Saturday, 17 October 2015
Hall D1 Foyer (Floor 3) (Coex Convention Center)
Although some studies have demonstrated that mitochondrial reactive oxygen species (ROS) is one of endogenous pathogen-associated molecular patterns (PAMPs) activating NLRP3 inflammasome, to date, there is little information on which molecular mechanisms contribute to the assembly of NLRP3 inflammasome induced by mitochondrial ROS, especially in lung. In this study, we used LPS-instilled mice to define the molecular mechanisms implicated in mitochondrial ROS-induced NLRP3 inflammasome activation in lung inflammation, specifically in the relationship with PI3K-HIF-VEGF axis activation. The administration of mitochondrial ROS inhibitors, Nerox-5 or -7 decreased the features of LPS-induced lung injury including mitochondrial ROS generation and the levels of NLRP3 expression. In addition, the increases in phosphorylation of Akt, activation of HIF-1α and HIF-2α, and expression of VEGF in lung tissues from LPS-instilled mice were significantly inhibited with the administration of NecroX compounds. Our results also revealed that LPS-induced increases of nuclear translocation of NF-κB, infiltration of DCs, and TLR4 expression in the lung were significantly reduced by inhibition of NecroX compounds. TLR4 inhibition using TAK-242 decreased mitochondrial ROS and the phosphorylation of Akt and p85 expression in lung tissues and attenuates the LPS-inflammation. Interestingly, blockade of VEGF resulted in the substantial suppression of the activation of NLRP3 inflammasome. These findings suggest that mitochondrial ROS activates NLRP3 inflammasome, a crucial player in the pathogenesis of LPS-induced lung inflammation, at least in part through PI3K-HIF-VEGF axis.