Induction of nasal polyps using house dust mite and Staphylococcal enterotoxin B in C57BL/6 mice

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Pink box is the differentially expressed genes." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Y. Wu, J.-F. Zhang, T. Xu, L. Xu, J. Qiao, F. Liu, H. Shan, X. Jiang" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Y." "apellidos" => "Wu" ] 1 => array:2 [ "nombre" => "J.-F." "apellidos" => "Zhang" ] 2 => array:2 [ "nombre" => "T." "apellidos" => "Xu" ] 3 => array:2 [ "nombre" => "L." "apellidos" => "Xu" ] 4 => array:2 [ "nombre" => "J." "apellidos" => "Qiao" ] 5 => array:2 [ "nombre" => "F." "apellidos" => "Liu" ] 6 => array:2 [ "nombre" => "H." "apellidos" => "Shan" ] 7 => array:2 [ "nombre" => "X." 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Morales, C. Flores, K. Pino, J. Angulo, M. López-Lastra, J.A. Castro-Rodriguez" "autores" => array:6 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Morales" ] 1 => array:2 [ "nombre" => "C." "apellidos" => "Flores" ] 2 => array:2 [ "nombre" => "K." "apellidos" => "Pino" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Angulo" ] 4 => array:2 [ "nombre" => "M." "apellidos" => "López-Lastra" ] 5 => array:2 [ "nombre" => "J.A." 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Khalmuratova, M. Lee, D.W. Kim, J.-W. Park, H.-W. Shin" "autores" => array:5 [ 0 => array:2 [ "nombre" => "R." "apellidos" => "Khalmuratova" ] 1 => array:2 [ "nombre" => "M." "apellidos" => "Lee" ] 2 => array:2 [ "nombre" => "D.W." "apellidos" => "Kim" ] 3 => array:2 [ "nombre" => "J.-W." "apellidos" => "Park" ] 4 => array:2 [ "nombre" => "H.-W." "apellidos" => "Shin" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054616300453?idApp=UINPBA00004N" "url" => "/03010546/0000004400000004/v1_201607130013/S0301054616300453/v1_201607130013/en/main.assets" ] ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "Original Article" "titulo" => "Induction of nasal polyps using house dust mite and Staphylococcal enterotoxin B in C57BL/6 mice" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "66" "paginaFinal" => "75" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "R. Khalmuratova, M. Lee, D.W. Kim, J.-W. Park, H.-W. Shin" "autores" => array:5 [ 0 => array:3 [ "nombre" => "R." "apellidos" => "Khalmuratova" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "M." "apellidos" => "Lee" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "D.W." "apellidos" => "Kim" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "J.-W." "apellidos" => "Park" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 4 => array:4 [ "nombre" => "H.-W." "apellidos" => "Shin" "email" => array:1 [ 0 => "charlie@snu.ac.kr" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Biomedical Science, Ischemic/Hypoxic Disease Institute, Seoul National University Graduate School, Seoul, Republic of Korea" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul, Republic of Korea" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Republic of Korea" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 3239 "Ancho" => 2574 "Tamanyo" => 604256 ] ] "descripcion" => array:1 [ "en" => "Representative sections of eosinophilic infiltration and total IgE production. (A–D) The presence of eosinophils was detected in groups B, C and D. Increased numbers of eosinophils were observed in groups C and D, with no significant difference in eosinophil distributions between groups C and D. (E) The numbers of eosinophils infiltrating the nasal mucosa were counted based on the Sirius red-stained sections. Data are expressed as means±SD. (F) The level of total IgE from serum was measured by enzyme-linked immunosorbent assay (ELISA). Data are expressed as means±SEM. *p<0.05, compared to group A (control); #p<0.05, compared to group B (HDM); Mann–Whitney U test. Scale bar=100μm." ] ] ] "textoCompleto" => "IntroductionChronic rhinosinusitis (CRS) encompasses a heterogeneous group of disorders defined by the inflammation of the paranasal sinuses and represents a significant health problem worldwide. CRS has been categorised typically as CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) based on endoscopic examination findings.<a class="elsevierStyleCrossRefs" href="#bib0160">1,2</a> CRSwNP is characterised by inflammatory cell infiltration and structural modifications of the epithelium (secretary hyperplasia and squamous metaplasia) and lamina propria (basement membrane thickening, extracellular matrix accumulation and fibrosis). However, the underlying mechanisms interlinking these pathological conditions to nasal polyp formation remain unclear.<a class="elsevierStyleCrossRef" href="#bib0170">3</a>To date, murine studies investigating CRS have employed systemic sensitisation and intranasal challenge with ovalbumin (OVA). Chronic challenge models in mice involve repeated exposure to antigen for up to 12 weeks. Low-dose Staphylococcal enterotoxin B (SEB) induced nasal polypoid lesions with increased eosinophilic infiltration in an allergic rhinosinusitis model.<a class="elsevierStyleCrossRef" href="#bib0175">4</a> OVA challenge models of CRSwNP offer opportunities for increasing our understanding of the pathogenesis underlying this disease, as well as for identifying novel therapeutic targets, although more relevant allergens such as the house dust mite (HDM) may also be considered.<a class="elsevierStyleCrossRefs" href="#bib0180">5,6</a>The HDM is ubiquitous in human habitats and is a significant factor underlying allergic rhinitis and allergic asthma. These features make it one of the important sources of indoor allergens.<a class="elsevierStyleCrossRefs" href="#bib0190">7,8</a> The predominant HDMs isolated from dust samples are Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farinae (Der f). Although HDM extracts are complex from an immunological perspective, they are ultimately more representative of real-life aeroallergen exposure.<a class="elsevierStyleCrossRefs" href="#bib0200">9,10</a> Recently, common parameters of airway allergy such as airway inflammation, Th2 cytokine production and elevated Der f-specific IgE levels were shown in an intranasal HDM sensitisation mouse model.<a class="elsevierStyleCrossRefs" href="#bib0210">11–13</a> Despite the high prevalence of HDM allergy, the cellular and molecular networks that initiate and regulate this Th2-biased response have been investigated using only the OVA-induced polyp model.<a class="elsevierStyleCrossRef" href="#bib0225">14</a>In this study, we established a model mimicking key aspects of CRSwNP using the clinically relevant aeroallergen HDM with co-administration of SEB. Additionally, we compared the immune-inflammatory and nasal polyp formation responses to intranasal delivery of HDM extract and OVA in the experimental murine model.MethodsExperimental animalsEighteen male C57BL/6 mice (4 weeks of age; 20–25g each) were purchased from Central Laboratory Animal, Inc. (Seoul, Korea) and housed for one week before initiating experiments. The animals were kept in a pathogen-free biohazard containment facility maintained at 22–24°C and 50–60% humidity. All experimental protocols complied with the Guidelines of the National Institute of Health and the Declaration of Helsinki, and were approved by the Committee on the Use and Care of Animals (SNU-140429-10).Experimental protocolsThe experimental protocol was designed as described previously with some modifications (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A).<a class="elsevierStyleCrossRefs" href="#bib0175">4,12</a> The mice were categorised into a control group (group A; n=3) and three experimental groups (B, C, and D; n=5 each). Purified HDM extract from species Der f (GREER Laboratories, Lenoir, NC, USA) was used in this study. Mice in experimental groups B and C were immunised intradermally at the base of the tail with 100μg of HDM extract dissolved in phosphate-buffered saline (PBS) and 100μL of complete Freund's adjuvant (CFA, Sigma, St. Louis, MO, USA) on days 0 and 5. The mice in experimental group D were systemically sensitised by intraperitoneal injection with 25μg of OVA (Grade V; Sigma, St. Louis, MO, USA) dissolved in 300mL of PBS in the presence of 2mg of aluminium hydroxide gel adjuvant. Seven days after the last immunisation, mice were challenged intranasally with 20-μg HDM extract dissolved in 40-μL PBS (groups B and C) or 6% OVA in 40μL of PBS (group D), and treated daily for seven days.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Prolonged continuous inflammation was maintained in the experimental groups by subsequent nasal treatment with 20-μg HDM extract or 6% OVA three times weekly for 12 consecutive weeks. Additionally, selected mice in groups C and D were challenged three times weekly with 10ng of SEB (List Biological laboratories, INC, CA, USA) diluted in PBS from the 5th week to the 12th week. PBS was applied for both systemic and local stimulation in group A (control). Mice were sacrificed 24h after the last intranasal administration.Histopathological analysisThe mice were euthanised and decapitated. The heads of the animals were stripped of skin, eyes and muscle, and the mandibles were excised. The tissues were immersed overnight in 4% paraformaldehyde and decalcified in 5% nitric acid for 4–5 days at 4°C. The specimens were dehydrated and processed according to standard paraffin-embedding procedures.