TRYPTASE MEDIATES HYPERRESPONSIVENESS IN ISOLATED GUINEA-PIG BRONCHI

Hyperresponsiveness of airway smooth muscle to allergens and environme ntal factors has long been associated with the pathophysiology of asth ma. Tryptase, a serine protease of lung mast cells, has been implicate d as one of the mediators involved in the induction of hyperresponsive ness. As a consequence, tryptase inhibitors have become the subject of study as potential novel therapeutic agents for asthma. Secretory leu kocyte protease inhibitor (SLPI) is a naturally occurring protein of h uman airways which exhibits anti-tryptase activity. To assess the pote ntial therapeutic utility of SLPI in asthma, its effects were evaluate d using in vitro and ex vivo models of airway hyperresponsiveness and compared with the effects of the small molecule tryptase inhibitor APC -366. Our results demonstrate that SLPI inhibits tryptase-mediated hyp erresponsiveness in vitro and attenuates the hyperresponsiveness obser ved in airway smooth muscle from antigen-sensitized animals subjected to antigen exposure. The small molecule tryptase inhibitor APC-366 has a similar inhibitory effect. Thus, tryptase appears to be a significa nt contributor to the development of hyperresponsiveness in these mode ls. To the extent that tryptase contributes to the development and pro gression of asthma, SLPI may posses therapeutic potential in this dise ase setting.