title: Airway Remodeling and Hyperreactivity in a Model of Bronchopulmonary Dysplasia and Their Modulation by IL-1 Receptor Antagonist.
abstract: Bronchopulmonary dysplasia (BPD) is a chronic disease of extreme prematurity that has serious long-term consequences including increased asthma risk. We earlier identified IL-1 receptor antagonist (IL-1Ra) as a potent inhibitor of murine BPD induced by combining perinatal inflammation (intraperitoneal LPS to pregnant dams) and exposure of pups to hyperoxia (fraction of inspired oxygen = 0.65). In this study, we determined whether airway remodeling and hyperresponsiveness similar to asthma are evident in this model, and whether IL-1Ra is protective. During 28-day exposure to air or hyperoxia, pups received vehicle or 10 mg/kg IL-1Ra by daily subcutaneous injection. Lungs were then prepared for histology and morphometry of alveoli and airways, or for real-time PCR, or inflated with agarose to prepare precision-cut lung slices to visualize ex vivo intrapulmonary airway contraction and relaxation by phase-contrast microscopy. In pups reared under normoxic conditions, IL-1Ra treatment did not affect alveolar or airway structure or airway responses. Pups reared in hyperoxia developed a severe BPD-like lung disease, with fewer, larger alveoli, increased subepithelial collagen, and increased expression of α-smooth muscle actin and cyclin D1. After hyperoxia, methacholine elicited contraction with similar potency but with an increased maximum reduction in lumen area (air, 44%; hyperoxia, 89%), whereas dilator responses to salbutamol were maintained. IL-1Ra treatment prevented hyperoxia-induced alveolar disruption and airway fibrosis but, surprisingly, not the increase in methacholine-induced airway contraction. The current study is the first to demonstrate ex vivo airway hyperreactivity caused by systemic maternal inflammation and postnatal hyperoxia, and it reveals further preclinical mechanistic insights into IL-1Ra as a treatment targeting key pathophysiological features of BPD.
authors.affiliation: 1 Biomedicine Discovery Institute, Department of Pharmacology.
authors.forename: Simon G
authors.identifier: 0000-0001-5841-1775
authors.initials: SG
authors.lastname: Royce
authors.affiliation: 2 Ritchie Centre, Hudson Institute of Medical Research, and.|3 Department of Paediatrics, Monash University, Clayton, Victoria, Australia.
authors.forename: Marcel F
authors.identifier: 0000-0001-9682-4618
authors.initials: MF
authors.lastname: Nold
authors.affiliation: 2 Ritchie Centre, Hudson Institute of Medical Research, and.|3 Department of Paediatrics, Monash University, Clayton, Victoria, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Bui
authors.affiliation: 1 Biomedicine Discovery Institute, Department of Pharmacology.
authors.forename: Chantal
authors.initials: C
authors.lastname: Donovan
authors.affiliation: 1 Biomedicine Discovery Institute, Department of Pharmacology.
authors.forename: Maggie
authors.initials: M
authors.lastname: Lam
authors.affiliation: 1 Biomedicine Discovery Institute, Department of Pharmacology.
authors.forename: Emma
authors.initials: E
authors.lastname: Lamanna
authors.affiliation: 2 Ritchie Centre, Hudson Institute of Medical Research, and.|3 Department of Paediatrics, Monash University, Clayton, Victoria, Australia.
authors.forename: Ina
authors.initials: I
authors.lastname: Rudloff
authors.affiliation: 1 Biomedicine Discovery Institute, Department of Pharmacology.
authors.forename: Jane E
authors.identifier: 0000-0001-7314-9234
authors.initials: JE
authors.lastname: Bourke
authors.affiliation: 2 Ritchie Centre, Hudson Institute of Medical Research, and.|3 Department of Paediatrics, Monash University, Clayton, Victoria, Australia.
authors.forename: Claudia A
authors.identifier: 0000-0002-7439-3834
authors.initials: CA
authors.lastname: Nold-Petry
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000150:complications* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001997:Bronchopulmonary Dysplasia / Q000150:complications* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D018496:Hyperoxia / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D011247:Pregnancy; D011650:Pulmonary Alveoli / Q000473:pathology
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D000420:Albuterol
keywords: IL-1 receptor antagonist; airway hyperresponsiveness; airway remodeling; bronchopulmonary dysplasia; precision-cut lung slice