基于COX-2/HIF-1/VEGF通路探讨胃祺饮治疗慢性萎缩性胃炎的作用机制

Chinese medicine believes that qi deficiency and blood stasis, are the important pathogenesis of chronic atrophic gastritis. Modern scientific research also showed that gastric tissue micro-environment ischemia and hypoxia-induced angiogenesis and microcirculation disturbance are important pathological material basis for chronic gastric mucosal injury. HIF-1α and VEGF pathways play a very important role in mediating angiogenesis and microcirculation disturbance; studies have also shown that overexpression of COX-2 also up-regulated the expression of VEGF, then induced vascular endothelial dysfunction,angiogenesis and tumor formation. Compared to the western medicine, the traditional Chinese medicine performed better in the prevention of chronic atrophic gastritis, however, its material basis of effecacy and mechanism of action has not been fully elucidated. "Yiqihuoxue" method is commonly used in Chinese Medicine formula to treat patients with chronic atrophic gastritis. Previous clinical and experimental research results showed that with the effect of raising "Qi" and smoothing the "Blood", Weiqi decoction was very effective against chronic atrophic gastritis, and could regulate gastrointestinal mucosal blood flow, inhibit the proliferation of AGS cells and induce cell apoptosis. However, the material basis of "Yiqihuoxue" effect remains to be elucidated. This study aimed to explore the action and mechanism of anti-angiogenesis and anti-microcirculation disturbance effect on chronic atrophic gastritis based on COX-2/HIF 1/VEGF pathway, revealing the material basis of "Yiqihuoxue" effect.

中医学认为气虚血瘀是慢性萎缩性胃炎（CAG）的重要病机。研究表明胃组织微环境缺血缺氧诱发胃黏膜微循环障碍、微血管新生异常是胃黏膜损伤的重要病理物质基础，但其在CAG病理发生中的作用尚待深入研究。HIF-1α和VEGF通路在介导微循环障碍和血管新生中起着非常重要的作用；研究也表明，COX-2的过表达也能上调VEGF的表达，诱发血管内皮功能异常、血管新生和肿瘤形成。中医药在防治CAG方面较西医有优势，但其药效物质基础和作用机制尚未完全阐明。益气活血是中医辨证治疗CAG的常用有效方法。前期临床和实验研究结果表明，益气活血的胃祺饮能有效对抗CAG，并调节胃肠黏膜血流，抑制AGS细胞增殖和诱导细胞凋亡，但其益气活血的功效物质基础尚待阐明。本研究基于COX-2/HIF-1/VEGF通路探讨胃祺饮抗CAG胃黏膜微循环障碍、微血管生成和内皮功能异常的作用机制，及益气活血的部分物质基础。

中医学认为慢性萎缩性胃炎（CAG）属于“胃脘痛”、“痞满”、“嘈杂”、“腹胀”、“嗳气”等范畴。其中“气虚血瘀”贯穿CAG整个发病的始终。临床上合理选用“益气活血”复方，具有改善胃黏膜血液循环、抑制组织异常增生、消除炎症、镇痛和调节免疫等作用，从而可以达到改善临床症状，逆转胃黏膜萎缩、肠上皮化生及不典型增生的目的。然而长期以来，CAG胃黏膜微循环障碍和血管内皮功能障碍在CAG中的重要病理作用未得到足够的重视，也未有大量的临床与实验研究进一步深入挖掘和探索。通过本研究，我们证实，中医学理论认为的CAG病机的“气虚血瘀”与CAG胃黏膜微循环障碍、微血管新生异常和血管内皮功能紊乱存在密切的关系，在慢性萎缩性胃炎尚未形成病理性改变之前，胃局部尤其是幽门部位即存在微循环障碍，血流速度显著降低，随着慢性萎缩性胃炎病理发展进程的进一步加深，出现明显的缺氧（缺氧诱导因子HIF-1的高表达），继而又出现明显的炎症（炎症相关因子如COX-2等的高表达），HIF-1a/COX-2/VEGF信号通路的异常，病理性血管新生的存在，从而导致慢性萎缩性胃炎伴肠化生和不典型增生。而益气活血的方药如胃祺饮则是通过调控胃黏膜微循环和血流速度、微血管生成和血管内皮功能，调控HIF-1a/COX-2/VEGF信号通路，增加血清PGE2含量，从而达到治疗CAG的目的。本研究结果也提示我们祖国医学理论的正确性，及在临床诊治中重视中医理论对临床指导的重要性，并且深入挖掘和领悟中医理论在临床实践中的重要意义。