文献类型：期刊文献

英文题名：Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H

作者：Xiao, Qiang[1];Dong, Ningning[2];Yao, Xue[2];Wu, Dang[2];Lu, Yanli[2];Mao, Fei[2];Zhu, Jin[2];Li, Jian[2];Huang, Jin[2];Chen, Aifang[3];Huang, Lu[3];Wang, Xuehai[3];Yang, Guangxiao[1];He, Guangyuan[1];Xu, Yong[3];Lu, Weiqiang[4]

机构：[1]Huazhong Univ Sci & Technol, Genet Engn Int Cooperat Base, Chinese Minist Sci & Technol, Key Lab Mol Biophys,Chinese Minist Educ,Coll Life, Wuhan 430074, Peoples R China;[2]E China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China;[3]Hubei Biopharmaceut Ind Technol Inst Inc, Wuhan 430075, Peoples R China;[4]E China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China

年份：2016

卷号：6

外文期刊名：SCIENTIFIC REPORTS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000375113500002)】；

基金：We thank the staff at Shanghai Synchrotron Radiation Facility beamline BL17U for assistances with data collection. We appreciate Prof. Colin D Funk (Queen's University, Canada) for LOXs in pCDNA3 and Prof. Marcia E. Newcomer (Louisiana State University, USA) for stable 5-LOX expression vector. The authors appreciate Prof. Luhua Lai and Dr. Hu Meng (Peking University, China) for their help on the LTA4H activity assay. This work was supported by the National Natural Science Foundation of China (grants 51477066, 81402482, 21222211, 91313303, 81573020), the Shanghai Committee of Science and Technology (grants 14ZR1411100, 15431902000), China Postdoctoral Science Foundation grant (2014M551361, 2015T80415).

语种：英文

摘要：Neutrophils play an important role in the occurrence and development of acute lung injury (ALI). Leukotriene B4 (LTB4), a hydrolysis product of epoxide leukotriene A4 (LTA4) catalyzed by LTA4 hydrolase (LTA4H), is one of the most potent chemoattractants for neutrophil. Bufexamac is a drug widely used as an anti-inflammatory agent on the skin, however, the mechanism of action is still not fully understood. In this study, we found bufexamac was capable of specifically inhibiting LTA4H enzymatic activity and revealed the mode of interaction of bufexamac and LTA4H using X-ray crystallography. Moreover, bufexamac significantly prevented the production of LTB4 in neutrophil and inhibited the fMLP-induced neutrophil migration through inhibition of LTA4H. Finally, bufexamac significantly attenuated lung inflammation as reflected by reduced LTB4 levels and weakened neutrophil infiltration in bronchoalveolar lavage fluid from a lipopolysaccharide-induced ALI mouse model. In summary, our study indicates that bufexamac acts as an inhibitor of LTB4 biosynthesis and may have potential clinical applications for the treatment of ALI.