Inhibition of GGPPS1 attenuated LPS-induced acute lung injury and was associated with NLRP3 inflammasome suppression
| Autor: | Bing Wan, Lin Wu, Jia-jia Jin, Suhua Zhu, Ping Zhan, Xiaoxia Wang, Yong Song, Tangfeng Lv, Ning-wei Zhao, Chao-jun Li, Wujian Xu, Hongbing Liu, Qian Zou |
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| Rok vydání: | 2019 |
| Předmět: |
Lipopolysaccharides
0301 basic medicine Pulmonary and Respiratory Medicine Inflammasomes Physiology Acute Lung Injury Mice Transgenic Pharmacology Lung injury 03 medical and health sciences 0302 clinical medicine Physiology (medical) NLR Family Pyrin Domain-Containing 3 Protein Animals Medicine Inflammation business.industry Inflammasome Pneumonia Cell Biology respiratory system respiratory tract diseases Partial inhibition 030104 developmental biology 030220 oncology & carcinogenesis TLR4 Mevalonate pathway business medicine.drug |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 316:L567-L577 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | 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 intratracheally 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 was 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 ALI mice. Compared with wild-type and simvastatin treated mice, the specific deletion of pulmonary GGPPS1 attenuated the severity of lung injury by inhibiting apoptosis of AECs. Furthermore, deletion of GGPPS1 inhibited LPS-induced inflammasome activation, in terms of IL-1β release and pyroptosis, by downregulating NLRP3 expression. Finally, downregulation of GGPPS1 reduced the membrane expression of Ras-related protein Rab10 and Toll-like receptor 4 (TLR4) and inhibited the phosphonation of IκB. This effect might be attributed to the downregulation of GGPP levels. Our results suggested that inhibition of pulmonary GGPPS1 attenuated LPS-induced ALI predominantly by suppressing the NLRP3 inflammasome through Rab10-mediated TLR4 replenishment. |
| Databáze: | OpenAIRE |
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