Division of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA; VC-CAST Signature Center, Indianapolis, IN, USA; Roudebush Veterans Affairs Medical Center, Indiana University, Indianapolis, IN, USA.
VC-CAST Signature Center, Indianapolis, IN, USA; Roudebush Veterans Affairs Medical Center, Indiana University, Indianapolis, IN, USA; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
Mol Ther. 2018 Aug 1;26(8):2060-2069. doi: 10.1016/j.ymthe.2018.05.017. Epub 2018 Jun 15.
Influenza A virus (IAV) remains a major worldwide health threat, especially to high-risk populations, including the young and elderly. There is an unmet clinical need for therapy that will protect the lungs from damage caused by lower respiratory infection. Here, we analyzed the role of EMAPII, a stress- and virus-induced pro-inflammatory and pro-apoptotic factor, in IAV-induced lung injury. First, we demonstrated that IAV induces EMAPII surface translocation, release, and apoptosis in cultured endothelial and epithelial cells. Next, we showed that IAV induces EMAPII surface translocation and release to bronchoalveolar lavage fluid (BALF) in mouse lungs, concomitant with increases in caspase 3 activity. Injection of monoclonal antibody (mAb) against EMAPII attenuated IAV-induced EMAPII levels, weight loss, reduction of blood oxygenation, lung edema, and increase of the pro-inflammatory cytokine TNF alpha. In accordance with the pro-apoptotic properties of EMAPII, levels of caspase 3 activity in BALF were also decreased by mAb treatment. Moreover, we detected EMAPII mAb-induced increase in lung levels of M2-like macrophage markers YM1 and CD206. All together, these data strongly suggest that EMAPII mAb ameliorates IAV-induced lung injury by limiting lung cell apoptosis and shifting the host inflammatory setting toward resolution of inflammation.
甲型流感病毒（IAV）仍然是全球主要的健康威胁，特别是对高危人群，包括年轻人和老年人。目前临床上需要一种能够保护肺部免受下呼吸道感染损伤的治疗方法。在这里，我们分析了 EMAPII 在 IAV 引起的肺损伤中的作用。首先，我们证明了 IAV 诱导培养的内皮细胞和上皮细胞中 EMAPII 的表面易位、释放和凋亡。接下来，我们表明 IAV 诱导小鼠肺部的 EMAPII 表面易位和释放，同时伴有 caspase 3 活性增加。针对 EMAPII 的单克隆抗体（mAb）注射可减轻 IAV 诱导的 EMAPII 水平、体重减轻、血氧饱和度降低、肺水肿和促炎细胞因子 TNF-α增加。与 EMAPII 的促凋亡特性一致，mAb 治疗也降低了 BALF 中 caspase 3 活性的水平。此外，我们检测到 EMAPII mAb 诱导的 M2 样巨噬细胞标志物 YM1 和 CD206 在肺中的水平增加。综上所述，这些数据强烈表明，EMAPII mAb 通过限制肺细胞凋亡并将宿主炎症状态转向炎症消退来改善 IAV 引起的肺损伤。
