基于恒河猴模型的百草枯肺损伤机制和MSCs干预研究

百草枯（PQ）中毒可致急性肺损伤、多器官功能衰竭及肺纤维化，导致高病死率及致残率，失控的系统性炎症反应可能为主要致病机制，但至今缺乏有效治疗手段。我们在急性中毒性肝损伤猴模型中发现单核-巨噬细胞及其分泌的IL-6是启动细胞因子风暴和系统性炎症反应的关键环节，早期输入人脐带间充质干细胞（hUC-MSCs）可显著抑制单核-巨噬细胞活化，改善病程，该效应可能依赖于hUC-MSCs源性外泌体及其内含物。因肺泡巨噬细胞（AM）与肝巨噬细胞（Kupffer细胞）来源相同，功能相近，推测其在PQ肺损伤中有相似作用，也是潜在治疗靶点。本项目我们拟基于大型非人灵长类动物PQ肺损伤模型，全面动态揭示PQ肺损伤的病理生理过程，尤其是AM在其中的关键作用，进而探讨hUC-MSCs及其衍生物是否通过抑制AM活化改善病程进展和预后，以期为PQ肺损伤寻找新的治疗手段，也为干细胞及其衍生物在相关疾病中的应用研究提供参考。

Paraquat(PQ) poisoning can cause acute lung injury, multiple organ failure and pulmonary fibrosis, which has high mortality and disability. Uncontrolled systemic inflammatory responseis one of the important pathogenic mechanism, while effective treatment is not yet available. We have previously reported the key role of mono-macrophages, by over producting IL-6, in promoting cytokine storm and systemic inflammatory response in an amatoxin induced acute liver failure in a non-human primate. We also found that early peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) suppressed the activation of mono-macrophages, probably dependent on the hUC-MSCs-derived exosomes and miRNA enclosed, resulted in significantly improved systemic homeostasis and liver histology. Alveolar macrophages (AM) share the same origin and have similar function as liver macrophages (Kupffer cells), it is speculated that AM play similar role in PQ-induced lung injury and are also a potential therapeutic target. In current study, by establishing a rhesus monkey model of PQ-induced lung injury, we aim to systematically and dynamically reveal the full physiopathological process of this disease, particularly the behavior of mono-macrophages. Also, we will explore whether hUC-MSCs and their derivates, such as exosomes and miRNA, can inhibit mono-macrophage activation and therefore improve the prognosis in PQ-treated monkey model. We expect to find a novel effective treatment for PQ-induced lung injury and also to provide a theoretical basis for the application of stem cells and their derivates in other inflammatory diseases.