Endothelin-1 impairs alveolar epithelial function via endothelial ET B receptor

Alejandro P. Comellas, Arturo Briva, Laura A. Dada, Maria L. Butti, Humberto E. Trejo, Cecilia Yshii, Zaher S. Azzam, Juan Litvan, Jiwang Chen, Emilia Lecuona, Liuska M. Pesce, Masashi Yanagisawa, Jacob I. Sznajder

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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 ETB 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 ETB, but not ETA. 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 ETB 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 ETB receptors and NO generation leading to alveolar epithelial Na,K-ATPase down-regulation in a cGMP-independent manner.

Original languageEnglish (US)
Pages (from-to)113-122
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Issue number2
StatePublished - Jan 15 2009


  • Acute respiratory distress syndrome
  • Endothelium
  • Lung injury
  • Sodium-potassium-exchanging ATPase

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Pulmonary and Respiratory Medicine


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