title: Ozone-induced airway hyperresponsiveness: roles of ROCK isoforms.
abstract: Acute ozone (O3) inhalation has been shown to cause airway and pulmonary epithelial injury with accompanying inflammation responses. Robust evidence exists that O3 induces airway hyperresponsiveness (AHR) in humans and in animal models. Several pathways exist that culminate in airway smooth muscle contraction, but the mechanism(s) by which O3 elicits AHR are unclear. Here, we review the recent report by Kasahara et al. (Kasahara DI, Mathews JA, Park CY, Cho Y, Hunt G, Wurmbrand AP, Liao JK, Shore SA. Am J Physiol Lung Cell Mol Physiol 309: L736-L746, 2015.) describing the role of two Rho kinase (ROCK) isoforms in O3-induced AHR utilizing a murine haploinsufficiency model. Compared with wild-type (WT) mice, the authors report that ROCK1(+/-) and ROCK2(+/-) mice exhibited significantly reduced AHR following acute exposure to O3. Additionally, WT mice treated with fasudil, an FDA-approved ROCK1/2 inhibitor, recapitulated reduction in AHR as seen in ROCK haplotypes. It was suggested that, although the two ROCK isoforms are both induced by Rho, they have different mechanisms by which they mediate O3-induced AHR: ROCK1 via hyaluronan signaling vs. ROCK2 acting downstream of inflammation at the level of airway smooth muscle contraction. These observations provide an important framework to develop novel ROCK-targeting therapies for acute O3-induced AHR.
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: James A
authors.initials: JA
authors.lastname: Lambert
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and Pulmonary Injury and Repair Center, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama wsong@uabmc.edu.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Song
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D010126:Ozone / Q000009:adverse effects*; D020033:Protein Isoforms / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D010126:Ozone; D054460:rho-Associated Kinases
keywords: airway hyperresponsiveness (AHR), Rho kinase (ROCK), hyaluronan; ozone