<a class="elsevierStyleCrossRef" href="#bib0230">15</a> Tissues were then cut into 3-μm-thick coronal sections. An atlas of normal murine sinonasal anatomy was used to standardise the anatomic locations being examined.<a class="elsevierStyleCrossRef" href="#bib0235">16</a> The histological changes in the nasal mucosa were determined by haematoxylin and eosin (H&E) for overall inflammation, Sirius red for eosinophils, periodic acid–Schiff (PAS) stain for goblet cells, and Masson's trichrome stain for collagen deposition in the subepithelial layer.To determine the degree of inflammation, the sections were examined with a light microscope (400× magnification), and two individuals independently counted the number of eosinophils, mast cells and goblet cells in the nasal mucosa in four fields. The results of inflammatory and goblet cells were expressed as cells per high-power field. Subepithelial thickness was measured from four mucosal sampling areas under a high-power field (400× magnification). Three consecutive slides were reviewed to rule-out processing errors. Polyp-like lesions were defined as distinct mucosal elevations with eosinophilic infiltration and/or microcavity formation (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A and B). Polypoid lesions and epithelial disruption were counted microscopically and expressed as a total number. Simple protruded lesions were not regarded as polyp-like lesions (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Immunohistochemical analysis for mast cellsImmunohistochemistry (IHC) was performed to identify the presence of mast cells. IHC staining was performed using the polink-2+polymerised horseradish peroxidase (HRP) broad DAB Detection System (Golden Bridge International Labs, WA, USA). Briefly, tissue sections were deparaffinised, rehydrated and treated with 3% hydrogen peroxide in methanol to quench endogenous peroxidase activity. Heat-induced epitope retrieval was then performed by microwaving the samples in 10mmol/L citrate buffer (pH 6.0). The sections were incubated for 1h at room temperature with primary antibody against mast cell tryptase (1:100, Abcam, Cambridge, MA, USA). The sections were incubated in broad antibody enhancer and polymer-HRP and then stained with the DAB Detection System. Sections were counterstained with Gill's haematoxylin and dehydrated through a graded ethanol series, cleared with xylene, and coverslipped with mountant. Negative controls were obtained by omitting the primary antibody. To confirm mast cells, Giemsa staining was also performed according to standard procedures.Quantitative determination of total IgEBlood was collected via cardiac puncture 24h after the last intranasal administration. The blood was centrifuged, and the serum was stored at −80°C for the measurement of IgE. Serum samples from three animals per group were analysed. Quantitative assessments of total IgE were performed using an enzyme-linked immunosorbent assay (ELISA) kit purchased from BioLegend (San Diego, CA, USA). The sensitivity of total IgE was 0.1ng/mL. All procedures were performed according to the manufacturer's instructions.Statistical analysesData are expressed as means±SD. The Mann–Whitney U-test was performed to compare the number of eosinophils, mast cells, goblet cells and subepithelial thicknesses between the groups. Statistical analyses and data plotting were performed using SigmaPlot (version 10, Richmond, CA, USA). A value of p<0.05 was considered to indicate statistical significance.ResultsThe formation of nasal polypoid lesionsNo polyp-like lesions were observed in groups A and B (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). Polypoid lesions were found only in mice that received SEB intranasally (groups C and D). Five lesions were observed in three of five mice in group C (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C). Similarly, six lesions were evident in four of five mice in group D (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>D). Thickened mucosae with polyp-like lesions were observed primarily at the transition zone of the olfactory and respiratory epithelia. Morphological changes such as secretory hyperplasia as well as eosinophilic infiltrates with Charcot–Leyden-like crystal formations were observed in the epithelial lining of nasal polyps (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Epithelial disruptions as well as polypoid lesions were found more often in the group treated with OVA+SEB (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C and D).Inflammatory responses in the airwayIntranasal delivery of HDM extract alone or HDM+SEB elicited robust inflammatory responses in the airways of mice, which was clearly evident histopathologically. Therefore, we next characterised the inflammatory cells in the nasal mucosa. The magnitude of the inflammatory response was estimated by the number of inflammatory cells recruited into the tissue.As shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>, HDM only or HDM+SEB treatment induced tissue inflammation in the nasal mucosa, and the inflammatory infiltrate was composed mainly of eosinophils. The numbers of eosinophils per high-power field in groups A, B, C and D were 1.3±0.5, 42.8±9.6, 55.6±3.5, and 62.2±7.5, respectively. Mice challenged with HDM+SEB and OVA+SEB exhibited significantly higher numbers of tissue eosinophils than mice challenged with HDM only (p<0.05), whereas no significant difference was detected between mice treated with HDM+SEB and OVA+SEB. In addition, the total serum IgE levels were elevated markedly in the three experimental groups, with no significant difference among groups B, C and D (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>F).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>The distribution of mast cells in nasal tissue sample in mice was determined by IHC (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). The numbers of tryptase-positive mast cells per high-power field (mean±SD) in groups A, B, C and D were 1.3±0.5, 12.4±2.0, 14.5±3.5 and 4.2±0.5, respectively. Similarly, Giemsa staining of the nasal tissue sections revealed abundant mast cells after instillation with HDM or HDM+SEB, but an absence of mast cells in the airways of PBS-treated mice. The numbers of mast cells per high-power field (mean±SD) in groups A, B, C and D were 0.0±0.0, 19.4±2.1, 19.5±3.3 and 5.3±0.6, respectively. Mast cells were most numerous in the lamina propria but were also frequent in the epithelial layer. We found that after intranasal administration of OVA+SEB, the degree of mast cell infiltration was significantly lower than that in groups B and C (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>C and D; p<0.05).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>Changes in airway goblet cell numbers in all groups are illustrated in <a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>. The numbers of goblet cells per high-power field (mean±SD) in groups A, B, C and D were 7.3±2.0, 11.8±3.4, 16.0±2.5 and 16.6±1.5, respectively. Our results showed that the number of goblet cells of the nasal mucosa increased significantly in the experimental groups (p<0.05). However, no significant difference in the degree of goblet cell hyperplasia was detected between groups C and D (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>C and D).<elsevierMultimedia ident="fig0025"></elsevierMultimedia>Masson's trichrome staining of nasal mucosa tissue revealed accumulation of collagen in groups B, C and D (<a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>). The subepithelial thicknesses (mean±SD) in groups A, B, C and D were 17.3±2.0, 48.2±5.6, 53.2±5.4 and 52.2±4.6μm.<elsevierMultimedia ident="fig0030"></elsevierMultimedia>DiscussionThe inflammatory response to intranasal delivery of HDM was characterised by infiltrate with a considerable proportion comprised of eosinophils and mast cells. Our data demonstrated that mast cells might play an important role in the generation of Th2 sensitisation and airway eosinophilic inflammation in C57BL/6 mice exposed to HDM extract in vivo. Yu and Chen<a class="elsevierStyleCrossRef" href="#bib0240">17</a> demonstrated that Der f could rapidly activate mast cells in mice. Der f could trigger the release of mMCP-1 in mice 30min after an intratracheal challenge, indicating an early activation of airway mucosal mast cells after an encounter with inhaled HDM allergens. In contrast, OVA did not activate mast cells in mice inoculated in a similar manner. Importantly, in Der f-challenged mice, the allergic features were significantly lower or absent after blocking the mast cells using sodium cromoglycate, a mast cell stabiliser. These data indicated that mast cells might be an important cell type during the initiation of Der f sensitisation in the airway.<a class="elsevierStyleCrossRef" href="#bib0240">17</a> Similarly, we found a significantly higher number of mast cells in the nasal mucosa in mice challenged with HDM compared to the OVA/SEB-treated group.In vivo activation of mast cells appears to be a critical step in the development of HDM-induced allergic inflammation. Upon activation, mast cells release pro-inflammatory mediators such as tryptase, histamine, serotonin, lipid mediators such as PGE2 and LTB4, and a vast range of interleukins.