树鼩败血症模型的创制

Sepsis is a systemic inflammatory response syndrome following bacterial infection with 30-70% of mortality and limited therapeutic options. Experimental sepsis models in rodent are not absolutely in accordance with human sepsis, which limit the investigation of pathogenesis and novel therapeutic strategies to sepsis. Thus, the animal sepsis models with similar pathogenesis to human sepsis are urgently needed. Emerging evidences demonstrate that tree shrew (Tupaia belangeri chinensis) is a small non-human primate, and is suitable to replicate several human diseases without disadvantages existed in other non-human primates. In our previous study, two bacterial infection models have been established in tree shrew burned skin suggesting tree shrew is more susceptible to human bacterial pathogens such as P. aeruginosa and S. aureus than that of kunming mice do. We also find similar dynamics of pro-inflammatory cytokine expression in tree shrew macrophages and human monocytes after stimulation with LPS. In this study, we aim to establish tree shrew sepsis model by bacteria, LPS, and cecal ligation and puncture, and investigate whether tree shrew sepsis model is a promising experimental model to replicate human sepsis. Our study may facilitate the further understanding of pathogenesis and the development of novel therapeutic strategy to human sepsis.

败血症（Sepsis）是主要由细菌感染导致的全身性炎症反应综合症，具有非常高的死亡率(30-70%)，且治疗手段非常有限。目前主要用啮齿类动物建立败血症模型，但其病理机制同人类败血症具有较大差异，成为人类败血症病理机制研究和治疗药物研发的瓶颈。因此创制同人类败血症具有相似病理机制的动物模型是非常迫切需要的。树鼩是一种与灵长类亲缘关系很近的小型、新型实验动物，已应用于人类疾病动物模型研究。我们前期建立了两种细菌感染皮肤的树鼩模型，发现树鼩对绿脓杆菌和金黄色葡萄球菌比昆明小鼠更易感。内毒素（LPS）刺激树鼩巨噬细胞和人单核细胞具有相似的的细胞因子动态表达。本项目旨在采用外源性细菌感染、脂多糖及盲肠结扎与穿孔等方法创制树鼩败血症模型,并通过比较其病理过程同小鼠和人类败血症的异同,评价树鼩败血症模型是否能够更好地模拟人类败血症。研究结果有助于深入理解人类败血症的病理机制和筛选潜在的治疗药物。

败血症（Sepsis）是主要由细菌感染导致的全身性炎症反应综合症，具有非常高的死亡率(30-70%)，且治疗手段非常有限。目前主要用啮齿类动物建立败血症模型，但其病理机制同人类败血症具有较大差异，成为人类败血症病理机制研究和治疗药物研发的瓶颈。因此创制同人类败血症具有相似病理机制的动物模型是非常迫切需要的。在本研究项目中,我们采用与灵长类亲缘关系很近的小型、新型实验动物(树鼩)创制败血症模型。经过3年的研究，我们成功建立了多种树鼩败血症模型，包括：免疫抑制的树鼩绿脓杆菌败血症模型，树鼩盲肠结扎与穿孔导致的多种细菌感染败血症模型，树鼩内毒素败血症模型。利用这些模型研究发现：树鼩败血症模型中促炎细胞因子以及一氧化氮的动态变化水平及肝组织病理切片改变同人败血症比较一致；天然抗菌肽选择性调节免疫反应对树鼩败血症有预防和保护效果。研究结果表明树鼩是一种建立败血症模型的新型实验动物，树鼩败血症模型能够较好地模拟人类败血症，为研究败血症疾病机理以及药物研发提供了一种新型的实验动物模型。