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Published ahead of print on October 24, 2003, doi:10.1164/rccm.200304-472OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 407-412, (2004)
© 2004 American Thoracic Society

Leukotriene D4 Activates Alveolar Epithelial Na,K-ATPase and Increases Alveolar Fluid Clearance

Daniel E. Sloniewsky, Karen M. Ridge, Yochai Adir, Francine P. Fries, Arturo Briva, Jacob I. Sznajder and Peter H. S. Sporn

Divisions of Pulmonary and Critical Care Medicine, Departments of Pediatrics and Medicine, Feinberg School of Medicine, Northwestern University; and Medical Service, Veteran Affairs Chicago Health Care System-Lakeside Division, Chicago, Illinois

Correspondence and requests for reprints should be addressed to Peter H. S. Sporn, M.D., Division of Pulmonary and Critical Care Medicine, The Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Tarry 14-707, Chicago, IL 60611-3008. E-mail: p-sporn{at}northwestern.edu

Cysteinyl leukotrienes are increased during acute lung injury in animals and humans. In this study, we determined the effect of leukotriene D4 (LTD4) on the function of Na,K-ATPase in alveolar epithelial cells and on alveolar fluid clearance in rat lungs. LTD4 (1 x 10-7 M) increased Na,K-ATPase activity at 1 and 5 minutes by 14% (p < 0.05) and 31% (p < 0.001), respectively, in A549 alveolar epithelial cells. This was accompanied by recruitment of Na,K-ATPase {alpha}1 subunits from intracellular compartment(s) to the basolateral plasma membrane. LTD4-induced {alpha}1 Na,K-ATPase membrane translocation was blocked by the dual cysteinyl LT1 (cysLT1)/ cysteinyl LT2 (cysLT2) receptor antagonist BAY-u9773, but not by the cysLT1 antagonist MK571, implicating the cysLT2 receptor. Expression of mRNA for cysLT2, but not cysLT1, was confirmed in A549 cells and rat alveolar type 2 cells by reverse transcriptase-polymerase chain reaction. Finally, compared with control, LTD4 (1 x 10-11 M) increased alveolar fluid clearance by 41% (p < 0.001) in isolated, perfused rat lungs; this was also blocked by BAY-u9773 but not MK571. By activating alveolar epithelial Na,K-ATPase and increasing alveolar fluid reabsorption, cysteinyl leukotrienes may, in part, have a beneficial role in the acute respiratory distress syndrome.

Key Words: leukotriene D4 • cysteinyl leukotriene receptors • Na(+)-K(+)–exchanging ATPase • pulmonary edema • adult respiratory distress syndrome




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