Role of Eosinophils in Hepatic Ischemia Reperfusion Injury

项目摘要 本研究的目的是探讨嗜酸性粒细胞在肝缺血和肝硬化中的功能作用， 再灌注损伤（IRI）。肝脏IRI是主要肝脏疾病期间发病率和死亡率的重要来源。 切除术和肝移植期间。先前的研究表明，肝移植后， 先天免疫细胞如嗜中性粒细胞或巨噬细胞被激活并运输到肝同种异体移植物中。 出乎意料的是，我们观察到，嗜酸性粒细胞也积累在肝脏后原位肝 人体移植。相比之下，我们不能检测到任何嗜酸性粒细胞在健康的肝活检。同样地， 在鼠模型中，嗜酸性粒细胞在肝IRI后以时间依赖性方式在肝中积累。 使用基于遗传和抗体的嗜酸性粒细胞耗竭的功能研究表明， 这些细胞在肝IRI期间。嗜酸性粒细胞耗竭后基因表达谱的无偏筛选 提示嗜酸性粒细胞依赖性ST 2具有肝保护作用。遗传和过继转移研究的结合 表明嗜酸性粒细胞特异性IL-33/ST 2信号转导通过以下途径减弱缺血性肝脏的炎症： 抑制肝中性粒细胞积聚/活化。这些发现导致我们的假设， 在肝IRI中，嗜酸性粒细胞通过IL-33/ST 2信号传导保护肝脏。提出了三个具体目标 i）研究嗜酸性粒细胞和IL-33/ST 2信号传导在肝IRI中的作用，ii）通过 其中嗜酸性粒细胞中的IL-33/ST 2信号传导保护免于肝IRI，和iii）嗜酸性粒细胞中的靶向IL-33/ST 2信号传导， 嗜酸性粒细胞用于治疗肝IRI。

PROJECT SUMMARY The goal of this proposal is to investigate the functional role of eosinophils during hepatic ischemia and reperfusion injury (IRI). Hepatic IRI is a significant source of morbidity and mortality during major hepatic resection and during liver transplantation. Previous studies have shown that following liver transplantation innate immune cells, such as neutrophils or macrophages, are activated and traffic into the hepatic allograft. Unexpectedly, we observed that eosinophils also accumulate in the liver following orthotopic liver transplantation in humans. In contrast, we could not detect any eosinophils in healthy liver biopsies. Similarly, in a murine model, eosinophils accumulate in the liver in a time-dependent fashion following hepatic IRI. Functional studies using genetic and antibody-based depletion of eosinophils demonstrate a protective role of these cells during hepatic IRI. An unbiased screen of gene expression profiles following eosinophil depletion implicated eosinophil-dependent ST2 in liver protection. Combination of genetic and adoptive transfer studies suggest that eosinophil-specific IL-33/ST2 signaling attenuates inflammation of the ischemic liver by dampening hepatic neutrophil accumulation/activation. These findings led to our hypothesis that during hepatic IRI, eosinophils protect the liver through IL-33/ST2 signaling. Three Specific Aims are proposed to i) investigate the role of eosinophils and IL-33/ST2 signaling in hepatic IRI, ii) elucidate the mechanism by which IL-33/ST2 signaling in eosinophils protects against hepatic IRI, and iii) Target IL-33/ST2 signaling in eosinophils for the treatment of hepatic IRI.