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Masterson J.C.,Digestive Health Institute | Masterson J.C.,University of Colorado at Denver | McNamee E.N.,University of Colorado at Denver | Hosford L.,Digestive Health Institute | And 15 more authors.
Gut | Year: 2014

Objective Eosinophilic oesophagitis (EoE) is a chronic inflammatory condition of the oesophagus with limited treatment options. No previous transgenic model has specifically targeted the oesophageal mucosa to induce oesophageal eosinophilia. Design We developed a mouse model that closely resembles EoE by utilising oxazolone haptenation in mice with transgenic overexpression of an eosinophil poietic and survival factor (interleukin (IL)-5) in resident squamous oesophageal epithelia. Results Overexpression of IL-5 in the healthy oesophagus was achieved in transgenic mice (L2-IL5) using the squamous epithelial promoter Epstein-Barr virus ED-L2. Oxazolone-challenged L2-IL5 mice developed dose-dependent pan-oesophageal eosinophilia, including eosinophil microabscess formation and degranulation as well as basal cell hyperplasia. Moreover, oesophagi expressed increased IL-13 and the eosinophil agonist chemokine eotaxin-1. Treatment of these mice with corticosteroids significantly reduced eosinophilia and epithelial inflammation. Conclusions L2-IL5 mice provide a novel experimental model that can potentially be used in preclinical testing of EoE-related therapeutics and mechanistic studies identifying pathogenetic features associated with mucosal eosinophilia.

Furuta G.T.,Digestive Health Institute | Furuta G.T.,Aurora University | Furuta G.T.,University of Colorado at Denver | Atkins F.D.,Gastrointestinal Eosinophilic Diseases Program | And 3 more authors.
Annals of Allergy, Asthma and Immunology | Year: 2014

Objective To review and highlight the unappreciated roles of eosinophils suggested by recent studies. Data Sources The literature, unpublished observations, and insights by the authors. Study Selections Basic studies of mouse models and patient-based clinical studies of disease. Results Eosinophils are often thought of as destructive end-stage effector cells primarily linked to parasite host defense and dysregulated immune responses associated with allergic diseases, such as asthma. However, recent studies (ie, research focused on mechanisms of action and translational studies examining disease/inflammatory pathways) are suggesting far more complex roles for eosinophils. The goal of this review is 3-fold. (1) The authors examine the dynamic history of eosinophils and how physicians over time used this information to formulate defining hypotheses. Particular emphasis is placed on recent studies challenging the parochial view of host defense in favor of roles maintaining homeostasis through immune modulation and tissue remodeling/repair. (2) They discuss diagnostic approaches to assess eosinophils in clinical settings as a means of disease identification and subsequently as a measurement of disease severity. (3) They examine how contemporary views of eosinophils and their perceived roles in diseases have led to specific therapeutic strategies. The emphasis is to review the successes and failures of these strategies as the basis of formulating future clinical studies targeting eosinophils as potential therapies of disease. Conclusion Despite the complexities of eosinophil-mediated activities and the less than overwhelming success of initial attempts targeting these cells, eosinophils remain a potentially important focal target of disease diagnosis and subsequent treatment strategies. © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Saeedi B.J.,Mucosal Inflammation Program | Kao D.J.,Mucosal Inflammation Program | Kitzenberg D.A.,Mucosal Inflammation Program | Dobrinskikh E.,Gastrointestinal Eosinophilic Diseases Program | And 12 more authors.
Molecular Biology of the Cell | Year: 2015

Intestinal epithelial cells (IECs) are exposed to profound fluctuations in oxygen tension and have evolved adaptive transcriptional responses to a low-oxygen environment. These adaptations are mediated primarily through the hypoxia-inducible factor (HIF) complex. Given the central role of the IEC in barrier function, we sought to determine whether HIF influenced epithelial tight junction (TJ) structure and function. Initial studies revealed that short hairpin RNA-mediated depletion of the HIF1β in T84 cells resulted in profound defects in barrier and nonuniform, undulating TJ morphology. Global HIF1α chromatin immunoprecipitation (ChIP) analysis identified claudin-1 (CLDN1) as a prominent HIF target gene. Analysis of HIF1β-deficient IEC revealed significantly reduced levels of CLDN1. Overexpression of CLDN1 in HIF1β-deficient cells resulted in resolution of morphological abnormalities and restoration of barrier function. ChIP and site-directed mutagenesis revealed prominent hypoxia response elements in the CLDN1 promoter region. Subsequent in vivo analysis revealed the importance of HIF-mediated CLDN1 expression during experimental colitis. These results identify a critical link between HIF and specific tight junction function, providing important insight into mechanisms of HIF-regulated epithelial homeostasis. © 2015 Saeedi, Kao, et al.

