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: 10658011
• 负责人: Cynthia Ju
• 金额: $ 45.56万
• 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 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658011
• 关键词: Acceleration; Acute; Adoptive Transfer; Allografting; Animals; Antibodies; Bone Marrow; CCL24 gene; Cell Therapy; Cells; Clinical; DTR gene; Data; Endothelial Cells; Epidermal Growth Factor Receptor; Excision; Exhibits; Funding; Goals; Hemorrhagic Shock; Hepatic; Human; Impaired wound healing; Impairment; Injury; Interleukin-13; Interleukin-4; Kupffer Cells; Liver; Liver Dysfunction; Liver Regeneration; Macrophage; Measures; Modeling; Molecular; Mus; Natural regeneration; Operative Surgical Procedures; Organ; Organ Donor; Phase; Play; Predisposition; Production; Productivity; Recovery; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Resolution; Role; Signal Transduction; Therapeutic; Time; Transplantation; Transplantation Surgery; Trauma; acute liver injury; cellular targeting; clinical practice; design; eosinophil; experimental study; human tissue; improved; improved outcome; insight; ischemic injury; liver injury; liver ischemia; liver repair; liver transplantation; neutrophil; novel therapeutic intervention; receptor; recruit; repair function; tissue regeneration; tissue repair; translational model; translational study

PROJECT SUMMARY The goal of this proposal is to investigate the functional role of eosinophils in promoting tissue repair and regeneration after hepatic ischemia and reperfusion (IR) injury. Hepatic IR injury, which occurs during transplantation surgery, is a major factor contributing to acute liver dysfunction and long-term complications. Timely and robust liver repair and regeneration is vital to the resolution and recovery from ischemic liver damage. Thus, there is a critical need to identify key pro-reparative molecular and cellular mechanisms in order to develop therapeutic strategies to improve the outcomes of liver surgery and transplantation. Our preliminary data demonstrated that the peak of eosinophil accumulation in the liver after IR injury coincided with the critical time point of liver repair and regeneration. Eosinophil-deficient mice exhibited markedly delayed and impaired tissue repair after hepatic IR injury. In contrast, adoptive transfer of WT bone marrow-derived eosinophils (bmEos) to eosinophil-deficient mice dramatically improved liver repair to a similar rate and extent as in the WT mice. However, interleukin (IL)-4- and IL-13-deficient bmEos could not improve liver repair. We also found reduced EGFR activation and lower levels of HB-EGF in eosinophil-deficient mice. Together, these findings support our hypothesis that eosinophil-derived IL-4 and/or IL-13, through inducing HB-EGF production, play an essential role in promoting tissue repair after hepatic IR injury. We propose three Specific Aims to (1) Investigate the role of eosinophils in liver repair after IR injury, (2) Elucidate the mechanism by which eosinophils promote liver repair after IR injury, and (3) Explore the potential of targeting eosinophils to accelerate liver repair after IR injury.

项目摘要 本研究的目的是研究嗜酸性粒细胞在促进组织修复中的作用， 肝缺血再灌注损伤后的再生。肝脏IR损伤，发生在 移植手术是导致急性肝功能障碍和长期并发症的主要因素。 及时和强大的肝脏修复和再生是解决和恢复缺血肝脏的关键 损害因此，迫切需要确定关键的促修复分子和细胞机制， 目的：为改善肝脏手术和移植的预后提供治疗策略。 我们的初步数据表明，在IR损伤后， 与肝脏修复和再生的关键时间点相吻合。嗜酸性粒细胞缺陷小鼠表现出 肝脏IR损伤后组织修复明显延迟和受损。相比之下，WT骨的过继转移 骨髓来源的嗜酸性粒细胞（bmEos）对嗜酸性粒细胞缺陷小鼠的肝修复显著改善， 在WT小鼠中的速率和程度。然而，白细胞介素（IL）-4和IL-13缺陷的bmEos不能改善 肝脏修复我们还发现，在嗜酸性粒细胞缺陷小鼠中，EGFR活化减少，HB-EGF水平降低。 总之，这些发现支持了我们的假设，即嗜酸性粒细胞来源的IL-4和/或IL-13，通过 诱导HB-EGF的产生，在促进肝脏IR损伤后的组织修复中起重要作用。 我们提出了三个具体的目标：（1）研究嗜酸性粒细胞在IR损伤后肝脏修复中的作用，（2） 阐明嗜酸性粒细胞促进肝脏缺血再灌注损伤后修复的机制;（3）探讨嗜酸性粒细胞对肝脏缺血再灌注损伤的保护作用。 靶向嗜酸性粒细胞加速IR损伤后肝脏修复的潜力。

项目成果

Chitinase 3-like-1 contributes to acetaminophen-induced liver injury by promoting hepatic platelet recruitment.

• DOI: 10.7554/elife.68571
• 发表时间: 2021-06-10
• 期刊: eLife
• 影响因子: 7.7
• 作者: Shan Z;Li L;Atkins CL;Wang M;Wen Y;Jeong J;Moreno NF;Feng D;Gui X;Zhang N;Lee CG;Elias JA;Lee WM;Gao B;Lam FW;An Z;Ju C
• 通讯作者: Ju C

Updates on the Immune Cell Basis of Hepatic Ischemia-Reperfusion Injury.

• DOI: 10.14348/molcells.2023.0099
• 发表时间: 2023-09-30
• 期刊: Molecules and cells
• 影响因子: 3.8