Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H.
Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H.
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Bufexamac 通过靶向 LTA4H 改善 LPS 诱导的小鼠急性肺损伤
DOI：
10.1038/srep25298
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发表时间：
2016-04-29
影响因子：
4.6
通讯作者：
Lu W
中科院分区：
文献类型：
--
作者：
Xiao Q;Dong N;Yao X;Wu D;Lu Y;Mao F;Zhu J;Li J;Huang J;Chen A;Huang L;Wang X;Yang G;He G;Xu Y;Lu W
中性粒细胞在急性肺损伤（ALI）的发生、发展中起重要作用。白三烯B4（Leukotriene B4，LTB 4）是环氧白三烯A4（LTA 4）经LTA 4水解酶（LTA 4 H）催化的水解产物，是中性粒细胞最强的化学引诱剂之一。Bufexamac是一种广泛用作皮肤抗炎剂的药物，然而，其作用机制仍不完全清楚。在这项研究中，我们发现bufexamac能够特异性抑制LTA 4 H酶活性，并揭示了bufexamac和LTA 4 H的相互作用模式，使用X-射线晶体学。此外，bufexamac显着防止在中性粒细胞中产生LTB 4，并通过抑制LTA 4 H抑制fMLP诱导的中性粒细胞迁移。最后，bufexamac显着减弱肺部炎症，反映了从脂多糖诱导的ALI小鼠模型的支气管肺泡灌洗液中LTB 4水平降低和中性粒细胞浸润减弱。总之，我们的研究表明，丁非西酸可作为LTB 4生物合成的抑制剂，可能在治疗ALI方面具有潜在的临床应用。
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.