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Published ahead of print on October 24, 2003, doi:10.1164/rccm.200304-472OC

Am. J. Respir. Crit. Care Med., Volume 169, Number 3, February 2004, 407-412

A more recent version of this article appeared on February 1, 2004
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Submitted on April 2, 2003
Accepted on October 23, 2003

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

Daniel E Sloniewsky1, Karen M Ridge2, Yochai Adir1, Francine P Fries2, Arturo Briva1, Jacob I Sznajder1, and Peter H S Sporn2*

1 Division of Pulmonary and Critical Care Medicine and Departments of Pediatrics and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, 2 Division of Pulmonary and Critical Care Medicine and Departments of Pediatrics and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Medical Service, Veteran Affairs Chicago Health Care System-Lakeside Division, Chicago, IL, USA

* To whom correspondence should be addressed. 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 on the function of Na,K-ATPase in alveolar epithelial cells and on alveolar fluid clearance in rat lungs. Leukotriene D4 (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. Leukotriene D4-induced {alpha}1 Na,K-ATPase membrane translocation was blocked by the dual cysLT1/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-PCR. Finally, compared to control, leukotriene D4 (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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