Nicorandil Attenuates LPS-Induced Acute Lung Injury by Pulmonary Endothelial Cell Protection via NF-κB and MAPK Pathways

Acute lung injury (ALI) is a devastating critical disease characterized by diffuse inflammation and endothelial dysfunction. Increasing evidence, including from our laboratory, has revealed that the opening of ATP-sensitive potassium (K(ATP)) channels has promising anti-inflammation and endothelial protection activities in various disorders. However, the impacts of K(ATP) channels on ALI remain obscure. In this study, we used nicorandil (Nico), a classic K(ATP) channel opener, to investigate whether opening of K(ATP) channels could alleviate ALI with an emphasis on human pulmonary artery endothelial cell (HPAEC) modulation. The results showed that Nico inhibited lipopolysaccharide- (LPS-) induced inflammatory response, protein accumulation, myeloperoxidase activity, and endothelial injury. In vitro, Nico reduced LPS-induced HPAEC apoptosis and the expression of cleaved-caspase-3, caspase-9, and CCAAT/enhancer-binding protein homologous protein (CHOP). Additionally, Nico inhibited inflammation by suppressing monocyte-endothelial adhesion and decreasing the expression of proinflammatory proteins. Moreover, Nico restored the expression and the distribution of adherens junction vascular endothelial- (VE-) cadherin. Further, Nico abolished the increase in intracellular reactive oxygen species (ROS) and the activation of NF-κB and mitogen-activated protein kinase (MAPK) in HPAECs. Glibenclamide (Gli), a nonselective K(ATP) channel blocker, abrogated the effects of Nico, implying that opening of K(ATP) channels contributes to the relief of ALI. Together, our findings indicated that Nico alleviated LPS-induced ALI by protecting ECs function via preventing apoptosis, suppressing endothelial inflammation and reducing oxidative stress, which may be attributed to the inhibition of NF-κB and MAPK signaling pathways.