ALPHA-THROMBIN INCREASES CYTOSOLIC CALCIUM AND INDUCES HUMAN AIRWAY SMOOTH-MUSCLE CELL-PROLIFERATION

In a variety of diseases including asthma, inflammation causes microva scular leakage and activates thrombin. In addition to cleaving fibrino gen to fibrin, thrombin may have other important cellular effects. Bec ause airway inflammation and vascular permeability are important deter minants of airway hyperreactivity, we have studied the effects of thro mbin on airway smooth muscle. Using cultured human airway smooth muscl e cells, we have examined whether alpha-thrombin can evoke calcium res ponses, phosphoinositide turnover, or cell proliferation. We have demo nstrated that alpha-thrombin does increase cytosolic calcium and phosp hoinositide hydrolysis in a dose- and time-dependent manner that may b e inhibited by pretreating cells with r-hirudin. In addition, we have shown that thrombin stimulates airway smooth muscle cell proliferation . By contrast, bradykinin, which evoked comparable increases in cytoso lic calcium and phosphoinositide turnover, did not stimulate airway sm ooth muscle cell growth. We conclude that thrombin effectively increas es cytosolic calcium and induces PI hydrolysis and, in addition, is ca pable of stimulating airway smooth muscle cell growth. However, the la ck of an effect of bradykinin on cell growth suggests that increases i n calcium and PI turnover alone will not induce airway smooth muscle c ell proliferation. We suggest that alpha-thrombin may be important in the pathogenesis of both increased airway resistance as well as the st ructural changes seen as a consequence of chronic asthma.