FABP4 inhibitors suppress inflammation and oxidative stress in murine and cell models of acute lung injury.
Acute lung injury (ALI) is a severe disease with high morbidity and mortality, and is characterized by devastating inflammation of the lung and increased production of reactive oxygen species (ROS). Recent studies have indicated that fatty acid binding protein (FABP4) is important in the regulation of inflammation. However, the role of FABP4 in sepsis-related ALI, and the specific mechanism of action have not been examined. In vitro, the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) and recombinant FABP4 (hrFABP4) resulted in the production of pro-inflammatory cytokines, inflammatory cytokines, and ROS, while these changes were ameliorated by pretreatment with the FABP4 inhibitor BMS309403 and FABP4 siRNA. Sequentially, treatment of A549 cells with N-acetylcysteine (NAC) significantly attenuated LPS and hrFABP4-induced the generation of ROS and the release of inflammatory cytokines. In vivo, a cecal ligation and puncture (CLP)-induced ALI murine model was successfully established. Then, the mice were treated with FABP4 inhibitor BMS309403. The results showed treatment with BMS309403 improved the survival rate of CLP-induced ALI mice, and prevented lung inflammation, histopathological changes, and increase of FABP4 induced by CLP. These data indicate that FABP4 plays an important role in lung inflammation of sepsis-induced ALI. Blockade of FABP4 signaling exhibits a protective effect in a CLP-induced ALI mouse model, and in A549 cell LPS specifically induces enhanced expression of FABP4, which then causes inflammatory cytokine production by elevating the ROS level.
['Gong|Yuanqi|Y|', 'Yu|Zhihong|Z|', 'Gao|Yi|Y|', 'Deng|Linlin|L|', 'Wang|Meng|M|', 'Chen|Yu|Y|', 'Li|Jingying|J|', 'Cheng|Bin|B|']
D000072283:A549 Cells D055371:Acute Lung Injury D000818:Animals D000893:Anti-Inflammatory Agents D001713:Biphenyl Compounds D016207:Cytokines D050556:Fatty Acid-Binding Proteins D006801:Humans D018836:Inflammation Mediators D008070:Lipopolysaccharides D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018384:Oxidative Stress D011720:Pyrazoles D017382:Reactive Oxygen Species D015996:Survival Rate D016896:Treatment Outcome
Acute lung injury ROS Fatty acid binding protein Lung inflammation