Hu Bingfang, Li Yujin, Gao Li, Guo Yan, Zhang Yiwen, Chai Xiaojuan, Xu Meishu, Yan Jiong, Lu Peipei, Ren Songrong, Zeng Su, Liu Yulan, Xie Wen, Huang Min
Institute of Clinical Pharmacology and Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, China; Department of Pharmaceutical Sciences, Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Institute of Clinical Pharmacology and Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou, China.
Am J Pathol. 2017 May;187(5):1059-1067. doi: 10.1016/j.ajpath.2017.01.002. Epub 2017 Mar 6.
Sepsis is defined as the host's deleterious systemic inflammatory response to microbial infections. Herein, we report an essential role of the fatty acid binding protein 4 (FABP4; alias adipocyte protein 2 or aP2), a lipid-binding chaperone, in sepsis response. Bioinformatic analysis of the Gene Expression Omnibus data sets showed the level of FABP4 was higher in the nonsurvival sepsis patients' whole blood compared to the survival cohorts. The expression of Fabp4 was induced in a liver-specific manner in cecal ligation and puncture (CLP) and lipopolysaccharide treatment models of sepsis. The induction of Fabp4 may have played a pathogenic role, because ectopic expression of Fabp4 in the liver sensitized mice to CLP-induced inflammatory response and worsened the animal's survival. In contrast, pharmacological inhibition of Fabp4 markedly alleviated the CLP responsive inflammation and tissue damage and improved survival. We conclude that FABP4 is an important mediator of the sepsis response. Early intervention by pharmacological inhibition of FABP4 may help to manage sepsis in the clinic.
脓毒症被定义为宿主对微生物感染产生的有害全身炎症反应。在此，我们报告了脂肪酸结合蛋白4（FABP4；别名脂肪细胞蛋白2或aP2），一种脂质结合伴侣蛋白，在脓毒症反应中的重要作用。对基因表达综合数据库数据集的生物信息学分析表明，与存活队列相比，非存活脓毒症患者全血中FABP4水平更高。在盲肠结扎和穿刺（CLP）及脂多糖治疗的脓毒症模型中，Fabp4的表达以肝脏特异性方式被诱导。Fabp4的诱导可能起到了致病作用，因为肝脏中Fabp4的异位表达使小鼠对CLP诱导的炎症反应敏感，并使动物存活率降低。相反，对Fabp4的药理学抑制显著减轻了CLP反应性炎症和组织损伤，并提高了存活率。我们得出结论，FABP4是脓毒症反应的重要介质。通过对FABP4的药理学抑制进行早期干预可能有助于临床治疗脓毒症。
