LPS-IRAK4与TGF-β-ERK串话在“通腑利肺法”治疗肠源性肺损伤中的作用及机制研究

Gut-derived endotoxin-mediated lung damage (GELD) is the result of endotoxemia due to large amount of LPS absorbed into the blood circulation because of the intestinal mucosal barrier damage. There is no specific treatment for GELD up to now. It is clinicallyconfirmed that TongfuLifei method can effectively promote the recovery of patients with GELD and reduce mortality. Our previous study indicates that TongfuLifei method can protect lung tissue by reducing LPS in intestines and downregulating expression of inflammation-related genes. If we further explore the target of TongfuLifei method with the guidance of the classic Chinese theory that the lung and the large intestine are exterior-interiorly related, we might be able to provide a new way for the prevention and treatment of GELD. Based on the above work, we aim to focus our study on the effects and mechanisms of the cross-talk between LPS-IRAK4 and TGF-β-ERK in gut-derived endotoxin-mediated lung damage, to observe the influences of TongfuLifei method on the above pathways, and to confirm the efficacy of TongfuLifei method on GELD on the level of gene regulation. Our study may gain new insight into the targets of TongfuLifei method. In the meantime, our research is promising to provide scientific evidence andmaterial basis for the theory that the lung and the large intestine areexterior-interiorly related, giving the theory a new explanation.

肠源性肺损伤是肠粘膜屏障破坏使内毒素（LPS）大量吸收入血形成内毒素血症的结果，迄今尚无特效治疗方法。目前研究证实，中医通腑利肺法可以治疗肠源性肺损伤，能明显促进患者脏器功能恢复，降低病死率。课题组前期研究显示通腑利肺法通过降低LPS在肠道的聚集，降低炎症相关基因的表达，对肺组织起保护作用。我们推测，如果以中医肺与大肠相表里理论为指导，深入研究通腑利肺法的作用靶点，将为肠源性肺损伤的防治提供新的思路。本项目将在前期工作的基础上，进一步研究LPS-IRAK4与TGF-β-ERK“串话”在肠源性肺损伤中的作用及机制，最终观察中医通腑利肺法治疗对上述指标的影响，并在基因表达调控的高度上证实通腑利肺法治疗思路对肠源性肺损伤的治疗效果，将对通腑利肺法的作用靶点有一个全新的认识。本课题在相应研究的基础上，也为中医“肺与大肠相表里”理论赋予科学依据和物质基础，对“肺与大肠相表里”理论将有一个更新的诠释。

肠源性肺损伤是肠粘膜屏障破坏使内毒素（LPS）大量吸收入血形成内毒素血症的结果，迄今尚无特效治疗方法。本课题结合分子生物学，从体内及体外两方面，在蛋白、基因表达的层面，探讨了中医“通腑利肺法”治疗肠源性肺损伤的物质基础。研究中通过部分盲肠结扎穿刺法建立肠源性肺损伤模型，大承气汤为通腑利肺法的代表方剂，观察大承气汤是否可通过调控IRAK4与TGF-β-ERK信号通路，从而减轻急性肺损伤。本实验观察到大承气汤可通过抑制IRAK4与TGF-β-ERK 信号通路，进而降低大鼠肺组织的炎症水平，减轻其组织损伤。本课题在基因表达调控的高度上证实通腑利肺法治疗思路对肠源性肺损伤的治疗效果，为临床中急性肺损伤的治疗提供新的方法，同时对通腑利肺法的作用靶点有一个全新的认识，也为中医“肺与大肠相表里”理论赋予科学依据和物质基础, 对“肺与大肠相表里”理论有一个更新的诠释。