<a class="elsevierStyleCrossRefs" href="#bib0245">18–20</a> Mast cells might contribute to changes related to chronic allergy. Mast cells are major effector cells contributing to allergic conditions, but their precise involvement in HDM-induced allergic inflammation is unclear.Mast cells are involved in the pathophysiological process of CRSwNP.<a class="elsevierStyleCrossRefs" href="#bib0260">21–23</a> Interestingly, patients with nasal polyps sensitive to HDMs had higher tryptase, histamine and eosinophil cationic protein (ECP) levels in the nasal lavage fluid than patients without nasal polyps. ECP is a well-described and standardised marker of tissue eosinophilia and activation of eosinophils.<a class="elsevierStyleCrossRef" href="#bib0275">24</a> In the present study, nasal polypoid lesions in mice were characterised mainly by the presence of recruited effector cells—mast cells and eosinophils—typical of allergic inflammation. These results imply that mast cells along with eosinophils play potential roles in the development of nasal polyps.Although treatment with HDM alone recruited eosinophils and mast cells, inflammation was insufficient to create nasal polypoid lesions in the sinonasal tissue. Administration of low-dose SEB in underlying allergic inflammation induced nasal polypoid lesions with increased eosinophilic infiltration, which corresponds to a previous report.<a class="elsevierStyleCrossRef" href="#bib0175">4</a> Nasal exposure to staphylococcal enterotoxin enhances the development of allergic rhinitis in mice.<a class="elsevierStyleCrossRef" href="#bib0280">25</a> HDM-induced allergic airway inflammation in mice, in combination with SEB, is emerging as a physiologically relevant model for human CRSwNP; this model shares many of the features of human CRSwNP including tissue eosinophilia, goblet cell hyperplasia, epithelial thickening, and subepithelial fibrosis.In recent years it has become clear that airway epithelial cells, the first cells exposed to inhaled airborne allergens, play a role beyond passive barrier function, as they actively contribute to the induction of the allergic response. In particular, the release of interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP) from nasal epithelial cells in response to allergen induces the recruitment and the activation of dendritic cells, mast cells, basophils and eosinophils to promote Th2-biased airway inflammation.<a class="elsevierStyleCrossRefs" href="#bib0285">26–28</a> Studies on epithelial-derived cytokines in response to allergen challenge may lead to an understanding of the signalling pathways and the cellular feedback loops involved. Moreover, such studies may shed light on how the immune system senses HDM allergens and triggers aberrant inflammation.<a class="elsevierStyleCrossRef" href="#bib0300">29</a>Advances in the understanding of the pathophysiology of CRSwNP are made possible with animal models. In considering the use of mice, several distinct components need consideration: the allergen, the genetic background of the mice, the experimental approach and the outcome measures. BALB/c and C57BL/6 mice are the most widely used strains due to their well-characterised immunological responses.<a class="elsevierStyleCrossRefs" href="#bib0210">11,12,30</a> The dose of antigen used for sensitisation and the route of administration are important variables in the models. Although no mouse model fully mimics the full range of clinical manifestations of CRSwNP, many reproduce a collection of the features that characterise its most common forms.<a class="elsevierStyleCrossRef" href="#bib0310">31</a>The HDM challenge model of CRSwNP may increase our understanding of the basic mechanisms of allergic inflammation and the underlying immunological response, and specific questions can be addressed that are difficult to study in patients. In particular, further studies are planned to focus on the role of cytokines in the chronic airway changes associated with this model. Improved animal models that more closely reflect CRSwNP in relevant human systems will broaden our knowledge of the disease, and might help in the identification and evaluation of new therapeutic targets.Conflict of interestThe authors have no conflict of interest to declare.FundingThis work was supported by grant no 03-2014-0120 from the SNUH Research Fund, by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (0411-20130037), by the Education and Research Encouragement Fund of Seoul National University Hospital (2015), and by Research Resettlement Fund for the new faculty of Seoul National University.Ethical responsibilitiesProtection of human subjects and animals in researchProtection of human and animal subjects. The authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration.Patients’ data protectionConfidentiality of Data. The authors declare that no patient data appear in this article.Right to privacy and informed consentRight to privacy and informed consent. The authors declare that no patient data appear in this article." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres594880" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec609808" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Experimental animals" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Experimental protocols" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Histopathological analysis" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Immunohistochemical analysis for mast cells" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Quantitative determination of total IgE" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Statistical analyses" ] ] ] 4 => array:3 [ "identificador" => "sec0045" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "The formation of nasal polypoid lesions" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Inflammatory responses in the airway" ] ] ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of interest" ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Funding" ] 8 => array:3 [ "identificador" => "sec0075" "titulo" => "Ethical responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0080" "titulo" => "Protection of human subjects and animals in research" ] 1 => array:2 [ "identificador" => "sec0085" "titulo" => "Patients’ data protection" ] 2 => array:2 [ "identificador" => "sec0090" "titulo" => "Right to privacy and informed consent" ] ] ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-01-15" "fechaAceptado" => "2015-04-11" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec609808" "palabras" => array:9 [ 0 => "Nasal polyps" 1 => "Eosinophils" 2 => "Mast cells" 3 => "Animal model" 4 => "House dust mite" 5 => "Staphylococcus aureus enterotoxin B" 6 => "Rhinosinusitis" 7 => "Allergic rhinitis" 8 => "Ovalbumin" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundThe murine polyp model was developed previously using ovalbumin and Staphylococcus aureus enterotoxin B (SEB). Here, we established a model mimicking key aspects of chronic eosinophilic rhinosinusitis with nasal polyps using the house dust mite (HDM), a clinically relevant aeroallergen, co-administered with SEB. We assessed the inflammatory response and formation of nasal polypoid lesions in an experimental murine model using intranasal delivery of HDM and ovalbumin. MethodsAfter induction of HDM-induced allergic rhinosinusitis in C57BL/6 mice, SEB (10ng) was instilled into the nasal cavity of mice for eight weeks. Phosphate-buffered saline-challenged mice served as control. Histopathological changes were evaluated using haematoxylin and eosin for overall inflammation, Sirius red for eosinophils, and periodic acid–Schiff stain for goblet cells. The distribution of mast cells in mouse nasal tissue was determined by immunohistochemistry. Serum total IgE was measured using enzyme-linked immunosorbent assay. ResultsCompared to mice treated with HDM only, the HDM+SEB-treated mice demonstrated nasal polypoid lesion formation and a significant increase in the number of secretory cells and eosinophilic infiltration. Moreover, mice challenged intranasally with HDM showed highly abundant mast cells in the nasal mucosa. In contrast, OVA+SEB-challenged mice showed a significantly lower degree of mast cell infiltration. ConclusionWe established an in vivo model of chronic allergic rhinosinusitis with nasal polypoid lesions using HDM aeroallergen. This study demonstrated that the HDM+SEB-induced murine polyp model could be utilised as a suitable model for nasal polyps, especially with both eosinophil and mast cell infiltration." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3984 "Ancho" => 2673 "Tamanyo" => 757163 ] ] "descripcion" => array:1 [ "en" => "Development of allergic rhinosinusitis with nasal polypoid lesions in C57BL/6 mice. (A) Protocol for allergen sensitisation and administration of Staphylococcus aureus enterotoxin B. HDM, house dust mite; SEB, Staphylococcus aureus enterotoxin B; OVA, ovalbumin; PBS, phosphate buffered saline; i.p., intraperitoneal injection; i.n., intranasal instillation; W, week. (B) Mice in groups A, B, C and D were treated with PBS, HDM extract, HDM extract+SEB (10ng), and OVA (6%)+SEB (10ng), respectively. Nasal polypoid lesions (arrows) were detected only in groups C and D (haematoxylin and eosin stain, H&E). (C and D) Numbers of nasal polyps and epithelial disruptions were compared. *p<0.05, Mann–Whitney U test." