Role of Eosinophils in Hepatic Ischemia Reperfusion Injury

嗜酸性粒细胞在肝缺血再灌注损伤中的作用

• 批准号: 10365939
• 负责人: Cynthia Ju
• 金额: $ 38.83万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10365939
• 关键词: Acute; Adoptive Transfer; Antibodies; Attenuated; Autologous; Bone Marrow; Cadaver; Cells; Chronic; Data; Excision; Gene Expression; Genetic; Goals; Hemorrhagic Shock; Hepatic; Hepatitis C; Human; Immune; Inflammation; Injury; Interleukin-1 Receptors; Interleukin-13; Interleukin-4; Liver; Living Donors; Mediating; Modality; Morbidity - disease rate; Mus; Operative Surgical Procedures; Patients; Perioperative; Phenotype; Play; Production; Recurrence; Regulation; Reperfusion Injury; Role; Signal Transduction; Source; Therapeutic Effect; Time; Transplantation; Trauma; base; design; eosinophil; graft failure; improved outcome; insight; liver allograft; liver biopsy; liver injury; liver ischemia; liver transplantation; macrophage; mortality; mouse model; neutrophil; new therapeutic target; novel; novel therapeutic intervention; prevent; receptor

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.

项目概要 该提案的目的是研究嗜酸性粒细胞在肝缺血和肝损伤期间的功能作用。 再灌注损伤（IRI）。肝脏 IRI 是重大肝病期间发病率和死亡率的重要来源。 切除和肝移植期间。此前的研究表明，肝移植后 先天免疫细胞，如中性粒细胞或巨噬细胞，被激活并运输到同种异体肝移植物中。 出乎意料的是，我们观察到，原位肝移植后，嗜酸性粒细胞也在肝脏中积聚。 移植到人体。相反，我们在健康肝脏活检中无法检测到任何嗜酸性粒细胞。相似地， 在小鼠模型中，肝脏 IRI 后嗜酸性粒细胞以时间依赖性方式在肝脏中积聚。 使用遗传和基于抗体的嗜酸性粒细胞耗竭的功能研究证明了嗜酸性粒细胞的保护作用 这些细胞在肝脏 IRI 过程中。嗜酸性粒细胞耗竭后基因表达谱的无偏筛选 涉及嗜酸性粒细胞依赖性 ST2 的肝脏保护作用。遗传和收养转移研究的结合 表明嗜酸性粒细胞特异性 IL-33/ST2 信号传导通过以下方式减轻缺血性肝脏的炎症： 抑制肝脏中性粒细胞积累/激活。这些发现导致我们的假设是，在 肝脏 IRI，嗜酸性粒细胞通过 IL-33/ST2 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/ST2 信号传导在肝脏 IRI 中的作用，ii) 通过以下方式阐明其机制： 嗜酸性粒细胞中的 IL-33/ST2 信号传导可预防肝脏 IRI，以及 iii) 靶向嗜酸性粒细胞中的 IL-33/ST2 信号传导 嗜酸性粒细胞用于治疗肝 IRI。