title: Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H.
abstract: 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.
authors.affiliation: The Genetic Engineering International Cooperation Base of Chinese Ministry of Science and Technology, Key Laboratory of Molecular Biophysics of Chinese Ministry of Education, College of Life Science and Technology, Huazhong University of Science &Technology, Wuhan 430074, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Dong
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Yao
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Dang
authors.initials: D
authors.lastname: Wu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.affiliation: Hubei Bio-pharmaceutical Industrial Technological Institute Inc., Wuhan 430075, China.
authors.forename: Aifang
authors.initials: A
authors.lastname: Chen
authors.affiliation: Hubei Bio-pharmaceutical Industrial Technological Institute Inc., Wuhan 430075, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Hubei Bio-pharmaceutical Industrial Technological Institute Inc., Wuhan 430075, China.
authors.forename: Xuehai
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Genetic Engineering International Cooperation Base of Chinese Ministry of Science and Technology, Key Laboratory of Molecular Biophysics of Chinese Ministry of Education, College of Life Science and Technology, Huazhong University of Science &Technology, Wuhan 430074, China.
authors.forename: Guangxiao
authors.initials: G
authors.lastname: Yang
authors.affiliation: The Genetic Engineering International Cooperation Base of Chinese Ministry of Science and Technology, Key Laboratory of Molecular Biophysics of Chinese Ministry of Education, College of Life Science and Technology, Huazhong University of Science &Technology, Wuhan 430074, China.
authors.forename: Guangyuan
authors.initials: G
authors.lastname: He
authors.affiliation: Hubei Bio-pharmaceutical Industrial Technological Institute Inc., Wuhan 430075, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Lu
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002019:Bufexamac / Q000008:administration & dosage* / Q000737:chemistry; D002633:Chemotaxis / Q000187:drug effects; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D002019:Bufexamac; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase