Na+ transport in normal and CF human bronchial epithelial cells is inhibited by BAY 39-9437

To test the hypothesis that Na+ transport in human bronchial epithelial (HB E) cells is regulated by a protease-mediated mechanism, we investigated the effects of BAY 39-9437, a recombinant Kunitz-type serine protease inhibito r, on amiloride-sensitive short-circuit current of normal [non-cystic fibro sis (CF) cells] and CF HBE cells. Mucosal treatment of non-CF and CF HBE ce lls with BAY 39-9437 decreased the short-circuit current, with a half-life of similar to 45 min. At 90 min, BAY 39-9437 (470 nM) reduced Na+ transport by similar to 70%. The inhibitory effect of BAY 39-9437 was concentration dependent, with a half-maximal inhibitory concentration of similar to 25 nM . Nai transport was restored to control levels, with a half-life of similar to 15 min, on washout of BAY 39-9437. In addition, trypsin (1 muM) 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, endogen ously expressed serine protease. BAY 39-9437 inhibition of this serine prot ease maybe of therapeutic potential for the treatment of Na+ hyperabsorptio n in CF.