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Endothelin-1 Impairs Alveolar Epithelial Function via Endothelial ET_B Receptor

¹ Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; ² Departamento de Fisiopatologia, Facultad de Medicina, Universidad de la Republica, Montevideo, Uruguay; ³ Department of Physiology and Biophysics, Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel; and ⁴ Department of Biophysics and Molecular Genetics, Southwestern Medical School, University of Texas Southwestern Medical Center, Dallas, Texas

Correspondence and requests for reprints should be addressed to Alejandro P. Comellas, M.D., Division of Pulmonary, Critical Care, and Occupational Medicine, 200 Hawkins Drive, C331-GH, University of Iowa, Iowa City, IA 52242. E-mail: alejandro-comellas{at}uiowa.edu

Rationale: Endothelin-1 (ET-1) is increased in patients with high-altitude pulmonary edema and acute respiratory distress syndrome, and these patients have decreased alveolar fluid reabsorption (AFR).

Objectives: To determine whether ET-1 impairs AFR via activation of endothelial cells and nitric oxide (NO) generation.

Methods: Isolated perfused rat lung, transgenic rats deficient in ET_B receptors, coincubation of lung human microvascular endothelial cells (HMVEC-L) with rat alveolar epithelial type II cells or A549 cells, ouabain-sensitive ⁸⁶Rb⁺ uptake.

Measurements and Main Results: The ET-1–induced decrease in AFR was prevented by blocking the endothelin receptor ET_B, but not ET_A. Endothelial–epithelial cell interaction is required, as direct exposure of alveolar epithelial cells (AECs) to ET-1 did not affect Na,K-ATPase function or protein abundance at the plasma membrane, whereas coincubation of HMVEC-L and AECs with ET-1 decreased Na,K-ATPase activity and protein abundance at the plasma membrane. Exposing transgenic rats deficient in ET_B receptors in the pulmonary vasculature (ET-B^–/–) to ET-1 did not decrease AFR or Na,K-ATPase protein abundance at the plasma membrane of AECs. Exposing HMVEC-L to ET-1 led to increased NO, and the ET-1–induced down-regulation of Na,K-ATPase was prevented by the NO synthase inhibitor L-NAME, but not by a guanylate cyclase inhibitor.

Conclusions: We provide the first evidence that ET-1, via an endothelial–epithelial interaction, leads to decreased AFR by a mechanism involving activation of endothelial ET_B receptors and NO generation leading to alveolar epithelial Na,K-ATPase down-regulation in a cGMP-independent manner.

Key Words: endothelium • lung injury • sodium-potassium-exchanging ATPase • acute respiratory distress syndrome

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Although it is well known that alveolar epithelial injury decreases alveolar fluid reabsorption (AFR), there has been a paucity of data regarding the role of the endothelium in affecting the alveolar epithelial function and thus the regulation of AFR. What This Study Adds to the Field In this study, we show that there is cross-talk between the pulmonary endothelium and alveolar epithelium, specifically that endothelin-1 (ET-1) activates the endothelial ETB receptor that generates nitric oxide and thus causes alveolar epithelial dysfunction.