Silencing Angiopoietin-Like Protein 4 (ANGPTL4) Protects Against Lipopolysaccharide-Induced Acute Lung Injury Via Regulating SIRT1 /NF-kB Pathway.
Lung inflammation and alveolar epithelial cell death are critical events in the development and progression of acute lung injury (ALI). Although angiopoietin-like protein 4 (ANGPTL4) participates in inflammation, whether it plays important roles in ALI and alveolar epithelial cell inflammatory injury remains unclear. We therefore investigated the role of angptl4 in lipopolysaccharide (LPS)-induced ALI and the associated mechanisms. Lentivirus-mediated short interfering RNA targeted to the mouse angptl4 gene (AngsiRNA) and a negative control lentivirus (NCsiRNA) were intranasally administered to mice. Lung inflammatory injury and the underlying mechanisms for regulation of angptl4 on the LPS-induced ALI were subsequently determined. We reported that angptl4 levels were increased both in human alveolar epithelial A549 cells and lung tissues obtained from a mouse model of LPS-induced ALI. Angptl4 expression was induced by LPS in alveolar epithelial cells, whereas LPS-induced lung inflammation (neutrophils infiltration in the lung tissues, tumor necrosis factor α, interleukin 6), lung permeability (lung wet/dry weight ratio and bronchoalveolar lavage fluid (BALF) protein concentration), tissue damage (caspase3 activation), and mortality rates were attenuated in AngsiRNA-treated mice. The inflammatory reaction (tumor necrosis factor α, interleukin 6) and apoptosis rates were reduced in AngsiRNA(h)-treated A549 cells. Moreover, angptl4 promoted NF-kBp65 expression and suppressed SIRT1 expression both in mouse lungs and A549 cells. Additionally, SIRT1 antagonist nicotinamide (NAM) attenuated the inhibitory effects of AngsiRNA both on LPS-induced NF-kBp65 expression and IL6 expression. These findings suggest that silencing angptl4 protects against LPS-induced ALI via regulating SIRT1/NF-kB signaling pathway.
Institute of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Liang
L
Guo
Institute of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Shaoying
S
Li
Department of Respiratory Medicine, Pudong New Area Gongli Hospital, Shanghai, China.
Yunfeng
Y
Zhao
Institute of Field Internal Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Pin
P
Qian
Institute of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Fuyun
F
Ji
Institute of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Lanlan
L
Qian
Institute of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Xueling
X
Wu
Institute of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Guisheng
G
Qian
D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D020868:Gene Silencing; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D056564:Sirtuin 1 / Q000235:genetics*
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D008070:Lipopolysaccharides; D016328:NF-kappa B; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1