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1925 "Ancho" => 2478 "Tamanyo" => 627500 ] ] "descripcion" => array:1 [ "en" => "Photographs of representative nasal polypoid lesions stained with H&E. Sinonasal tissue sections were examined microscopically to detect polypoid lesions. (A and B) Polyp-like lesions were observed in mice treated with HDM+SEB or OVA+SEB. Polypoid lesions were characterised mainly by the presence of eosinophils and mast cells. Simple protruding lesions (C) and eosinophilic infiltrates with Charcot–Leyden-like crystal formations (D) were also found. Scale bar=100μm." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 3239 "Ancho" => 2574 "Tamanyo" => 604256 ] ] "descripcion" => array:1 [ "en" => "Representative sections of eosinophilic infiltration and total IgE production. (A–D) The presence of eosinophils was detected in groups B, C and D. Increased numbers of eosinophils were observed in groups C and D, with no significant difference in eosinophil distributions between groups C and D. (E) The numbers of eosinophils infiltrating the nasal mucosa were counted based on the Sirius red-stained sections. Data are expressed as means±SD. (F) The level of total IgE from serum was measured by enzyme-linked immunosorbent assay (ELISA). Data are expressed as means±SEM. *p<0.05, compared to group A (control); #p<0.05, compared to group B (HDM); Mann–Whitney U test. Scale bar=100μm." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 3416 "Ancho" => 3166 "Tamanyo" => 835814 ] ] "descripcion" => array:1 [ "en" => "Increased infiltration of mast cells in house-dust-mite-induced polyp model. (A) Immunohistochemical detection of tryptase positive-mast cells in the nasal mucosa. (B) Mast cells were identified by their characteristic cytoplasmic granules using Giemsa staining. Mast cells were distributed throughout the lamina propria and also localised within the epithelium. (C and D) Groups B and C showed markedly denser distributions of mast cells than group D. Data are expressed as means±SD. *p<0.05, compared to group A (CTL); #p<0.05, compared to group C (HDM/SEB), Mann–Whitney U test). Scale bar=100μm." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 2667 "Ancho" => 2584 "Tamanyo" => 404762 ] ] "descripcion" => array:1 [ "en" => "Goblet cell hyperplasia in house-dust-mite-induced polyp model. (A–D) Representative photomicrographs of nasal mucosa sections of mice stained with periodic acid–Schiff (PAS). (E) Increased numbers of goblet cells in the experimental groups, especially in groups C and D. *p<0.05, compared to group A (CTL); Mann–Whitney U test. Data are expressed as means±SD. Scale bar=100μm." ] ] 5 => array:7 [ "identificador" => "fig0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 3324 "Ancho" => 2666 "Tamanyo" => 676911 ] ] "descripcion" => array:1 [ "en" => "Comparison of subepithelial thicknesses among the groups. (A–E) Masson's trichrome staining showed that groups B, C and D had increased subepithelial collagen deposition compared with control. *p<0.05, compared to group A (CTL); Mann–Whitney U test. Data are expressed as means±SD. 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R. Khalmuratovaa, M. Leea,b, D.W. Kimc, J.-W. Parka,b, H.-W. Shina,d,

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charlie@snu.ac.kr

Corresponding author.

a Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea

b Department of Biomedical Science, Ischemic/Hypoxic Disease Institute, Seoul National University Graduate School, Seoul, Republic of Korea

c Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul, Republic of Korea

d Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Republic of Korea

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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Representative sections of eosinophilic infiltration and total IgE production&#46; &#40;A&#8211;D&#41; The presence of eosinophils was detected in groups B&#44; C and D&#46; Increased numbers of eosinophils were observed in groups C and D&#44; with no significant difference in eosinophil distributions between groups C and D&#46; &#40;E&#41; The numbers of eosinophils infiltrating the nasal mucosa were counted based on the Sirius red-stained sections&#46; Data are expressed as means<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#46; &#40;F&#41; The level of total IgE from serum was measured by enzyme-linked immunosorbent assay &#40;ELISA&#41;&#46; Data are expressed as means<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SEM&#46; &#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; compared to group A &#40;control&#41;&#59; &#35;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; compared to group B &#40;HDM&#41;&#59; Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test&#46; Scale bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>&#956;m&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic rhinosinusitis &#40;CRS&#41; encompasses a heterogeneous group of disorders defined by the inflammation of the paranasal sinuses and represents a significant health problem worldwide&#46; CRS has been categorised typically as CRS with nasal polyps &#40;CRSwNP&#41; and without nasal polyps &#40;CRSsNP&#41; based on endoscopic examination findings&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">1&#44;2</span></a> CRSwNP is characterised by inflammatory cell infiltration and structural modifications of the epithelium &#40;secretary hyperplasia and squamous metaplasia&#41; and lamina propria &#40;basement membrane thickening&#44; extracellular matrix accumulation and fibrosis&#41;&#46; However&#44; the underlying mechanisms interlinking these pathological conditions to nasal polyp formation remain unclear&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">To date&#44; murine studies investigating CRS have employed systemic sensitisation and intranasal challenge with ovalbumin &#40;OVA&#41;&#46; Chronic challenge models in mice involve repeated exposure to antigen for up to 12 weeks&#46; Low-dose <span class="elsevierStyleItalic">Staphylococcal</span> enterotoxin B &#40;SEB&#41; induced nasal polypoid lesions with increased eosinophilic infiltration in an allergic rhinosinusitis model&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">4</span></a> OVA challenge models of CRSwNP offer opportunities for increasing our understanding of the pathogenesis underlying this disease&#44; as well as for identifying novel therapeutic targets&#44; although more relevant allergens such as the house dust mite &#40;HDM&#41; may also be considered&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The HDM is ubiquitous in human habitats and is a significant factor underlying allergic rhinitis and allergic asthma&#46; These features make it one of the important sources of indoor allergens&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">7&#44;8</span></a> The predominant HDMs isolated from dust samples are <span class="elsevierStyleItalic">Dermatophagoides pteronyssinus</span> &#40;Der p&#41; and <span class="elsevierStyleItalic">Dermatophagoides farinae</span> &#40;Der f&#41;&#46; Although HDM extracts are complex from an immunological perspective&#44; they are ultimately more representative of real-life aeroallergen exposure&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">9&#44;10</span></a> Recently&#44; common parameters of airway allergy such as airway inflammation&#44; Th2 cytokine production and elevated Der f-specific IgE levels were shown in an intranasal HDM sensitisation mouse model&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">11&#8211;13</span></a> Despite the high prevalence of HDM allergy&#44; the cellular and molecular networks that initiate and regulate this Th2-biased response have been investigated using only the OVA-induced polyp model&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">14</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In this study&#44; we established a model mimicking key aspects of CRSwNP using the clinically relevant aeroallergen HDM with co-administration of SEB&#46; Additionally&#44; we compared the immune-inflammatory and nasal polyp formation responses to intranasal delivery of HDM extract and OVA in the experimental murine model&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Experimental animals</span><p id="par0025" class="elsevierStylePara elsevierViewall">Eighteen male C57BL&#47;6 mice &#40;4 weeks of age&#59; 20&#8211;25<span class="elsevierStyleHsp" style=""></span>g each&#41; were purchased from Central Laboratory Animal&#44; Inc&#46; &#40;Seoul&#44; Korea&#41; and housed for one week before initiating experiments&#46; The animals were kept in a pathogen-free biohazard containment facility maintained at 22&#8211;24<span class="elsevierStyleHsp" style=""></span>&#176;C and 50&#8211;60&#37; humidity&#46; All experimental protocols complied with the Guidelines of the National Institute