title: Role of cathepsin S in ozone-induced airway hyperresponsiveness and inflammation.
abstract: Ambient ozone has been linked to the worsening of symptoms of patients with obstructive diseases such as chronic obstructive pulmonary disease (COPD) and asthma. We investigated the role of cathepsin S on ozone-induced airway hyperresponsiveness (AHR) and inflammation, using the selective cathepsin S inhibitor, Compound A. Balb/c mice were exposed to ozone at a concentration of 3 ppm or air for 3 h, following administration by gavage of Compound A or vehicle. Bronchoalveolar lavage (BAL) was performed 3 h and 20-24 h following exposure, AHR was measured at 20-24 h only. Ozone exposure, compared to air exposure increased BAL cathepsin S levels, AHR and BAL inflammatory cells. Compound A (30 mg kg(-1) p.o.) dosing compared to vehicle dosing inhibited ozone-induced AHR (-logPC100 vehicle: -0.70+/-0.12, n=8 vs. cathepsin S inhibitor: -1.30+/-0.06, P<0.001, n=8) at 20-24 h and BAL neutrophilia at 3 h and 20-24 h (P<0.05, n=6). Ozone exposure increased levels of BAL cytokines IL-6, TNF-alpha and IFN-gamma. Compound A reduced IL-6 at 3 h and 20-24 h (P<0.05, n=5) and TNF-alpha, at 20-24 h (P<0.05, n=6). These data indicate an important role for cathepsin S in the regulation of ozone-induced AHR and neutrophil cell recruitment and suggest that cathepsin S may be a target in the treatment of oxidative stress-induced AHR and inflammation.
authors.affiliation: Experimental Studies Unit, Airway Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse St., SW3 6LY London, UK.
authors.forename: Alison S
authors.initials: AS
authors.lastname: Williams
authors.forename: Paul R
authors.initials: PR
authors.lastname: Eynott
authors.forename: Sum-Yee
authors.initials: SY
authors.lastname: Leung
authors.forename: Puneeta
authors.initials: P
authors.lastname: Nath
authors.forename: Ray
authors.initials: R
authors.lastname: Jupp
authors.forename: George T
authors.initials: GT
authors.lastname: De Sanctis
authors.forename: Robert
authors.initials: R
authors.lastname: Resnick
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
mesh_terms: D000393:Air Pollutants / Q000633:toxicity; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology*; D018893:Bronchoalveolar Lavage; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016503:Drug Delivery Systems; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010126:Ozone / Q000633:toxicity*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: D000393:Air Pollutants; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D010126:Ozone; D007371:Interferon-gamma; D002403:Cathepsins; C028217:cathepsin S