p38MAPK通路与NF-κB/IκB-α通路在溃疡性结肠炎肺肠屏障共损伤中的交互作用及益气活血解毒方影响

According the study on Ulcerative Colitis (UC) by clinical and animal research before we found that: 1.Iung injury always happened with UC; 2.Intestinal mucosal barrier and lung barrier damaged together; 3.Damp-heat blood stasis toxin damaging the intestine collateral and then upward attacking the lung maybe the key cause for relapses of UC and so many extra-intestinal manifestations. So, on the basis of the original work, through the animal and cell experiment, we observing the air-blood barrier damage in UC systematically, studying the interaction between p38MAPK pathway and NF-κB/IκB-α pathway in UC with both air-blood barrier and intestinal barrier injury. Then, we deeply analyze the related regularity between biological effects of Chinese medicine and air-blood barrier damage in UC, find effective links of Yiqi Huoxue Jiedu Fang and its separations in treating UC and preventing air-blood barrier damage, so could supple TCM pathogenesis theory of UC and provide evidence for clinical application of Yiqi Huoxue Jiedu Fang.

前期对溃疡性结肠炎（Ulcerative Colitis, UC）的临床及实验研究发现：1、UC存在肺损伤；2、UC时肺肠屏障发生共损伤，可能是UC合并肺损伤的重要病理学基础；3、“湿热瘀毒损伤肠络，毒邪上攻损肺”可能是UC反复发作及众多肠外表现的病机关键。因此本课题在原有工作基础上，通过动物和细胞实验，进一步系统观察UC肺气血屏障损伤情况，研究p38MAPK通路和NF-κB/IκB-α通路在UC肺肠屏障损伤中的调控机制及交互作用，并以益气活血解毒立法组成的中药复方进行干预，深入剖析中药生物效应与UC肺肠屏障损伤病理机制的关联规律，找出益气活血解毒方抗UC及UC肺损伤的作用环节，补充UC中医病机理论，为其临床应用提供依据。

溃疡性结肠炎（UC）是一种病因不明的慢性非特异性肠道炎症性疾病，治愈难度大，常反复发作，可伴有肠外病变，被世界卫生组织列为现代难治病之一。西医多采用氨基水杨酸类、皮质类固醇和免疫抑制剂治疗，毒副反应较大。团队前期临床及实验研究发现：UC存在肺损伤；UC大鼠肠黏膜屏障受损的同时，存在肺气血屏障紧密连接结构异常；“湿热于毒损伤肠络，毒邪上攻损肺”可能是UC反复发作及众多肠外表现的病机关键。本项目通过免疫复合法复制大鼠UC模型，结合体外分离培养AEC-Ⅱ，系统评价UC肺气血屏障的病理改变，研究p38MAPK通路和NF-κB/IκB-α通路在UC肺肠屏障损伤中的调控机制及相互关系，观察以补益肺气、清肺活血解毒立法的益气活血解毒方的作用。研究结果表明UC大鼠肠屏障损伤的同时，出现AECⅡ超微结构变化及异常增殖，肺屏障紧密连接蛋白ZO-1和骨架蛋白F-actin表达减少，通透性增高，肺组织NF-κB、IκB-α、Caspase-3、BaxmRNA表达升高，IκB-α、Bcl-2mRNA表达降低，p38MAPK、C-jun、C-fos蛋白表达增多，炎性细胞因子TNF-α、IL-1β含量增加；细胞实验通过p38MAPK和NF-κB特异性抑制剂干预，结果提示两通路在UC肺肠屏障共损伤中存在交互作用，共同调节UC肺肠组织中TNF-α、IL-1β产生。益气活血解毒方能够通过抑制p38MAPK通路和NF-κB/IκB-α通路拮抗肺气血屏障损伤，同时促进UC肠黏膜溃疡愈合，以中药中剂量组疗效更明显。项目为“肺与大肠相表里”理论提供了实验依据，为UC防治提供新思路，为研究开发UC肺肠同治的益气活血解毒制剂提供了药效学基础。