of Health and the Declaration of Helsinki&#44; and were approved by the Committee on the Use and Care of Animals &#40;SNU-140429-10&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Experimental protocols</span><p id="par0030" class="elsevierStylePara elsevierViewall">The experimental protocol was designed as described previously with some modifications &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">4&#44;12</span></a> The mice were categorised into a control group &#40;group A&#59; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41; and three experimental groups &#40;B&#44; C&#44; and D&#59; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5 each&#41;&#46; Purified HDM extract from species Der f &#40;GREER Laboratories&#44; Lenoir&#44; NC&#44; USA&#41; was used in this study&#46; Mice in experimental groups B and C were immunised intradermally at the base of the tail with 100<span class="elsevierStyleHsp" style=""></span>&#956;g of HDM extract dissolved in phosphate-buffered saline &#40;PBS&#41; and 100<span class="elsevierStyleHsp" style=""></span>&#956;L of complete Freund&#39;s adjuvant &#40;CFA&#44; Sigma&#44; St&#46; Louis&#44; MO&#44; USA&#41; on days 0 and 5&#46; The mice in experimental group D were systemically sensitised by intraperitoneal injection with 25<span class="elsevierStyleHsp" style=""></span>&#956;g of OVA &#40;Grade V&#59; Sigma&#44; St&#46; Louis&#44; MO&#44; USA&#41; dissolved in 300<span class="elsevierStyleHsp" style=""></span>mL of PBS in the presence of 2<span class="elsevierStyleHsp" style=""></span>mg of aluminium hydroxide gel adjuvant&#46; Seven days after the last immunisation&#44; mice were challenged intranasally with 20-&#956;g HDM extract dissolved in 40-&#956;L PBS &#40;groups B and C&#41; or 6&#37; OVA in 40<span class="elsevierStyleHsp" style=""></span>&#956;L of PBS &#40;group D&#41;&#44; and treated daily for seven days&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Prolonged continuous inflammation was maintained in the experimental groups by subsequent nasal treatment with 20-&#956;g HDM extract or 6&#37; OVA three times weekly for 12 consecutive weeks&#46; Additionally&#44; selected mice in groups C and D were challenged three times weekly with 10<span class="elsevierStyleHsp" style=""></span>ng of SEB &#40;List Biological laboratories&#44; INC&#44; CA&#44; USA&#41; diluted in PBS from the 5th week to the 12th week&#46; PBS was applied for both systemic and local stimulation in group A &#40;control&#41;&#46; Mice were sacrificed 24<span class="elsevierStyleHsp" style=""></span>h after the last intranasal administration&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Histopathological analysis</span><p id="par0040" class="elsevierStylePara elsevierViewall">The mice were euthanised and decapitated&#46; The heads of the animals were stripped of skin&#44; eyes and muscle&#44; and the mandibles were excised&#46; The tissues were immersed overnight in 4&#37; paraformaldehyde and decalcified in 5&#37; nitric acid for 4&#8211;5 days at 4<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; The specimens were dehydrated and processed according to standard paraffin-embedding procedures&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">15</span></a> Tissues were then cut into 3-&#956;m-thick coronal sections&#46; An atlas of normal murine sinonasal anatomy was used to standardise the anatomic locations being examined&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">16</span></a> The histological changes in the nasal mucosa were determined by haematoxylin and eosin &#40;H&#38;E&#41; for overall inflammation&#44; Sirius red for eosinophils&#44; periodic acid&#8211;Schiff &#40;PAS&#41; stain for goblet cells&#44; and Masson&#39;s trichrome stain for collagen deposition in the subepithelial layer&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">To determine the degree of inflammation&#44; the sections were examined with a light microscope &#40;400&#215; magnification&#41;&#44; and two individuals independently counted the number of eosinophils&#44; mast cells and goblet cells in the nasal mucosa in four fields&#46; The results of inflammatory and goblet cells were expressed as cells per high-power field&#46; Subepithelial thickness was measured from four mucosal sampling areas under a high-power field &#40;400&#215; magnification&#41;&#46; Three consecutive slides were reviewed to rule-out processing errors&#46; Polyp-like lesions were defined as distinct mucosal elevations with eosinophilic infiltration and&#47;or microcavity formation &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A and B&#41;&#46; Polypoid lesions and epithelial disruption were counted microscopically and expressed as a total number&#46; Simple protruded lesions were not regarded as polyp-like lesions &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>C&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Immunohistochemical analysis for mast cells</span><p id="par0050" class="elsevierStylePara elsevierViewall">Immunohistochemistry &#40;IHC&#41; was performed to identify the presence of mast cells&#46; IHC staining was performed using the polink-2<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>polymerised horseradish peroxidase &#40;HRP&#41; broad DAB Detection System &#40;Golden Bridge International Labs&#44; WA&#44; USA&#41;&#46; Briefly&#44; tissue sections were deparaffinised&#44; rehydrated and treated with 3&#37; hydrogen peroxide in methanol to quench endogenous peroxidase activity&#46; Heat-induced epitope retrieval was then performed by microwaving the samples in 10<span class="elsevierStyleHsp" style=""></span>mmol&#47;L citrate buffer &#40;pH 6&#46;0&#41;&#46; The sections were incubated for 1<span class="elsevierStyleHsp" style=""></span>h at room temperature with primary antibody against mast cell tryptase &#40;1&#58;100&#44; Abcam&#44; Cambridge&#44; MA&#44; USA&#41;&#46; The sections were incubated in broad antibody enhancer and polymer-HRP and then stained with the DAB Detection System&#46; Sections were counterstained with Gill&#39;s haematoxylin and dehydrated through a graded ethanol series&#44; cleared with xylene&#44; and coverslipped with mountant&#46; Negative controls were obtained by omitting the primary antibody&#46; To confirm mast cells&#44; Giemsa staining was also performed according to standard procedures&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Quantitative determination of total IgE</span><p id="par0055" class="elsevierStylePara elsevierViewall">Blood was collected via cardiac puncture 24<span class="elsevierStyleHsp" style=""></span>h after the last intranasal administration&#46; The blood was centrifuged&#44; and the serum was stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C for the measurement of IgE&#46; Serum samples from three animals per group were analysed&#46; Quantitative assessments of total IgE were performed using an enzyme-linked immunosorbent assay &#40;ELISA&#41; kit purchased from BioLegend &#40;San Diego&#44; CA&#44; USA&#41;&#46; The sensitivity of total IgE was 0&#46;1<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46; All procedures were performed according to the manufacturer&#39;s instructions&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Statistical analyses</span><p id="par0060" class="elsevierStylePara elsevierViewall">Data are expressed as means<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#46; The Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span>-test was performed to compare the number of eosinophils&#44; mast cells&#44; goblet cells and subepithelial thicknesses between the groups&#46; Statistical analyses and data plotting were performed using SigmaPlot &#40;version 10&#44; Richmond&#44; CA&#44; USA&#41;&#46; A value of <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 was considered to indicate statistical significance&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">The formation of nasal polypoid lesions</span><p id="par0065" class="elsevierStylePara elsevierViewall">No polyp-like lesions were observed in groups A and B &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46; Polypoid lesions were found only in mice that received SEB intranasally &#40;groups C and D&#41;&#46; Five lesions were observed in three of five mice in group C &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#41;&#46; Similarly&#44; six lesions were evident in four of five mice in group D &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>D&#41;&#46; Thickened mucosae with polyp-like lesions were observed primarily at the transition zone of the olfactory and respiratory epithelia&#46; Morphological changes such as secretory hyperplasia as well as eosinophilic infiltrates with Charcot&#8211;Leyden-like crystal formations were observed in the epithelial lining of nasal polyps &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Epithelial disruptions as well as polypoid lesions were found more often in the group treated with OVA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C and D&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Inflammatory responses in the airway</span><p id="par0070" class="elsevierStylePara elsevierViewall">Intranasal delivery of HDM