Friedlander J.A.,Aurora University | Deboer E.M.,Aerodigestive Program | Deboer E.M.,Aurora University | Soden J.S.,Aurora University | And 12 more authors.
Gastrointestinal Endoscopy | Year: 2016

Background and Aims Unsedated transnasal endoscopy (TNE) is safer and less costly than sedated EGD. The aim of this study was to evaluate the performance of TNE with biopsies in monitoring the esophageal mucosa of pediatric patients with eosinophilic esophagitis. Methods Patients between 8 and 17 years of age with eosinophilic esophagitis and their parents were enrolled. Unsedated TNE was performed. A 2.8-mm (1.2-mm channel) or a 4-mm flexible bronchoscope (2-mm channel) was used, and esophageal biopsy specimens were obtained. Biopsy specimen analysis, duration, adverse events, and billing charges of TNE were assessed. Immediately after TNE and a minimum of 2 weeks later, a modified Group Health Association of America 9 survey and a preference questionnaire were completed, respectively. Results Twenty-one of 22 enrolled patients underwent TNE. TNE was performed with no serious adverse events. Histopathological analysis revealed 0 eosinophils per high-power field (n = 12), fewer than 15 eosinophils per high-power field (n = 4), and more than 15 eosinophils per high-power field (n = 5). The total epithelial surface area of mucosal biopsy samples from either TNE Forceps (1.2 mm or 2 mm biopsy channel forceps) compared with those obtained during the subject's previous EGD by using standard endoscopic forceps was not statistically different (P =.308 [1.2 mm]/P =.492 [2 mm]). All parents and 76.2% of subjects would undergo the TNE again. TNE was preferred over EGD by 85.7% of parents and 52.4% of subjects. The modified Group Health Association of America 9 survey revealed a high degree of satisfaction (average, 43.19 ± 2.6; maximum score, 45). Charges associated with TNE were 60.1% lower than for previous EGDs. Conclusions Unsedated TNE is an effective, lower-cost procedure for monitoring the esophageal mucosa of children with eosinophilic esophagitis. © 2016 American Society for Gastrointestinal Endoscopy.

Mukkada V.A.,Gastrointestinal Eosinophilic Diseases Program | Haas A.,Gastrointestinal Eosinophilic Diseases Program | Maune N.C.,Gastrointestinal Eosinophilic Diseases Program | Capocelli K.E.,Gastrointestinal Eosinophilic Diseases Program | And 8 more authors.
Pediatrics | Year: 2010

OBJECTIVES: Feeding dysfunction (FD) seen in younger children with eosinophilic gastrointestinal disease (EGID) has not been well described. Thus, our aim was to further characterize FD in children with EGIDs. METHODS: A retrospective medical record analysis of 200 children seen over 12 months in a multidisciplinary Gastrointestinal Eosinophilic Diseases Program was performed. The clinical data of 33 children identified as also having FD were examined, including information obtained by history, physical examination, feeding evaluation, review of nutritional data, allergy testing and histologic assessment of mucosal biopsies. RESULTS: Of 200 children with EGIDs, 16.5% had significant FD. The median age of this group was 34 months (range: 14-113 months). A variety of learned maladaptive feeding behaviors were reported in 93.9%. Frequent gagging or vomiting occurred in 84.8%. Food sensitivity was documented in 88% while 52% had other allergic disease. Twenty one percent were diagnosed with failure to thrive and 69.7% required individual or group feeding therapy. Forty-two percent had residual eosinophilia of >15 per HPF on esophageal biopsies performed at the time of symptoms. CONCLUSIONS: FD is prevalent in children with EGIDs often presenting as maladaptive learned feeding behaviors with altered mealtime dynamics and physical difficulties in eating mechanics. FD can persist even after eosinophilic inflammation is successfully treated. Awareness of the increased prevalence of FD in children with EGIDs with enable earlier recognition of this problem, resulting in a comprehensive, individualized treatment plan with the desired outcome of improving the development, feeding, and nutrition of these children. Copyright © 2010 by the American Academy of Pediatrics.

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