Ghrelin-obestatin信号调节通路在肺脾两虚型慢性阻塞性肺疾病的动态表达及培土生金法的干预研究

Chronic obstructive pulmonary disease (COPD) is frequently occurring illness with progressive course. As an independent risk factor for unfavorable prognosis of COPD, malnutrition is one of the main complications which is still lack of specific therapy and effective drugs. As clinically proved by TCM doctors, the mainly pathogenesis evolution of this disease is deficiency of both Lung and Spleen. By the method of 'reinforcing earth to generate metal', the treatment of Chinese medicine has a definite clinical curative effect in improving nutrition and prognosis. But there is no significant progress in experimental research. The Ghrelin-obestatin signal regulatory pathway plays an important role in digestion and metabolism. Based on the law of pathogenesis and previous study, we not only observe the expression of ghrelin and obestatin and their receptors in stomach and hypothalamus, the dynamic changes of Ghrelin-obestatin signal regulatory pathway, but also the relationship between the changes of ghrelin and obestatin and their receptors and leping, IL-6 and TNF-α with the method of Immunohistochemistry, Immunoblotting and RT-PCR.We intervene by using the Shen ling bai zhu Powder which is a representative decoction, so as to clarify the mechanisms of the method in preventing and treating COPD due to deficiency of Lung and Spleen and the location of the target cites by the theory of brain-gut signal pathway and inflammatory mediators response By elucidating the scientific mechanism we hope to provide theoretical support in using Chinese medicine to prevent and treat COPD.

慢性阻塞性肺疾病(COPD)是常见病，呈进行性发展。营养不良是其重要并发症，是COPD预后不良的独立危险因素，迄今尚无特异治疗方法。中医临床证实其病机演变多为肺脾两虚，以培土生金法治疗COPD对改善其营养状况及预后疗效显著，但其相关实验研究基础尚未取得进展。Ghrelin-obestatin信号调节通路对人体营养物质的消化吸收及代谢发挥重要作用。基于COPD病机规律及前期研究基础，本研究采用免疫组化、免疫印迹及RT-PCR法技术观察Ghrelin-obestatin信号调节通路及其受体在肺脾两虚型COPD大鼠胃组织、下丘脑的动态表达及与炎症介质瘦素、IL-1、TNF-α之间的相关性；在此基础上采用培土生金常用方参苓白术散进行干预，从脑肠信号通路及与炎症介质的对话效应揭示参苓白术散防治肺脾两虚型COPD的作用机制和药靶部位，以期阐明其科学内涵，为开发防治COPD的优势中成药提供理论支撑。

慢性阻塞性肺疾病（COPD）是临床上常见的疾病，已成为全球主要死因，除了肺部表现外，还与多种系统表现有关，包括贫血、骨质疏松症和营养不良等。营养不良作为COPD患者1年死亡率和医疗保健使用的独立预测指标，对COPD的预后极为不利。肺脾两虚是COPD稳定期常见证型，前期研究认为脾气虚是COPD合并营养不良的关键环节，肺脾两虚是COPD营养不良发病中的主要病机。培土生金法对于COPD稳定期患者常有较好疗效，生长激素释放肽（Ghrelin）与肥胖抑制素（Obestatin）及其受体（GHSR、GPR39）与中枢食欲调节网络相互作用，具有调节摄食，影响胃肠功能、控制体重的作用。培土生金法是否通过调节Ghrelin-Obestatin信号通路起到防治COPD的作用，为证实该假说，本研究利用复合造模法（烟熏+气管内滴注脂多糖+灌服番泻叶）制备肺脾两虚型COPD大鼠模型，观察Ghrelin-Obestatin信号通路在肺脾两虚型COPD大鼠的动态表达，同时观察培土生金法代表方参苓白术散干预对Ghrelin-Obestatin信号调节通路的影响，探讨其机制。研究表明，肺脾两虚型COPD大鼠下丘脑及胃组织中Ghrelin，GHSR，Obestatin，GPR39蛋白及mRNA均减少，并且炎症介质处于高表达水平，肺组织切片病变明显。参苓白术散可以升高肺脾两虚型COPD大鼠下丘脑及胃组织中Ghrelin，GHSR，Obestatin，GPR39蛋白及mRNA的表达水平，降低体内炎症介质的表达，改善肺组织病变。本项目证实了Ghrelin-Obestatin信号调节通路通过影响机体能量代谢和营养状态而参与了COPD合并营养不良的发病，揭示了培土生金法干预在肺脾两虚型COPD中的防治作用及机理。