title: Interleukin-1 receptor antagonist attenuates airway hyperresponsiveness following exposure to ozone.
abstract: The role of an interleukin (IL)-1 receptor antagonist (IL-1Ra) on the development of airway hyperresponsiveness (AHR) and airway inflammation following acute O(3) exposure in mice was investigated. Exposure of C57/BL6 mice to O(3) at a concentration of 2.0 ppm or filtered air for 3 h resulted in increases in airway responsiveness to inhaled methacholine (MCh) 8 and 16 h after the exposure, and an increase in neutrophils in the bronchoalveolar lavage (BAL) fluid. IL-1beta expression, assessed by gene microarray, was increased 2-fold 4 h after O(3) exposure, and returned to baseline levels by 24 h. Levels of IL-1beta in lung homogenates were also increased 8 h after O(3) exposure. Administration of (human) IL-1Ra before and after O(3) exposure prevented development of AHR and decreased BAL fluid neutrophilia. Increases in chemokine levels in lung homogenates, tumor necrosis factor-alpha, MIP-2, and keratinocyte chemoattractant following O(3) exposure were prevented by IL-1Ra. Inhalation of dexamethasone, an inhibitor of IL-1 production, blocked the development of AHR, BAL fluid neutrophilia, and decreased levels of IL-1 following O(3) exposure. In summary, acute exposure to O(3) induces AHR, neutrophilic inflammation, epithelial damage, and IL-1. An IL-1Ra effectively prevents the development of altered airway function, inflammation, and structural damage.
authors.affiliation: Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
authors.forename: Jung-Won
authors.initials: JW
authors.lastname: Park
authors.forename: Christian
authors.initials: C
authors.lastname: Taube
authors.forename: Christina
authors.initials: C
authors.lastname: Swasey
authors.forename: Taku
authors.initials: T
authors.lastname: Kodama
authors.forename: Anthony
authors.initials: A
authors.lastname: Joetham
authors.forename: Annette
authors.initials: A
authors.lastname: Balhorn
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takeda
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Miyahara
authors.forename: Corrie B
authors.initials: CB
authors.lastname: Allen
authors.forename: Azzeddine
authors.initials: A
authors.lastname: Dakhama
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010083:Oxidants, Photochemical / Q000494:pharmacology; D010126:Ozone / Q000276:immunology* / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D016085:Bronchoconstrictor Agents; D016207:Cytokines; D005938:Glucocorticoids; D007375:Interleukin-1; D010083:Oxidants, Photochemical; D017472:Receptors, Interleukin-1; D016210:Methacholine Chloride; D010126:Ozone; D003907:Dexamethasone