Endothelin decreases lung edema clearance and Na,K‐ATPase activity in alveolar epithelial cells via ET‐B receptor and Nitric Oxide generation

Abstract

RATIONALE ALI is characterized by high levels of endothelin-1 (ET-1). Administration of ET-1 is associated with a rapid increase in edema formation. We hypothesized that ET-1 may impair the ability of the lung to reabsorb fluid from the alveoli by inhibiting the Na,K-ATPase. METHODS A) Isolated-perfused rat lung model: Alveolar fluid clearance was assessed in an isolated-perfused rat lung model by determining the concentration of Evans blue-tagged albumin in the airspace instillate as a function of time. B) Isolated rat alveolar epithelial cells (AEC) were treated with ET-1 to assess Na,K-ATPase activity by a ouabain-sensitive 86Rb+ uptake and protein analysis by Western blotting. RESULTS Isolated rat lungs perfused for 60 min with different concentrations of ET-1 had a dose dependent decrease in alveolar fluid reabsorption. Non-selective ET A/B receptor antagonist blocked the decrease in lung edema clearance, but not by a selective ET-A antagonist. ET-1 decreased alveolar fluid clearance was blocked by a nitric oxide antagonist (L-NAME). Based on ouabain-sensitivity curves, the endothelin-mediated decrease in edema clearance is due predominantly to AEC type I (AECI). CONCLUSIONS These data support the hypothesis that ET-1 impairs the ability of the lungs to clear fluid by decreasing the Na,K-ATPase activity in AECI cells via ET-B receptor activation and nitric oxide production, thus impairing epithelial lung recovery from lung injury. Funding: Supported by HL-48129, T32-HL076139 and 5F32HL071421