extract alone or HDM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB elicited robust inflammatory responses in the airways of mice&#44; which was clearly evident histopathologically&#46; Therefore&#44; we next characterised the inflammatory cells in the nasal mucosa&#46; The magnitude of the inflammatory response was estimated by the number of inflammatory cells recruited into the tissue&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#44; HDM only or HDM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB treatment induced tissue inflammation in the nasal mucosa&#44; and the inflammatory infiltrate was composed mainly of eosinophils&#46; The numbers of eosinophils per high-power field in groups A&#44; B&#44; C and D were 1&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#44; 42&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;6&#44; 55&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;5&#44; and 62&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;5&#44; respectively&#46; Mice challenged with HDM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB and OVA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB exhibited significantly higher numbers of tissue eosinophils than mice challenged with HDM only &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; whereas no significant difference was detected between mice treated with HDM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB and OVA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB&#46; In addition&#44; the total serum IgE levels were elevated markedly in the three experimental groups&#44; with no significant difference among groups B&#44; C and D &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>F&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">The distribution of mast cells in nasal tissue sample in mice was determined by IHC &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; The numbers of tryptase-positive mast cells per high-power field &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; in groups A&#44; B&#44; C and D were 1&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#44; 12&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;0&#44; 14&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;5 and 4&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#44; respectively&#46; Similarly&#44; Giemsa staining of the nasal tissue sections revealed abundant mast cells after instillation with HDM or HDM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB&#44; but an absence of mast cells in the airways of PBS-treated mice&#46; The numbers of mast cells per high-power field &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; in groups A&#44; B&#44; C and D were 0&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;0&#44; 19&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;1&#44; 19&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;3 and 5&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6&#44; respectively&#46; Mast cells were most numerous in the lamina propria but were also frequent in the epithelial layer&#46; We found that after intranasal administration of OVA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB&#44; the degree of mast cell infiltration was significantly lower than that in groups B and C &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>C and D&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">Changes in airway goblet cell numbers in all groups are illustrated in <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#46; The numbers of goblet cells per high-power field &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; in groups A&#44; B&#44; C and D were 7&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;0&#44; 11&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;4&#44; 16&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;5 and 16&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;5&#44; respectively&#46; Our results showed that the number of goblet cells of the nasal mucosa increased significantly in the experimental groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; However&#44; no significant difference in the degree of goblet cell hyperplasia was detected between groups C and D &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>C and D&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Masson&#39;s trichrome staining of nasal mucosa tissue revealed accumulation of collagen in groups B&#44; C and D &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>&#41;&#46; The subepithelial thicknesses &#40;mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#41; in groups A&#44; B&#44; C and D were 17&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;0&#44; 48&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;6&#44; 53&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;4 and 52&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;6<span class="elsevierStyleHsp" style=""></span>&#956;m&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">The inflammatory response to intranasal delivery of HDM was characterised by infiltrate with a considerable proportion comprised of eosinophils and mast cells&#46; Our data demonstrated that mast cells might play an important role in the generation of Th2 sensitisation and airway eosinophilic inflammation in C57BL&#47;6 mice exposed to HDM extract in vivo&#46; Yu and Chen<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">17</span></a> demonstrated that Der f could rapidly activate mast cells in mice&#46; Der f could trigger the release of mMCP-1 in mice 30<span class="elsevierStyleHsp" style=""></span>min after an intratracheal challenge&#44; indicating an early activation of airway mucosal mast cells after an encounter with inhaled HDM allergens&#46; In contrast&#44; OVA did not activate mast cells in mice inoculated in a similar manner&#46; Importantly&#44; in Der f-challenged mice&#44; the allergic features were significantly lower or absent after blocking the mast cells using sodium cromoglycate&#44; a mast cell stabiliser&#46; These data indicated that mast cells might be an important cell type during the initiation of Der f sensitisation in the airway&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">17</span></a> Similarly&#44; we found a significantly higher number of mast cells in the nasal mucosa in mice challenged with HDM compared to the OVA&#47;SEB-treated group&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">In vivo activation of mast cells appears to be a critical step in the development of HDM-induced allergic inflammation&#46; Upon activation&#44; mast cells release pro-inflammatory mediators such as tryptase&#44; histamine&#44; serotonin&#44; lipid mediators such as PGE2 and LTB4&#44; and a vast range of interleukins&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">18&#8211;20</span></a> Mast cells might contribute to changes related to chronic allergy&#46; Mast cells are major effector cells contributing to allergic conditions&#44; but their precise involvement in HDM-induced allergic inflammation is unclear&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Mast cells are involved in the pathophysiological process of CRSwNP&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">21&#8211;23</span></a> Interestingly&#44; patients with nasal polyps sensitive to HDMs had higher tryptase&#44; histamine and eosinophil cationic protein &#40;ECP&#41; levels in the nasal lavage fluid than patients without nasal polyps&#46; ECP is a well-described and standardised marker of tissue eosinophilia and activation of eosinophils&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">24</span></a> In the present study&#44; nasal polypoid lesions in mice were characterised mainly by the presence of recruited effector cells&#8212;mast cells and eosinophils&#8212;typical of allergic inflammation&#46; These results imply that mast cells along with eosinophils play potential roles in the development of nasal polyps&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Although treatment with HDM alone recruited eosinophils and mast cells&#44; inflammation was insufficient to create nasal polypoid lesions in the sinonasal tissue&#46; Administration of low-dose SEB in underlying allergic inflammation induced nasal polypoid lesions with increased eosinophilic infiltration&#44; which corresponds to a previous report&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">4</span></a> Nasal exposure to staphylococcal enterotoxin enhances the development of allergic rhinitis in mice&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">25</span></a> HDM-induced allergic airway inflammation in mice&#44; in combination with SEB&#44; is emerging as a physiologically relevant model for human CRSwNP&#59; this model shares many of the features of human CRSwNP including tissue eosinophilia&#44; goblet cell hyperplasia&#44; epithelial thickening&#44; and subepithelial fibrosis&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In recent years it has become clear that airway epithelial cells&#44; the first cells exposed to inhaled airborne allergens&#44; play a role beyond passive barrier function&#44; as they actively contribute to the induction of the allergic response&#46; In