The Disruption of the Endothelial Barrier Contributes to Acute Lung Injury Induced by Coxsackievirus A2 Infection in Mice.
The Disruption of the Endothelial Barrier Contributes to Acute Lung Injury Induced by Coxsackievirus A2 Infection in Mice.
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柯萨奇病毒A2感染致小鼠急性肺损伤的内皮屏障破坏机制
DOI：
10.3390/ijms22189895
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发表时间：
2021-09-13
影响因子：
5.6
通讯作者：
Duan G
中科院分区：
文献类型：
--
作者：
Ji W;Hu Q;Zhang M;Zhang C;Chen C;Yan Y;Zhang X;Chen S;Tao L;Zhang W;Jin Y;Duan G
近年来，由柯萨奇病毒A2(CVA2)引起的手足口病(HFMD)在全球范围内频繁发生和暴发，对公众健康构成了极大的挑战。流行病学研究表明，危重患者的主要死因是肺水肿。然而，这种潜在的合并症的发病机制仍不清楚。在这项研究中，我们利用5日龄BALB/c小鼠致死性CVA2感染模型来评估肺损伤。我们发现CVA2感染后肺微血管通透性明显增加。我们还观察到肺内皮细胞的直接感染和凋亡，以及内皮细胞之间紧密连接的破坏。CVA2感染导致紧密连接蛋白(如ZO-1、claudin-5和occludin)的降解。血管性假血友病因子(VWF)、内皮素(ET)、血栓调节蛋白(THBD)、颗粒膜蛋白140(GMP140)、细胞间黏附分子-1(ICAM-1)等与内皮功能障碍相关的基因转录水平均显著升高。此外，CVA2感染可诱导炎性细胞因子(IL-6、IL-1β和单核细胞趋化蛋白-1)表达增加，并激活p38丝裂原活化蛋白激酶。综上所述，内皮屏障的破坏参与了CVA2感染所致的急性肺损伤；靶向p38-MAPK信号通路可能为手足口病危重感染中的肺水肿提供一种治疗途径。
Sporadic occurrences and outbreaks of hand, foot, and mouth disease (HFMD) caused by Coxsackievirus A2 (CVA2) have frequently reported worldwide recently, which pose a great challenge to public health. Epidemiological studies have suggested that the main cause of death in critical patients is pulmonary edema. However, the pathogenesis of this underlying comorbidity remains unclear. In this study, we utilized the 5-day-old BALB/c mouse model of lethal CVA2 infection to evaluate lung damage. We found that the permeability of lung microvascular was significantly increased after CVA2 infection. We also observed the direct infection and apoptosis of lung endothelial cells as well as the destruction of tight junctions between endothelial cells. CVA2 infection led to the degradation of tight junction proteins (e.g., ZO-1, claudin-5, and occludin). The gene transcription levels of von Willebrand factor (vWF), endothelin (ET), thrombomodulin (THBD), granular membrane protein 140 (GMP140), and intercellular cell adhesion molecule-1 (ICAM-1) related to endothelial dysfunction were all significantly increased. Additionally, CVA2 infection induced the increased expression of inflammatory cytokines (IL-6, IL-1β, and MCP-1) and the activation of p38 mitogen-activated protein kinase (MAPK). In conclusion, the disruption of the endothelial barrier contributes to acute lung injury induced by CVA2 infection; targeting p38-MAPK signaling may provide a therapeutic approach for pulmonary edema in critical infections of HFMD.
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