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

Cysteinyl leukotrienes are increased during acute lung injury in animals and humans. In this study, we determined the effect of leukotriene D ₄ (LTD₄) on the function of Na,K-ATPase in alveolar epithelial cells and on alveolar fluid clearance in rat lungs. LTD₄ (1 × 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 α1 subunits from intracellular compartment(s) to the basolateral plasma membrane. LTD₄-induced α1 Na,K-ATPase membrane translocation was blocked by the dual cysteinyl LT₁ (cysLT₁)/ cysteinyl LT ₂ (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 × 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.