Endothelin-1 Impairs Alveolar Epithelial Function via Endothelial ET_B Receptor

Abstract

Rationale: Endothelin-1 (ET-1) is increased in patients with highaltitude 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 86 Rb 1 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 2/2 ) 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.

Improvement in lung diffusion by endothelin A receptor blockade at high altitude

“…Endothelin-1 acts on the renal distal tubules and collecting ducts by inhibiting endothelin B receptor-mediated reabsorption of sodium and water (28). Similar observations have been reported in experimental rat lung preparations (5,11). Accordingly, the intake of the endothelin A and B receptor blocker bosentan decreased free water clearance in healthy volunteers exposed to the altitude of 4,559 m (32).…”

“…Part of this improvement in exercise capacity could have been related to improved lung diffusing capacity, either as a consequence of decreased pulmonary vascular pressures (34) or inhibition of some negative effect of endothelin-1 at the alveolocapillary membrane (32). The latter would be unlikely after sitaxsentan, since there is experimental evidence that endothelin inhibits the alveolar epithelial transport of sodium and water but through the specific interaction with endothelin B receptors (5,11). We therefore here report on lung diffusion measurements at rest and after a maximal exercise test after the intake of sitaxsentan.…”

Concomitant Endothelin‐1 Overexpression in Lung Transplant Donors and Recipients Predicts Primary Graft Dysfunction

“…In addition, ET-1 pulmonary tissue mRNA expression was significantly higher (p = 0.01) in Figure 3A) Figure 3C). (27), increased vascular permeability and edema (17,28). Moreover, elevation of tissue ET-1 is associated with hypoxia-mediated vascular resistance (29), and mediates ischemia reperfusioninduced graft edema (17 …”

Involvement of Na+, K+-ATPase and its inhibitors in HuR-mediated cytokine mRNA stabilization in lung epithelial cells

“…, K ? -ATPase and ALI [27][28][29][30][31]. In addition, this cell line is widely used to explore the molecular mechanisms underlying pulmonary epithelial inflammation induced by various stimuli [32][33][34][35].…”