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1 Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; and 2 Bayer Pharmaceutical Division, Slough SL2 4LY, United Kingdom
To test the hypothesis that Na+ transport in human bronchial epithelial (HBE) cells is regulated by a protease-mediated mechanism, we investigated the effects of BAY 39-9437, a recombinant Kunitz-type serine protease inhibitor, on amiloride-sensitive short-circuit current of normal [non-cystic fibrosis (CF) cells] and CF HBE cells. Mucosal treatment of non-CF and CF HBE cells with BAY 39-9437 decreased the short-circuit current, with a half-life of ~45 min. At 90 min, BAY 39-9437 (470 nM) reduced Na+ transport by ~70%. The inhibitory effect of BAY 39-9437 was concentration dependent, with a half-maximal inhibitory concentration of ~25 nM. Na+ transport was restored to control levels, with a half-life of ~15 min, on washout of BAY 39-9437. In addition, trypsin (1 µM) rapidly reversed the inhibitory effect of BAY 39-9437. These data indicate that Na+ transport in HBE cells is activated by a BAY 39-9437-inhibitable, endogenously expressed serine protease. BAY 39-9437 inhibition of this serine protease maybe of therapeutic potential for the treatment of Na+ hyperabsorption in CF.
cystic fibrosis; Kunitz-type serine protease inhibitor; channel-activating protease; short-circuit current; primary cultures; epithelial sodium channel
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