Endothelin-1 impairs alveolar epithelial function via endothelial ETB receptor.
Am J Respir Crit Care Med
; 179(2): 113-22, 2009 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-18948426
ABSTRACT
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 MAINRESULTS:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Alvéolos Pulmonares
/
Endotélio Vascular
/
Água Extravascular Pulmonar
/
Endotelina-1
/
Receptor de Endotelina B
/
Óxido Nítrico
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article