Trauma center/Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei province, China.
Trauma center/Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei province, China.
Life Sci. 2020 Jun 1;250:117551. doi: 10.1016/j.lfs.2020.117551. Epub 2020 Mar 13.
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.
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.
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.
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.
越来越多的证据表明，FK866 是一种特异性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。自噬在脓毒症诱导的 ALI 中起着关键作用。然而，自噬的贡献以及 FK866 发挥肺保护作用的潜在机制仍不清楚。在此，我们旨在研究 FK866 是否可以通过 JNK 依赖性自噬来减轻脓毒症引起的 ALI。
雄性 C57BL/6 小鼠接受盲肠结扎穿孔（CLP）以建立多微生物脓毒症小鼠模型，并在 CLP 术前 24、12 和 0.5 小时用 FK866（10mg/kg）进行治疗。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 活性来衡量肺保护作用。用 LPS（1000ng/ml）刺激 A549 细胞生成 ALI 细胞模型，并用 FK866 或 SP600125 预处理 30 分钟来测量自噬相关蛋白表达和 JNK 活性。
我们的结果表明，FK866 降低了肺损伤评分、组织水肿、血管渗漏和炎症浸润，并上调了自噬。用 3-甲基腺嘌呤（3MA）和雷帕霉素进一步阐明了 FK866 通过自噬对 ALI 的保护作用。此外，FK866 抑制了 JNK 的活性，抑制 JNK 促进了自噬并显示出有益的作用。
本研究表明，FK866 通过诱导 JNK 依赖性自噬来保护脓毒症引起的 ALI。这可能为 NAMPT 抑制在脓毒症诱导的 ALI 中的功能机制提供新的见解。
