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 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 alpha1 subunits from intracellular compartment(s) to the basolateral plasma membrane. LTD4-induced alpha1 Na,K-ATPase membrane translocation was blocked by the dual cysteinyl LT1 (cysLT1)/ cysteinyl LT3 (cysLT3) receptor antagonist BAY-u9773, but not by the cysLT1 antagonist MK571, implicating the cysLT3 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.
Division of Pulmonary and Critical Care Medicine, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008, USA.
Daniel E
DE
Sloniewsky
Karen M
KM
Ridge
Yochai
Y
Adir
Francine P
FP
Fries
Arturo
A
Briva
Jacob I
JI
Sznajder
Peter H S
PH
Sporn
D000818:Animals; D001826:Body Fluids / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017998:Leukotriene D4 / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism*; D011654:Pulmonary Edema / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects* / Q000378:metabolism*
D017998:Leukotriene D4; D000254:Sodium-Potassium-Exchanging ATPase