Human SLPI inactivation after cigarette smoke exposure in a new in vivo model of pulmonary oxidative stress

The role of oxidative stress in inactivating antiproteases is the object of debate. To address this question, we developed an in vivo model of pulmona ry oxidative stress induced by cigarette smoke (CS) in mice. The major mous e trypsin inhibitor contrapsin is not sensitive to oxidation, and the mouse secretory leukoprotease inhibitor (SLPI) does not inhibit trypsin. Instead , human recombinant (hr) SLPI inhibits trypsin and is sensitive to oxidatio n. Thus we determined the effect of CS in vivo on hrSLPI antiproteolytic fu nction in the airways of mice. CS caused a significant decrease in total an tioxidant capacity in bronchoalveolar lavage fluid (BALF) and significant c hanges in oxidized glutathione, ascorbic acid, protein thiols, and 8-epi-PG F2(alpha). Intratracheal hrSLPI significantly increased BALF antitryptic ac tivity. CS induced a 50% drop in the inhibitory activity of hrSLPI. Pretrea tment with N-acetylcysteine prevented the CS-induced loss of hrSLPI activit y, the decrease in antioxidant defenses, and the elevation of 8-epi-PGF-2 a lpha. Thus an inactivation of hrSLPI was demonstrated in this model. This i s a novel model for studying in vivo the effects of CS oxidative stress on human protease inhibitors with antitrypsin activity.