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

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 281; no. 1; pp. 16 - L23
• Main Authors: Bridges, Robert J, Newton, Ben B, Pilewski, Joseph M, Devor, Daniel C, Poll, Christopher T, Hall, Rod L
• Format: Journal Article
• Language: English
• Published: United States 01.07.2001
• Subjects: Biological Transport - drug effects; Bronchi - metabolism; Cells, Cultured; Cystic Fibrosis - metabolism; Epithelial Cells - metabolism; Humans; Protease Inhibitors - pharmacology; Recombinant Proteins - pharmacology; Reference Values; Sodium - metabolism
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.2001.281.1.l16

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