清热解毒中药治疗呼吸系统病毒感染的药效物质与作用机制

Respiratory virus infections, such as severe acute respiratory syndrome (SARS) and influenza A, are severe life-threatening infectious diseases. Traditional Chinese medicines with heat-clearing and detoxification functions have played very important role in prevention and treatment of the respiratory virus infections such as SARS. However, their effective constituents and underlying mechanisms remain unclear mostly. This proposal is to elucidate the effective constituents and action mechanisms of the 6 selected medicines （Houttuyniae Herba, Scutellariae Radix, Indigo Naturalis, Lasiosphaera/Calvatia, Ilicis Asprellae Radix, Helicteres Radix）for treatment of acute lung injury (ALI) induced by influenza A virus. The chemical constituents of the selected medicines will be investigated under bioactivity-guided fractionation for isolation of anti-complementary and antiviral agents. The anti-inflammatory effects of the bioactive constituents will be evaluated in mice with acute lung injury induced by influenza A virus. This study will focus on the bioactive polysaccharides for their immune-modulating effects. The possible synergetic effect of the anti-inflammatory and antiviral constituents present in Houttuyniae Herba and combination of Indigo Naturalis-Lasiosphaera couple will be investigated in mice infected with influenza A virus. The protective effects on virus-induced ALI and metabolisms of some potential bioactive constituents in Scutellariae Radix will be studied with animal models. This study will provide the scientific evidence to understand the effective constituents and underlying mechanisms of traditional Chinese medicines for their beneficial effects on respiratory virus infections. The effective constituents obtained in this study might be the drug candidates for prevention and treatment of the lung infectious diseases including influenza A and SARS. This study will provide the scientific support to the rational clinic application and effective quality control of these Chinese medicines as well.

以非典和甲型流感为典型代表的呼吸系统病毒感染性疾病对人民生命健康带来严重危害，清热解毒中药在防治这些疾病方面扮演着极其重要的角色，但其药效物质基础和作用机制多不清楚。本项目选择鱼腥草、黄芩、青黛、马勃、岗梅根、山芝麻等6种常用清热解毒中药及岭南特色药材为研究对象，以补体抑制和抗病毒活性为生物学指标，活性导向分离鉴定活性成分，利用甲型流感病毒诱导的急性肺损伤动物模型评价抗炎和抗病毒作用，重点关注具有免疫调节作用的多糖成分及其作用机制，探讨鱼腥草和青黛马勃方中抗炎成分与抗病毒成分的可能协同作用，结合化学成分的动物体内代谢研究阐述黄芩发挥药效的化学成分。以期阐明清热解毒中药治疗呼吸系统病毒感染的药效物质与作用机制，找到对病毒性急性肺损伤具有显著治疗作用的有效成分，为甲型流感等呼吸系统病毒感染的防治发现新的药物候选物，并为相关中药的合理应用与有效质量控制提供科学依据。

以非典和甲型流感为典型代表的呼吸系统病毒感染性疾病对人民生命健康带来严重危害，清热解毒中药在防治这些疾病方面扮演着极其重要的角色，但其药效物质基础和作用机制多不清楚。本项目选择鱼腥草、黄芩、青黛、马勃、岗梅根、山芝麻等常用清热解毒中药为研究对象，以补体抑制和抗病毒活性为生物学指标，活性导向分离鉴定了387个小分子化合物，其中219个具有抗补体、抗病毒活性，涉及三萜、黄酮、木脂素、生物碱、甾醇等结构类型，抗补体活性化合物呈现出一定的构效关系及多样的作用靶点；穿心莲内酯等二萜类成分可经肠内菌代谢活化为抗补体活性产物；同时分离表征了12个抗补体活性均一多糖，发现活性多糖多具有复杂的单糖组成、较高的糖醛酸含量与分支结构。利用甲型流感病毒诱导的急性肺损伤动物模型评价抗炎和抗病毒作用，明确了鱼腥草多糖、鱼腥草总黄酮、黄芩总黄酮及火炭母多糖对流感病毒感染小鼠的治疗作用，抗炎、免疫调节是其主要作用机制；发现鱼腥草多糖仅口服有效，而静脉注射无效，深入机制研究明确了鱼腥草多糖具有通过调控流感病毒感染的粘膜免疫发挥“从肠治肺”的作用，为“肺与大肠相表里”的中医理论提供了新的科学证据。探讨了鱼腥草中抗炎成分与抗病毒成分以及青黛马勃药对的协同作用，发现鱼腥草多糖与总黄酮配伍可以多环节、多靶点地对甲型流感病毒感染小鼠发挥协同治疗作用，显著提高病毒感染小鼠的生存率、延长生存时间、减轻肺部病理损伤和水肿；马勃和青黛配伍后也具有协同作用。结合化学成分的动物体内代谢与肠内菌转化研究，阐明了体外无抗补体活性的黄芩总黄酮通过体内代谢转化为苷元类活性成分发挥药效的机制，且发现高纯度黄芩总黄酮的疗效明显优于同剂量的黄芩苷。研究结果较好阐释了以上清热解毒方药治疗呼吸系统病毒感染的药效物质与作用机制，为研发治疗呼吸系统病毒感染的新型药物提供了新思路，并为相关中药的合理应用与质量控制提供了科学依据。