Inhibition of GGPPS1 attenuated LPS-induced acute lung injury and was associated with NLRP3 inflammasome suppression

Inhibition of the mevalonate pathway using statins has been shown to be beneficial in the treatment of acute lung injury (ALI). Here, we investigated whether partial inhibition of this pathway by targeting Geranylgeranyl pyrophosphate synthase large subunit 1 (GGPPS1), a catalase downstream of the mevalonate pathway, was effective at treating lung inflammation in ALI. Lipopolysaccharide (LPS) was intra-tracheally instilled to induce ALI in lung specific GGPPS1 knockout and wild-type mice. Expression of GGPPS1 in lung tissues and alveolar epithelial cells was examined. The severity of lung injury and inflammation were determined in lung-specific GGPPS1 knockout and wild-type mice by measuring alveolar exudate, neutrophil infiltration, lung injury and cell death. Change in global gene expression in response to GGPPS1 depletion was measured using mRNA microarray and verified in vivo and in vitro. We found that GGPPS1 levels increased significantly in lung tissues and alveolar epithelial cells in LPS-induced ...