Club细胞蛋白10(CC10)抑制cPLA2保护RSV感染所致气道炎症与AHR的作用机制研究

Respiratory Syncytial Virus (RSV) is the most common viral pathogen causing lower respiratory tract infection in infants worldwide lacking safe and effective prevention and treatment. Epithelial cell is the first line of defense against RSV infection, and the degree of damage is closely related to the severity and prognosis. In our previous study, CC10 produced by Club epithelial cells was significantly reduced in RSV infected BALB/c mice. And we further found that CC10 level was negatively correlated with the severity and course of disease after RSV infection in clinic. As an important anti-inflammatory factor, CC10 plays its role by inhibiting cPLA2, so it is proposed that "CC10 plays a protective role in airway inflammation and AHR caused by RSV infection by inhibiting cPLA2 and its downstream pathways". In this study, recombinant CC10 and molecular inhibitor of cPLA2 were administrated to RSV infected mice to observe the changes of airway inflammation and airway hyperresponsiveness, and to compare the effectiveness and safety of recombinant CC10 and molecular inhibitor of cPLA2, so as to provide effective targets and alternative drugs for the clinical treatment of severe RSV infection.

呼吸道合胞病毒（Respiratory Syncytial Virus, RSV）是全球范围内引起婴幼儿下呼吸道感染最常见的病毒病原体，目前临床上尚无安全有效的防治方法。上皮细胞是抵御RSV感染的第一道防线，其受损程度与疾病严重程度及预后密切相关。课题组前期在动物模型中证实，RSV感染BALB/c小鼠后Club上皮细胞产生的CC10显著降低，进一步在临床中发现CC10水平与RSV感染后疾病严重程度及病程呈负相关。作为一种重要的抗炎因子，CC10通过抑制cPLA2发挥作用，故提出“CC10可能通过抑制cPLA2改善RSV感染后气道炎症及AHR”这一科学问题。本研究拟在RSV感染的小鼠模型中予CC10重组因子及cPLA2分子抑制剂干预，观察小鼠气道炎症、气道高反应性变化，比较CC10重组因子及cPLA2分子抑制剂的有效性及安全性，为临床上治疗重症RSV感染提供有效的靶点及可供选择的药物。

上皮细胞是抵御呼吸道合胞病毒（Respiratory Syncytial Virus，RSV）感染的第一道防线，其受损程度与急性期疾病严重程度及远期预后均密切相关。课题组预实验发现，RSV感染BALB/c小鼠后Club细胞蛋白10（Club cell 10-kDa protein，CC10）显著降低；临床上CC10水平越低，RSV感染患儿疾病严重程度越重，病程越长。本项目通过予重组CC10因子、小分子抑制剂阻断CC10下游胞浆磷酸酯酶A2（cytosolic phospholipase A2，cPLA2），进一步予cPLA2下游环氧合酶途径（Cyclooxygenases，COX）及脂氧合酶途径（Lipoxygenase，LOX）抑制剂干预小鼠证实：1.CC10在RSV感染后气道炎症及气道高反应性（Airway Hyperresponsiveness，AHR）中起到保护性作用 2.cPLA2及其下游COX、LOX通路参与RSV感染后气道炎症及AHR，且CC10可缓解cPLA2及其下游通路介导的炎症反应 3.CC10和cPLA2通路的分子抑制剂在缓解RSV感染后的气道炎症及AHR方面各有优劣，安全性方面无明显区别。本项目深入研究CC10作用的信号通路及其效应，为临床上治疗重症RSV感染提供有效的靶点及可供选择的药物。