title: IL-17A modulates oxidant stress-induced airway hyperresponsiveness but not emphysema.
abstract: IL-17A induces the release of pro-inflammatory cytokines and of reactive oxygen species which could lead to neutrophilic inflammation. We determined the role of IL-17 receptor (IL-17R) signalling in oxidant-induced lung emphysema and airway hyperresponsiveness. IL-17R(-/-) and wild-type C57/BL6 mice were exposed to ozone (3 ppm; 3 hours) for 12 times over 6 weeks. Bronchial responsiveness to acetylcholine was measured, and lungs were retrieved. Mean linear intercept (Lm) and isometric contractile responses of intrapulmonary airways to acetylcholine were determined. In wild-type mice but not in IL-17R(-/-), chronic ozone exposure caused airway hyperresponsiveness. The increase in Lm after chronic ozone exposure of wild-type mice was also observed in IL-17R(-/-) mice. The increased maximal contractile response to acetylcholine seen in airways of wild-type mice exposed to ozone was abolished in IL-17R(-/-) mice. p38-mitogen-activated protein kinase (MAPK) and dexamethasone-dependent increase in contractile response was reduced in airways from IL-17R(-/-) ozone-exposed mice. Lung inflammation scores were not altered in IL-17R(-/-) mice exposed to ozone compared to wild-type mice. The increased release of IL-17 and IL-1β, and the activation of p38 MAPK in the lungs of ozone-exposed mice was reduced in IL-17R(-/-) mice. IL-17R signalling underlies the increase in airway hyperresponsiveness seen after ozone exposure, mediated by the increased contractility of airway smooth muscle. The emphysema and lung inflammation induced by ozone is not dependent on IL-17.
authors.affiliation: Airways Disease, National Heart & Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Mariona
authors.initials: M
authors.lastname: Pinart
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Farhana
authors.initials: F
authors.lastname: Hussain
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Coen
authors.initials: C
authors.lastname: Wiegman
authors.forename: Bernard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004646:Emphysema / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D047428:Protein Kinase Inhibitors; D053722:Receptors, Interleukin-17; D003907:Dexamethasone; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000109:Acetylcholine