airways &#40;Av&#41;&#44; a thin&#44; regular subepithelial smooth muscle layer &#40;arrow with two heads&#41;&#44; and normal PAS-stained parenchymal structures &#40;Ib&#41;&#46; Parenchymal structures with toluidine blue staining were regular &#40;Ic&#41;&#46; Electron microscopy &#40;Id&#41; revealed goblet cells &#40;Gc&#41;&#44; and healthy epithelial cells with cilia &#40;C&#41;&#46; The basement membrane was thin and regular &#40;&#42;&#41;&#44; and there were two to three layers of subepithelial smooth muscle cells &#40;Sm&#41;&#46; In asthma group&#59; H&#38;E staining &#40;IIa&#41; revealed thickened epithelium&#44; thickened subepithelial smooth muscle &#40;arrow with two heads&#41;&#44; and peribronchial mononuclear infiltration &#40;&#42;&#41;&#46; High numbers of goblet cells &#40;Gc&#41; were seen with PAS-staining &#40;IIb&#41;&#44; and mast cells with toluidine blue staining &#40;IIc&#41;&#46; In dexa group&#59; no difference in light microscopic findings was found compared with control rats &#40;Va&#44; Vb&#44; Vc and Vd&#41;&#44; In EPO &#40;500<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#41; and EPO &#40;1000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#41; groups&#59; the pathological changes&#44; cellular infiltration around airways&#44; goblet cell hyperplasia and number of mast cells&#44; were significantly less than in asthma group&#46; Electron microscopic findings revealed a thickened basement membrane &#40;&#42;&#41; and smooth muscle cells &#40;Sm&#41; in asthma group &#40;IId&#41;&#46; Healthy respiratory epithelium with cilia &#40;C&#41; and goblet cells &#40;Gc&#41; in EPO &#40;500<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#41; &#40;IIId&#41;&#44; EPO &#40;1000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#41; &#40;IVd&#41; and dexa &#40;Vd&#41; groups&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
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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
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&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">Control &#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
                  \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">Asthma &#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
                  \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"><span class="elsevierStyleItalic">p</span>&nbsp;\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
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Basement membrane thickness &#40;nm&#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">272&#46;61<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;14&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">662&#46;05<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>33&#46;17&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">&#60;0&#46;05&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">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
                  \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;67<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;40&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;27<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;64&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">&#60;0&#46;05&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">Epithelium 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">38&#46;91<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#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">50&#46;96<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#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">&#60;0&#46;05&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 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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;32<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#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">2&#46;75<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;20&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">&#60;0&#46;05&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<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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;72<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;14&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;99<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;40&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">&#60;0&#46;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Comparison between asthma &#40;Group I&#41; and control groups&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
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            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">&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">Erythropoietin &#40;500<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#41;Group II &#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
                  \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">Erythropoietin &#40;1000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#41;Group III &#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
                  \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">Dexamethasone &#40;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;Group 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
                  \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">AsthmaGroup I &#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></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">Basement membrane thickness &#40;nm&#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">580&#46;56<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;53<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a><span class="elsevierStyleSup">&#44;&#42;&#42;</span>&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">503&#46;96<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;68<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;&#42;</span></a><span class="elsevierStyleSup">&#42;</span>&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">518&#46;29<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>30&#46;18<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">662&#46;05<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>33&#46;17&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">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
                  \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;90<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;42<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;&#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">8&#46;10<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;50<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a><span class="elsevierStyleSup">&#44;&#42;&#42;&#44;&#42;&#42;&#42;</span>&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">7&#46;49<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;14<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">11&#46;27<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;64&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">Epithelium 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">48&#46;82<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;66<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;&#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;10<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;58<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a><span class="elsevierStyleSup">&#44;&#42;&#42;&#42;</span>&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;07<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;09<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">50&#46;96<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;61&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 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
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Article information

ISSN: 03010546
Original language: English

DOI:10.1016/j.aller.2011.02.010

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2024 November	2	0	2
2024 October	9	6	15
2024 September	20	14	34
2024 August	24	16	40
2024 July	26	15	41
2024 June	24	15	39
2024 May	19	12	31
2024 April	19	6	25
2024 March	37	7	44
2024 February	15	3	18
2024 January	23	7	30
2023 December	26	14	40
2023 November	21	36	57
2023 October	34	16	50
2023 September	38	11	49
2023 August	23	7	30
2023 July	15	4	19
2023 June	24	4	28
2023 May	60	4	64
2023 April	59	4	63
2023 March	48	2	50
2023 February	33	6	39
2023 January	48	8	56
2022 December	35	5	40
2022 November	18	6	24
2022 October	29	11	40
2022 September	27	10	37
2022 August	27	9	36
2022 July	24	9	33
2022 June	12	7	19
2022 May	26	16	42
2022 April	19	10	29
2022 March	21	9	30
2022 February	15	9	24
2022 January	19	10	29
2021 December	31	15	46
2021 November	14	17	31
2021 October	32	14	46
2021 September	16	14	30
2021 August	9	17	26
2021 July	13	10	23
2021 June	12	12	24
2021 May	17	18	35
2021 April	30	38	68
2021 March	11	23	34
2021 February	6	18	24
2021 January	9	10	19
2020 December	0	7	7
2020 November	0	4	4
2020 October	0	1	1
2020 September	0	1	1
2020 August	0	4	4
2020 July	0	4	4
2020 June	0	2	2
2020 May	0	6	6
2020 April	0	2	2
2020 March	0	3	3
2020 February	0	1	1
2020 January	0	3	3
2019 December	0	4	4
2019 November	0	3	3
2019 October	0	1	1
2019 September	0	2	2
2019 July	0	2	2
2019 June	0	18	18
2019 May	0	54	54
2019 April	0	9	9
2018 February	8	3	11
2018 January	16	0	16
2017 December	8	3	11
2017 November	13	2	15
2017 October	13	1	14
2017 September	8	2	10
2017 August	9	5	14
2017 July	10	1	11
2017 June	30	11	41
2017 May	14	11	25
2017 April	19	5	24
2017 March	12	25	37
2017 February	18	5	23
2017 January	6	1	7
2016 December	11	7	18
2016 November	32	6	38
2016 October	27	12	39
2016 September	28	5	33
2016 August	17	8	25
2016 July	9	1	10
2016 June	22	8	30
2016 May	16	6	22
2016 April	15	13	28
2016 March	18	12	30
2016 February	16	13	29
2016 January	19	13	32
2015 December	11	11	22
2015 November	14	6	20
2015 October	25	4	29
2015 September	15	3	18
2015 August	38	1	39
2015 July	31	3	34
2015 June	5	1	6
2015 May	10	2	12
2015 April	8	13	21
2015 March	11	2	13
2015 February	13	7	20
2015 January	37	4	41
2014 December	19	4	23
2014 November	24	2	26
2014 October	15	7	22
2014 September	22	6	28
2014 August	14	0	14
2014 July	12	2	14
2014 June	9	0	9
2014 May	9	1	10
2014 April	8	1	9
2014 March	31	8	39
2014 February	39	5	44
2014 January	32	5	37
2013 December	34	7	41
2013 November	34	7	41
2013 October	36	13	49
2013 September	37	14	51
2013 August	40	7	47
2013 July	42	8	50
2013 June	30	3	33
2013 May	33	3	36
2013 April	31	9	40
2013 March	24	4	28
2013 February	13	6	19
2013 January	9	2	11
2012 December	7	4	11
2012 November	0	1	1
2012 October	1	2	3
2012 September	1	1	2
2012 March	418	0	418

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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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