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Endothelin-1 impairs alveolar epithelial function via endothelial ETB receptor.

Authors: Comellas, AP  Briva, A  Dada, LA  Butti, ML  Trejo, HE  Yshii, C  Azzam, ZS  Litvan, J  Chen, J  Lecuona, E  Pesce, LM  Yanagisawa, M  Sznajder, JI 
Citation: Comellas AP, etal., Am J Respir Crit Care Med. 2009 Jan 15;179(2):113-22. Epub 2008 Oct 23.
Pubmed: (View Article at PubMed) PMID:18948426
DOI: Full-text: DOI:10.1164/rccm.200804-540OC

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.


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RGD Object Information
RGD ID: 4892575
Created: 2011-02-24
Species: All species
Last Modified: 2011-02-24
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.