Role of cathepsin S in ozone-induced airway hyperresponsiveness and inflammation.
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.
Williams
Alison S
AS
Experimental Studies Unit, Airway Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse St., SW3 6LY London, UK.
Eynott
Paul R
PR
Leung
Sum-Yee
SY
Nath
Puneeta
P
Jupp
Ray
R
De Sanctis
George T
GT
Resnick
Robert
R
Adcock
Ian M
IM
Chung
Kian Fan
KF
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
D000393:Air Pollutants; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D010126:Ozone; D007371:Interferon-gamma; D002403:Cathepsins; C028217:cathepsin S