NDLI: ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma.

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ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma.

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ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Mueller, James L. Doherty, Taylor A. Suzukawa, Maho Niwa, Maho Broide, David H. Beppu, Andrew Tam, Arvin B. McGeough, Matthew D. Rosenthal, Peter Miller, Marina Hoffman, Hal M. Pena, Carla A.
Description	Author Affiliation: Miller M ( Department of Medicine, University of California, San Diego, La Jolla, CA 92093)
Abstract	Orosomucoid-like (ORMDL)3 has been strongly linked with asthma in genetic association studies. Because allergen challenge induces lung ORMDL3 expression in wild-type mice, we have generated human ORMDL3 zona pellucida 3 Cre (hORMDL3(zp3-Cre)) mice that overexpress human ORMDL3 universally to investigate the role of ORMDL3 in regulating airway inflammation and remodeling. These hORMDL3(zp3-Cre) mice have significantly increased levels of airway remodeling, including increased airway smooth muscle, subepithelial fibrosis, and mucus. hORMDL3(zp3-Cre) mice had spontaneously increased airway responsiveness to methacholine compared to wild-type mice. This increased airway remodeling was associated with selective activation of the unfolded protein response pathway transcription factor ATF6 (but not Ire1 or PERK). The ATF6 target gene SERCA2b, implicated in airway remodeling in asthma, was strongly induced in the lungs of hORMDL3(zp3-Cre) mice. Additionally, increased levels of expression of genes associated with airway remodeling (TGF-ß1, ADAM8) were detected in airway epithelium of these mice. Increased levels of airway remodeling preceded increased levels of airway inflammation in hORMDL3(zp3-Cre) mice. hORMDL3(zp3-Cre) mice had increased levels of IgE, with no change in levels of IgG, IgM, and IgA. These studies provide evidence that ORMDL3 plays an important role in vivo in airway remodeling potentially through ATF6 target genes such as SERCA2b and/or through ATF6-independent genes (TGF-ß1, ADAM8).
ISSN	00221767
e-ISSN	15506606
DOI	10.4049/jimmunol.1303047
Journal	The Journal of Immunology
Issue Number	8
Volume Number	192
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-04-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Airway Remodeling Genetics Immunology Asthma Membrane Proteins Activating Transcription Factor 6 Metabolism Allergens Animals Antibody Specificity Pathology Bronchial Hyperreactivity Chemically Induced Chemokines, Cc Chemokines, Cxc Cytokines Disease Models, Animal Eosinophils Gene Expression Gene Order Gene Targeting Immunoglobulin E Blood Inflammation Lung Methacholine Chloride Administration & Dosage Mice Mice, Transgenic Ovalbumin Th2 Cells Transgenes Unfolded Protein Response Eif-2 Kinase Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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