particular&#44; the release of interleukin &#40;IL&#41;-25&#44; IL-33 and thymic stromal lymphopoietin &#40;TSLP&#41; from nasal epithelial cells in response to allergen induces the recruitment and the activation of dendritic cells&#44; mast cells&#44; basophils and eosinophils to promote Th2-biased airway inflammation&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">26&#8211;28</span></a> Studies on epithelial-derived cytokines in response to allergen challenge may lead to an understanding of the signalling pathways and the cellular feedback loops involved&#46; Moreover&#44; such studies may shed light on how the immune system senses HDM allergens and triggers aberrant inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">29</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Advances in the understanding of the pathophysiology of CRSwNP are made possible with animal models&#46; In considering the use of mice&#44; several distinct components need consideration&#58; the allergen&#44; the genetic background of the mice&#44; the experimental approach and the outcome measures&#46; BALB&#47;c and C57BL&#47;6 mice are the most widely used strains due to their well-characterised immunological responses&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">11&#44;12&#44;30</span></a> The dose of antigen used for sensitisation and the route of administration are important variables in the models&#46; Although no mouse model fully mimics the full range of clinical manifestations of CRSwNP&#44; many reproduce a collection of the features that characterise its most common forms&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">31</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The HDM challenge model of CRSwNP may increase our understanding of the basic mechanisms of allergic inflammation and the underlying immunological response&#44; and specific questions can be addressed that are difficult to study in patients&#46; In particular&#44; further studies are planned to focus on the role of cytokines in the chronic airway changes associated with this model&#46; Improved animal models that more closely reflect CRSwNP in relevant human systems will broaden our knowledge of the disease&#44; and might help in the identification and evaluation of new therapeutic targets&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflict of interest</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Funding</span><p id="par0135" class="elsevierStylePara elsevierViewall">This work was supported by grant no <span class="elsevierStyleGrantNumber" refid="gs1">03-2014-0120</span> from the <span class="elsevierStyleGrantSponsor" id="gs1">SNUH Research Fund</span>&#44; by Basic Science Research Program through the <span class="elsevierStyleGrantSponsor" id="gs2">National Research Foundation of Korea</span> &#40;NRF&#41; funded by the Ministry of Science&#44; ICT and Future Planning &#40;<span class="elsevierStyleGrantNumber" refid="gs2">0411-20130037</span>&#41;&#44; by the <span class="elsevierStyleGrantSponsor" id="gs3">Education and Research Encouragement Fund of Seoul National University Hospital</span> &#40;2015&#41;&#44; and by Research Resettlement Fund for the new faculty of <span class="elsevierStyleGrantSponsor" id="gs4">Seoul National University</span>&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Ethical responsibilities</span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Protection of human subjects and animals in research</span><p id="par0140" class="elsevierStylePara elsevierViewall">Protection of human and animal subjects&#46; The authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Patients&#8217; data protection</span><p id="par0145" class="elsevierStylePara elsevierViewall">Confidentiality of Data&#46; The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Right to privacy and informed consent</span><p id="par0150" class="elsevierStylePara elsevierViewall">Right to privacy and informed consent&#46; The authors declare that no patient data appear in this article&#46;</p></span></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Methods"
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              "titulo" => "Histopathological analysis"
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              "identificador" => "sec0030"
              "titulo" => "Immunohistochemical analysis for mast cells"
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            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Quantitative determination of total IgE"
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            5 => array:2 [
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              "titulo" => "Statistical analyses"
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          "titulo" => "Results"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "The formation of nasal polypoid lesions"
            ]
            1 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Inflammatory responses in the airway"
            ]
          ]
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        5 => array:2 [
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          "titulo" => "Discussion"
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          "titulo" => "Ethical responsibilities"
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              "titulo" => "Protection of human subjects and animals in research"
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              "titulo" => "Patients&#8217; data protection"
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        9 => array:1 [
          "titulo" => "References"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec609808"
          "palabras" => array:9 [
            0 => "Nasal polyps"
            1 => "Eosinophils"
            2 => "Mast cells"
            3 => "Animal model"
            4 => "House dust mite"
            5 => "<span class="elsevierStyleItalic">Staphylococcus aureus</span> enterotoxin B"
            6 => "Rhinosinusitis"
            7 => "Allergic rhinitis"
            8 => "Ovalbumin"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The murine polyp model was developed previously using ovalbumin and <span class="elsevierStyleItalic">Staphylococcus aureus</span> enterotoxin B &#40;SEB&#41;&#46; Here&#44; we established a model mimicking key aspects of chronic eosinophilic rhinosinusitis with nasal polyps using the house dust mite &#40;HDM&#41;&#44; a clinically relevant aeroallergen&#44; co-administered with SEB&#46; We assessed the inflammatory response and formation of nasal polypoid lesions in an experimental murine model using intranasal delivery of HDM and ovalbumin&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">After induction of HDM-induced allergic rhinosinusitis in C57BL&#47;6 mice&#44; SEB &#40;10<span class="elsevierStyleHsp" style=""></span>ng&#41; was instilled into the nasal cavity of mice for eight weeks&#46; Phosphate-buffered saline-challenged mice served as control&#46; Histopathological changes were evaluated using haematoxylin and eosin for overall inflammation&#44; Sirius red for eosinophils&#44; and periodic acid&#8211;Schiff stain for goblet cells&#46; The distribution of mast cells in mouse nasal tissue was determined by immunohistochemistry&#46; Serum total IgE was measured using enzyme-linked immunosorbent assay&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Compared to mice treated with HDM only&#44; the HDM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB-treated mice demonstrated nasal polypoid lesion formation and a significant increase in the number of secretory cells and eosinophilic infiltration&#46; Moreover&#44; mice challenged intranasally with HDM showed highly abundant mast cells in the nasal mucosa&#46; In contrast&#44; OVA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB-challenged mice showed a significantly lower degree of mast cell infiltration&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">We established an in vivo model of chronic allergic rhinosinusitis with nasal polypoid lesions using HDM aeroallergen&#46; This study demonstrated that the HDM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB-induced murine polyp model could be utilised as a suitable model for nasal polyps&#44; especially with both eosinophil and mast cell infiltration&#46;</p></span>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Development of allergic rhinosinusitis with nasal polypoid lesions in C57BL&#47;6 mice&#46; &#40;A&#41; Protocol for allergen sensitisation and administration of <span class="elsevierStyleItalic">Staphylococcus aureus</span> enterotoxin B&#46; HDM&#44; house dust mite&#59; SEB&#44; <span class="elsevierStyleItalic">Staphylococcus aureus</span> enterotoxin B&#59; OVA&#44; ovalbumin&#59; PBS&#44; phosphate buffered saline&#59; i&#46;p&#46;&#44; intraperitoneal injection&#59; i&#46;n&#46;&#44; intranasal instillation&#59; W&#44; week&#46; &#40;B&#41; Mice in groups A&#44; B&#44; C and D were treated with PBS&#44; HDM extract&#44; HDM extract<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB &#40;10<span class="elsevierStyleHsp" style=""></span>ng&#41;&#44; and OVA &#40;6&#37;&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB &#40;10<span class="elsevierStyleHsp" style=""></span>ng&#41;&#44; respectively&#46; Nasal polypoid lesions &#40;arrows&#41; were detected only in groups C and D &#40;haematoxylin and eosin stain&#44; H&#38;E&#41;&#46; &#40;C and D&#41; Numbers of nasal polyps and epithelial disruptions were compared&#46; &#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1925
