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 (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 approximately 45 min. At 90 min, BAY 39-9437 (470 nM) reduced Na+ transport by approximately 70%. The inhibitory effect of BAY 39-9437 was concentration dependent, with a half-maximal inhibitory concentration of approximately 25 nM. Na+ transport was restored to control levels, with a half-life of approximately 15 min, on washout of BAY 39-9437. In addition, trypsin (1 microM) 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.
Bridges
R J
RJ
Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. bbridges+@pitt.edu
Newton
B B
BB
Pilewski
J M
JM
Devor
D C
DC
Poll
C T
CT
Hall
R L
RL
D001692:Biological Transport / Q000187:drug effects; D001980:Bronchi / Q000378:metabolism*; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology*; D012016:Reference Values; D012964:Sodium / Q000378:metabolism*
C430847:BAY 39-9437; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D012964:Sodium