Burn-Induced Apoptosis of Pulmonary Microvascular Endothelial Cell is NHE1 Dependent and Regulated by PI3K-Akt and p38 MAPK Pathways

Na+/H+ exchanger 1 (NHE1) is a ubiquitously expressed protein on mammalian plasma membranes and involved in cell apoptosis and tissue injury. Our previous study found that NHE1 inhibition prevents burn-induced acute lung injury (ALI). However, the potential mechanism of NHE1 in burn-induced ALI is still unclear. This study investigated the role of NHE1 in burn-induced apoptosis of human pulmonary microvascular endothelial cells. Based on the western blot analyses, real-time PCR, fluorescence spectroscopy, and apoptosis analysis, we found that burn serum significantly induced NHE1 activation, promoted intracellular Na+ accumulation, and elevated apoptosis ratio. Inhibition of NHE1 with cariporide reversed burn-induced intracellular Na+ accumulation and cell apoptosis. Different doses of cariporide also significantly decreased Ca(2+)i concentrations and calpain activity induced by burn serum. Furthermore, inhibition of PI3K contributed to the increase of NHE1 activation and cell apoptosis, whereas the inhibition of p38 MAPK led to inhibition of NHE1 activation and significant decreases of cell apoptosis. The data demonstrate that NHE1 activation facilitates burn-induced endothelial cell apoptosis, mediated by Ca2+-dependent pathway. PI3K-Akt and p38 MAPK were found to be upstream regulators of NHE1. This study provides new mechanisms underlying burn-induced ALI.