AIMS Increasing evidence indicates that FK866, a specific noncompetitive nicotinamide phosphoribosyl transferase inhibitor, exhibits a protective effect on acute lung injury (ALI). Autophagy plays a pivotal role in sepsis-induced ALI. However, the contribution of autophagy and the underlying mechanism by which FK866-confered lung protection remains elusive. Herein, we aimed to study whether FK866 could alleviate sepsis-induced ALI via the JNK-dependent autophagy. MAIN METHODS Male C57BL/6 mice were subjected to cecal ligation and puncture (CLP) to establish the polymicrobial sepsis mice model, and treated with FK866 (10 mg/kg) at 24, 12 and 0.5 h before the CLP procedure. The lung protective effects were measured by lung histopathology, tissue edema, vascular leakage, inflammation infiltration, autophagy-related protein expression and JNK activity. A549 cells were stimulated with LPS (1000 ng/ml) to generate the ALI cell model, and pretreated with FK866 or SP600125 for 30 min to measure the autophagy-related protein expression and JNK activity. KEY FINDINGS Our results demonstrated that FK866 reduced lung injury score, tissue edema, vascular leakage, and inflammatory infiltration, and upregulated autophagy. The protective effect of autophagy conferred by FK866 on ALI was further clarified by using 3-methyladenine (3MA) and rapamycin. Additionally, the activity of JNK was suppressed by FK866, and inhibition of JNK promoted autophagy and showed a benefit effect. SIGNIFICANCE Our study indicates that FK866 protects against sepsis-induced ALI by induction of JNK-dependent autophagy. This may provide new insights into the functional mechanism of NAMPT inhibition in sepsis-induced ALI.

中文翻译：

---

FK866通过c-jun-N-末端激酶（JNK）依赖性自噬减轻败血症诱导的急性肺损伤。

AIMS越来越多的证据表明，FK866是一种特殊的非竞争性烟酰胺磷酸核糖基转移酶抑制剂，对急性肺损伤（ALI）具有保护作用。自噬在败血症诱导的ALI中起关键作用。但是，自噬的作用和FK866赋予肺保护作用的潜在机制仍然难以捉摸。在本文中，我们旨在研究FK866是否可以通过依赖JNK的自噬减轻败血症诱导的ALI。主要方法对雄性C57BL / 6小鼠进行盲肠结扎和穿刺（CLP）建立多菌性脓毒症小鼠模型，并在CLP程序前24、12和0.5 h用FK866（10 mg / kg）处理。通过肺组织病理学，组织水肿，血管渗漏，炎症浸润，自噬相关蛋白表达和JNK活性。用LPS（1000 ng / ml）刺激A549细胞以生成ALI细胞模型，并用FK866或SP600125预处理30分钟以测量自噬相关蛋白的表达和JNK活性。主要发现我们的结果表明FK866降低了肺损伤评分，组织水肿，血管渗漏和炎性浸润，并上调了自噬。通过使用3-甲基腺嘌呤（3MA）和雷帕霉素，进一步阐明了FK866赋予自噬对ALI的保护作用。另外，FNK866抑制了JNK的活性，并且抑制JNK促进了自噬并显示出有益效果。意义我们的研究表明FK866通过诱导JNK依赖性自噬来预防败血症诱导的ALI。