title: Hypoxia potentiates allergen induction of HIF-1α, chemokines, airway inflammation, TGF-β1, and airway remodeling in a mouse model.
abstract: Whether hypoxia contributes to airway inflammation and remodeling in asthma is unknown. In this study we used mice exposed to a hypoxic environment during allergen challenge (simulating hypoxia during an asthma exacerbation) to investigate the contribution of hypoxia to airway inflammation and remodeling. Although neither hypoxia alone, nor OVA allergen alone, induced significant neutrophil influx into the lung, the combination of OVA and hypoxia induced a synergistic 27 fold increase in peribronchial neutrophils, enhanced expression of HIF-1α and one of its target genes, the CXC-family neutrophil chemokine KC. The combination of hypoxia and OVA allergen increased eotaxin-1, peribronchial eosinophils, lung TGB-β1 expression, and indices of airway remodeling (fibrosis and smooth muscle) compared to either stimulus alone. As hypoxia is present in >90% of severe asthma exacerbations, these findings underscore the potential of hypoxia to potentiate the airway inflammatory response, remodeling, and accelerate the decline of lung function in asthma exacerbations.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: kjbaekmd@kuh.ac.kr.
authors.forename: Kwang Je
authors.initials: KJ
authors.lastname: Baek
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: angelajyc858@gmail.com.
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Cho
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: prosenthal@ucsd.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenthal
authors.affiliation: Pulmonary Critical Care Section, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA; Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: lcrotty@ucsd.edu.
authors.forename: Laura E Crotty
authors.initials: LEC
authors.lastname: Alexander
authors.affiliation: Department of Pediatrics, University of California San Diego, San Diego, CA, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA, USA. Electronic address: vnizet@ucsd.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: dbroide@ucsd.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
mesh_terms: D056151:Airway Remodeling / Q000276:immunology*; D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054413:Chemokine CCL11 / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression / Q000276:immunology; D000860:Hypoxia / Q000276:immunology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology*; D012137:Respiratory System / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000276:immunology* / Q000378:metabolism
chemical_list: D000485:Allergens; D054413:Chemokine CCL11; D018925:Chemokines; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053773:Transforming Growth Factor beta1; D010047:Ovalbumin