聚焦肺泡长链酰基肉碱代谢探讨金欣口服液治疗RSV肺炎的疗效机制

Respiratory syncytial virus is the leading viral pathogen associated with viral pneumonia in young children worldwide. There is a relative paucity of strategies available to prevent and treat RSV pneumonia at the present time. Jinxin oral liquid has significant clinical efficacy in the treatment RSV pneumonia, but the specific mechanism needs to be further studied. Recent studies have shown that long-chain acylcarnitines may represent a risk factor for lung injury caused by viral infection. Previous studies by the applicant’s research team found that after RSV infection, alveolar long chain acylcarnitines and its downstream metabolites had obvious metabolic abnormalities, while jinxin oral liquid had significant callback effect. It is suggested that the metabolism of alveolar long-chain acylcarnitines may be the key link to treat RSV pneumonia by jinxin oral liquid. This project is planned to be carried out based on the latest lipidomic research of RSV pneumonia. In vivo and in vitro models are used to qualitatively and quantitatively analyze the dynamic changes of the metabolism of alveolar long-chain acylcarnitines after RSV infection. Combined with the key metabolic enzyme carnitine palmitoyltransferase (CPT1, CPT2), the project will focus on the metabolism of alveolar long-chain acylcarnitines to investigate the curative mechanism of jinxin oral liquid for treatment of RSV pneumonia.

呼吸道合胞病毒（respiratory syncytial virus, RSV）是儿童病毒性肺炎最常见的一类病原体，至今尚缺乏针对RSV肺炎有效的防治措施。金欣口服液治疗RSV肺炎临床疗效显著，但具体作用机制有待进一步研究。近期研究表明，长链酰基肉碱与病毒感染导致的肺损伤密切相关，申请者所在团队前期研究发现RSV感染后肺泡长链酰基肉碱及其下游代谢产物呈明显代谢异常，而金欣口服液具有显著的回调作用，提示肺泡长链酰基肉碱代谢可能是金欣口服液治疗RSV肺炎的关键环节。本项目拟在前期开展的RSV肺炎脂质组学研究基础上，通过体内外模型，定性、定量分析RSV感染后肺泡长链酰基肉碱代谢的动态变化，同时结合关键代谢酶肉碱棕榈酰转移酶（CPT1，CPT2），以期从肺泡长链酰基肉碱代谢出发，探讨金欣口服液治疗RSV肺炎的疗效机制。

呼吸道合胞病毒(Respiratory syncytial virus, RSV)是儿童病毒性肺炎最常见的一类病原体，至今尚缺乏有效的防治措施。金欣口服液治疗儿童RSV肺炎临床疗效显著，前期临床研究证实RSV肺炎患儿存在血浆脂质代谢紊乱，进一步开展动物实验发现金欣口服液可显著调节小鼠血浆脂质代谢紊乱，但其具体调控机制有待进一步研究。本研究以RSV感染BALB/c小鼠为模型，发现RSV感染小鼠肺组织、肺泡灌洗液、血清中长链酰基肉碱（Long chain acylcarnitines, LCACs, C>12）等脂质含量呈上调趋势，金欣口服液具有回调趋势。在体外细胞实验上，使用氘代十八烷酸（d3-FA18:0）稳定同位素标记A549细胞，检测其是否向线粒体转移并生成LCACs。结果证实RSV感染后M3模式下氘代十八烷烯酰肉碱(d3-ACar 18:1)代谢增加，7%金欣口服液含药血清干预可下调此种代谢趋势。结合LCACs在线粒体的关键转运、代谢酶肉毒碱棕榈酰转移酶（CPT1A、CPT2），证实金欣口服液可靶向抑制AMPK/p53/p21信号通路，下调其下游转运酶CPT1A的表达，上调其下游代谢酶CPT2的表达，抑制合成，促进氧化代谢，减少LCACs在肺部的累积。并进一步诱导小鼠肺组织中M1型巨噬细胞向M2型极化，从而缓解RSV肺炎引发的肺部免疫、炎症反应，从代谢-免疫角度为中医药治疗RSV肺炎机制研究提供新思路和新靶点。