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Photographs of representative nasal polypoid lesions stained with H&#38;E&#46; Sinonasal tissue sections were examined microscopically to detect polypoid lesions&#46; &#40;A and B&#41; Polyp-like lesions were observed in mice treated with HDM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB or OVA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SEB&#46; Polypoid lesions were characterised mainly by the presence of eosinophils and mast cells&#46; Simple protruding lesions &#40;C&#41; and eosinophilic infiltrates with Charcot&#8211;Leyden-like crystal formations &#40;D&#41; were also found&#46; Scale bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>&#956;m&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 3239
            "Ancho" => 2574
            "Tamanyo" => 604256
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Representative sections of eosinophilic infiltration and total IgE production&#46; &#40;A&#8211;D&#41; The presence of eosinophils was detected in groups B&#44; C and D&#46; Increased numbers of eosinophils were observed in groups C and D&#44; with no significant difference in eosinophil distributions between groups C and D&#46; &#40;E&#41; The numbers of eosinophils infiltrating the nasal mucosa were counted based on the Sirius red-stained sections&#46; Data are expressed as means<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#46; &#40;F&#41; The level of total IgE from serum was measured by enzyme-linked immunosorbent assay &#40;ELISA&#41;&#46; Data are expressed as means<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SEM&#46; &#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; compared to group A &#40;control&#41;&#59; &#35;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; compared to group B &#40;HDM&#41;&#59; Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test&#46; Scale bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>&#956;m&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 3416
            "Ancho" => 3166
            "Tamanyo" => 835814
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Increased infiltration of mast cells in house-dust-mite-induced polyp model&#46; &#40;A&#41; Immunohistochemical detection of tryptase positive-mast cells in the nasal mucosa&#46; &#40;B&#41; Mast cells were identified by their characteristic cytoplasmic granules using Giemsa staining&#46; Mast cells were distributed throughout the lamina propria and also localised within the epithelium&#46; &#40;C and D&#41; Groups B and C showed markedly denser distributions of mast cells than group D&#46; Data are expressed as means<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#46; &#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; compared to group A &#40;CTL&#41;&#59; &#35;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; compared to group C &#40;HDM&#47;SEB&#41;&#44; Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test&#41;&#46; Scale bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>&#956;m&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "fig0025"
        "etiqueta" => "Figure 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 2667
            "Ancho" => 2584
            "Tamanyo" => 404762
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Goblet cell hyperplasia in house-dust-mite-induced polyp model&#46; &#40;A&#8211;D&#41; Representative photomicrographs of nasal mucosa sections of mice stained with periodic acid&#8211;Schiff &#40;PAS&#41;&#46; &#40;E&#41; Increased numbers of goblet cells in the experimental groups&#44; especially in groups C and D&#46; &#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; compared to group A &#40;CTL&#41;&#59; Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test&#46; Data are expressed as means<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#46; Scale bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>&#956;m&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "fig0030"
        "etiqueta" => "Figure 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr6.jpeg"
            "Alto" => 3324
            "Ancho" => 2666
            "Tamanyo" => 676911
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Comparison of subepithelial thicknesses among the groups&#46; &#40;A&#8211;E&#41; Masson&#39;s trichrome staining showed that groups B&#44; C and D had increased subepithelial collagen deposition compared with control&#46; &#42;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; compared to group A &#40;CTL&#41;&#59; Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test&#46; Data are expressed as means<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#46; Scale bar<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>&#956;m&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
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                          "etal" => true
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                            0 => "D&#46;W&#46; Kim"
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                        0 => array:2 [
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                            0 => "S&#46;W&#46; Kim"
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                            2 => "R&#46; Khalmuratova"
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                  "contribucion" => array:1 [
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                        0 => array:2 [
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                            0 => "M&#46;A&#46; Calderon"
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                  "contribucion" => array:1 [
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                      "autores" => array:1 [
                        0 => array:2 [
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                            0 => "V&#46;D&#46; Gandhi"
                            1 => "C&#46; Davidson"
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
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                            0 => "E&#46;C&#46; Cates"
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                      ]
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                  ]
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                    0 => array:1 [
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Article information

ISSN: 03010546
Original language: English

DOI:10.1016/j.aller.2015.04.004

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	13	0	13
2024 October	21	13	34
2024 September	24	16	40
2024 August	22	27	49
2024 July	26	13	39
2024 June	24	20	44
2024 May	24	15	39
2024 April	22	13	35
2024 March	43	19	62
2024 February	42	18	60
2024 January	60	9	69
2023 December	61	13	74
2023 November	57	21	78
2023 October	85	20	105
2023 September	34	13	47
2023 August	40	28	68
2023 July	55	9	64
2023 June	74	24	98
2023 May	105	16	121
2023 April	76	6	82
2023 March	58	9	67
2023 February	52	13	65
2023 January	41	10	51
2022 December	74	11	85
2022 November	47	12	59
2022 October	56	18	74
2022 September	44	43	87
2022 August	40	28	68
2022 July	28	34	62
2022 June	27	17	44
2022 May	26	20	46
2022 April	43	29	72
2022 March	48	22	70
2022 February	29	12	41
2022 January	72	32	104
2021 December	58	28	86
2021 November	46	36	82
2021 October	96	42	138
2021 September	77	37	114
2021 August	39	33	72
2021 July	53	49	102
2021 June	42	38	80
2021 May	39	37	76
2021 April	101	113	214
2021 March	47	86	133
2021 February	28	69	97
2021 January	74	52	126
2020 December	3	21	24
2020 November	0	20	20
2020 October	0	16	16
2020 September	0	12	12
2020 August	0	12	12
2020 July	0	6	6
2020 June	0	26	26
2020 May	0	6	6
2020 April	0	5	5
2020 March	0	6	6
2020 February	0	7	7
2020 January	0	7	7
2019 December	0	13	13
2019 November	0	6	6
2019 October	0	8	8
2019 September	0	6	6
2019 August	0	4	4
2019 July	0	3	3
2019 June	0	18	18
2019 May	0	54	54
2019 April	0	53	53
2019 March	0	11	11
2019 February	0	6	6
2019 January	0	11	11
2018 December	0	9	9
2018 November	0	3	3
2018 September	0	2	2
2018 August	0	3	3
2018 June	0	6	6
2018 May	0	1	1
2018 March	4	1	5
2018 February	27	11	38
2018 January	27	4	31
2017 December	32	6	38
2017 November	28	21	49
2017 October	37	5	42
2017 September	27	14	41
2017 August	33	11	44
2017 July	35	13	48
2017 June	42	20	62
2017 May	53	14	67
2017 April	66	13	79
2017 March	164	35	199
2017 February	57	17	74
2017 January	32	16	48
2016 December	47	17	64
2016 November	24	16	40
2016 October	0	1	1
2016 September	0	6	6
2016 July	0	1	1
2016 June	0	3	3
2016 May	0	1	1
2016 April	1	0	1
2016 March	1	3	4
2016 February	1	0	1
2016 January	1	0	1

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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

Indexed in:

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