美国福克斯蔡斯癌症中心免疫学中心Siddharth Balachandran，美国塔夫茨大学医学院Alexei Degterev，美国圣裘德儿童研究医院Paul G. Thomas和美国休斯敦大学Gregory D. Cuny共同合作，近期取得重要工作进展。他们研究提出利用坏死阻断剂预防严重流感肺损伤的观点。相关研究成果2024年4月10日在线发表于《自然》杂志上。

据介绍，严重甲型流感病毒（IAV）感染可导致高度炎症、肺损伤和急性呼吸窘迫综合征（ARDS），目前尚无有效的药物治疗方法。坏死是ARDS和相关炎症疾病治疗干预的一个有吸引力的切入点，因为它在严重IAV感染期间会导致致病性肺部炎症和死亡，并且可能被受体相互作用蛋白激酶3（RIPK3）抑制剂靶向。

研究人员表明，一种新开发的RIPK3抑制剂UH15-38能在体内有效且选择性地阻断IAV引发的肺泡上皮细胞坏死。UH15-38在不影响抗病毒适应性免疫反应或阻碍病毒清除的情况下，改善了实验室适应型和大流行型IAV毒株感染后的肺部炎症并预防了死亡率。UH15-38即使在感染后期给药，也显示出强大的治疗效果，这表明RIPK3阻断可能为IAV驱动的ARDS和其他高炎症病理的患者提供临床益处。

附：英文原文

Title: Necroptosis blockade prevents lung injury in severe influenza

Author: Gautam, Avishekh, Boyd, David F., Nikhar, Sameer, Zhang, Ting, Siokas, Ioannis, Van de Velde, Lee-Ann, Gaevert, Jessica, Meliopoulos, Victoria, Thapa, Bikash, Rodriguez, Diego A., Cai, Kathy Q., Yin, Chaoran, Schnepf, Daniel, Beer, Julius, DeAntoneo, Carly, Williams, Riley M., Shubina, Maria, Livingston, Brandi, Zhang, Dingqiang, Andrake, Mark D., Lee, Seungheon, Boda, Raghavender, Duddupudi, Anantha L., Crawford, Jeremy Chase, Vogel, Peter, Loch, Christian, Schwemmle, Martin, Fritz, Lawrence C., Schultz-Cherry, Stacey, Green, Douglas R., Cuny, Gregory D., Thomas, Paul G., Degterev, Alexei, Balachandran, Siddharth

Issue&Volume: 2024-04-10

Abstract: Severe influenza A virus (IAV) infections can result in hyper-inflammation, lung injury and acute respiratory distress syndrome1,2,3,4,5 (ARDS), for which there are no effective pharmacological therapies. Necroptosis is an attractive entry point for therapeutic intervention in ARDS and related inflammatory conditions because it drives pathogenic lung inflammation and lethality during severe IAV infection6,7,8 and can potentially be targeted by receptor interacting protein kinase 3 (RIPK3) inhibitors. Here we show that a newly developed RIPK3 inhibitor, UH15-38, potently and selectively blocked IAV-triggered necroptosis in alveolar epithelial cells in vivo. UH15-38 ameliorated lung inflammation and prevented mortality following infection with laboratory-adapted and pandemic strains of IAV, without compromising antiviral adaptive immune responses or impeding viral clearance. UH15-38 displayed robust therapeutic efficacy even when administered late in the course of infection, suggesting that RIPK3 blockade may provide clinical benefit in patients with IAV-driven ARDS and other hyper-inflammatory pathologies.

DOI: 10.1038/s41586-024-07265-8

Source: https://www.nature.com/articles/s41586-024-07265-8