Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury.
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ABSTRACT:
SUBMITTER: Imai Y
PROVIDER: S-EPMC7112336 | biostudies-literature | 2008 Apr
REPOSITORIES: biostudies-literature
Publications
Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury.
Imai Yumiko Y Kuba Keiji K Neely G Greg GG Yaghubian-Malhami Rubina R Perkmann Thomas T van Loo Geert G Ermolaeva Maria M Veldhuizen Ruud R Leung Y H Connie YH Wang Hongliang H Liu Haolin H Sun Yang Y Pasparakis Manolis M Kopf Manfred M Mech Christin C Bavari Sina S Peiris J S Malik JS Slutsky Arthur S AS Akira Shizuo S Hultqvist Malin M Holmdahl Rikard R Nicholls John J Jiang Chengyu C Binder Christoph J CJ Penninger Josef M JM
Cell 20080401 2
Multiple lung pathogens such as chemical agents, H5N1 avian flu, or SARS cause high lethality due to acute respiratory distress syndrome. Here we report that Toll-like receptor 4 (TLR4) mutant mice display natural resistance to acid-induced acute lung injury (ALI). We show that TLR4-TRIF-TRAF6 signaling is a key disease pathway that controls the severity of ALI. The oxidized phospholipid (OxPL) OxPAPC was identified to induce lung injury and cytokine production by lung macrophages via TLR4-TRIF. ...[more]
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Project description:Acute kidney injury (AKI) often impairs the function of other organs leading to distant organ injury. The liver is the major organ that regulates metabolism and lipid homeostasis in the body. It has been reported that AKI causes liver injury with increased oxidative stress, inflammatory response and steatosis. In the present study, we investigated the mechanisms by which ischemia-reperfusion-induced AKI caused hepatic lipid accumulation. Kidney ischemia (45 min)-reperfusion (24 h) led to a significant increase in plasma creatinine and transaminase in Sprague Dawley rats, indicating kidney and liver injury. Histological and biochemical analyses revealed hepatic lipid accumulation with a significant elevation of triglyceride and cholesterol levels in the liver. This was accompanied by a decreased AMP-activated protein kinase (AMPK) phosphorylation, indicating the reduced activation of AMPK, which is an energy sensor that regulates lipid metabolism. The expression of AMPK-regulated genes that were responsible for fatty acid oxidation (CPTIα, ACOX) was significantly decreased, while the expression of lipogenesis genes (SREPB-1c, ACC1) was significantly elevated. The oxidative stress biomarker malondialdehyde was elevated in the plasma and liver. Incubation of HepG2 cells with an oxidative stress inducer hydrogen peroxide inhibited AMPK phosphorylation and caused cellular lipid accumulation. This was accompanied by decreased expression of genes responsible for fatty acid oxidation and increased expression of genes responsible for lipogenesis. These results suggest that AKI elicits hepatic lipid accumulation through decreased fatty acid metabolism and increased lipogenesis. Oxidative stress may contribute, in part, to the downregulation of the AMPK signaling pathway leading to hepatic lipid accumulation and injury.
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