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Endothelin-1 impairs alveolar epithelial function via endothelial ETB receptor
Journal article   Open access   Peer reviewed

Endothelin-1 impairs alveolar epithelial function via endothelial ETB 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, …
American journal of respiratory and critical care medicine, Vol.179(2), pp.113-122
01/15/2009
DOI: 10.1164/rccm.200804-540OC
PMCID: PMC2633058
PMID: 18948426
url
https://doi.org/10.1164/rccm.200804-540OCView
Published (Version of record) Open Access

Abstract

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). To determine whether ET-1 impairs AFR via activation of endothelial cells and nitric oxide (NO) generation. 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. 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. 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.
 Nitric Oxide - biosynthesis Rats, Transgenic Endothelin-1 - pharmacology Humans Adenosine Triphosphatases - metabolism Rats Male Respiratory Distress Syndrome, Adult - metabolism Extravascular Lung Water - metabolism Animals Cyclic GMP - metabolism Endothelium, Vascular - metabolism Pulmonary Alveoli - metabolism Lung Injury - metabolism Female Receptor, Endothelin A - metabolism Receptor, Endothelin B - metabolism In Vitro Techniques Disease Models, Animal

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