基于巨噬细胞极化研究天然产物Smiglaside A改善脓毒症的作用及机制

Sepsis is a major problem that has not to be solved in modern critical care medicine, and there has no effective treatment now. Although regulating macrophage polarization is a new strategy to ameliorate sepsis, the molecular mechanism is still unclear. Smilax riparia is a kind of medicinal and edible plants which has strong anti-inflammatory activity. However, few researches have been done on its active ingredients and mechanisms. In our previous works, we isolated and identified the monomeric compounds of Smilax riparia, and found that Smiglaside A, a phenylpropanoid glycoside, can significantly promote macrophage to M2 phenotype and ameliorate the lipopolysaccharide-induced mice sepsis. In addition, the regulating macrophage polarization effect of it may be related to fatty acid oxidation, but the specific mechanism is unclear. We will investigate whether Smiglaside A can ameliorate sepsis by promoting macrophage to M2 phenotype through regulating fatty acid oxidation, and illuminate the specific molecular mechanisms with technologies such as pathology, molecular biology, metabonomics. These findings aim to provide candidate drugs and theory basis for new treatment strategy of sepsis.

脓毒症是现代危重病医学中未解决的重大难题，目前尚无有效治疗手段。虽然调控巨噬细胞极化可能是改善脓毒症的全新策略，但巨噬细胞极化过程的分子机制仍不清楚。药食同源植物牛尾菜具有良好的抗炎活性，目前缺乏对其有效活性成分及作用机制的研究。前期我们分离、鉴定了牛尾菜中的单体化合物，首次发现苯丙素糖苷Smiglaside A能明显促进巨噬细胞向M2抗炎表型极化，并可改善脂多糖诱导的小鼠脓毒症，而且其促进巨噬细胞M2极化作用可能与脂肪酸氧化相关，但具体机制还不清楚。本项目拟在分子、细胞和动物水平，利用病理学、分子生物学、代谢组学等技术，以脂肪酸氧化为主线，巨噬细胞极化为研究对象，系统考察Smiglaside A如何通过能量代谢信号通路调控巨噬细胞脂肪酸氧化，从而促进其向M2表型极化，最终改善脓毒症，并深入探讨具体的分子机制。通过本项目研究，将为脓毒症治疗的新策略提供候选药物及理论依据。

脓毒症是现代危重病医学中未解决的重大难题，目前尚无有效治疗手段。虽然调控巨噬细胞极化可能是改善脓毒症的全新策略，但巨噬细胞极化过程的分子机制仍不清楚。药食同源植物牛尾菜具有良好的抗炎活性，目前缺乏对其有效活性成分及作用机制的研究。前期我们分离、鉴定了牛尾菜中的单体化合物，首次发现苯丙素糖苷Smiglaside A能明显促进巨噬细胞向M2抗炎表型极化，并可改善脂多糖诱导的小鼠脓毒症，而且其促进巨噬细胞M2极化作用可能与脂肪酸氧化相关，但具体机制还不清楚。在本项目的研究中，首先，我们利用脂多糖诱导的巨噬细胞炎症模型在体外水平明确了Smiglaside A促进巨噬细胞M2极化的作用，并且阐明了其通过激活AMPK-PPARγ信号通路调控能量代谢（增加脂肪酸氧化）从而促进巨噬细胞M2极化的机制。其次，我们进一步使用了小鼠脓毒症模型在体内水平观察Smiglaside A对小鼠脓毒症的影响，发现Smiglaside A能明显改善脓毒症小鼠的死亡及器官损伤，并且促进小鼠体内的巨噬细胞向M2表型极化。最后，我们利用细胞回输技术，明确了Smiglaside A促进巨噬细胞M2极化与改善脓毒症之间的关系。通过本项目研究，将为脓毒症治疗的新策略提供候选药物及理论依据。