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.

项目概要 该提案的目标是研究嗜酸性粒细胞在促进组织修复和 肝缺血再灌注（IR）损伤后的再生。肝 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。 及时而有力的肝脏修复和再生对于缺血性肝脏的解决和恢复至关重要 损害。因此，迫切需要确定关键的促修复分子和细胞机制 为了制定治疗策略以改善肝脏手术和移植的结果。 我们的初步数据表明，IR损伤后肝脏中嗜酸性粒细胞积累的峰值 恰逢肝脏修复和再生的关键时间点。嗜酸性粒细胞缺乏的小鼠表现出 肝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 将骨髓源性嗜酸性粒细胞（bmEos）注入嗜酸性粒细胞缺陷小鼠体内，可显着改善肝脏修复 速率和程度与 WT 小鼠相同。然而，白细胞介素 (IL)-4 和 IL-13 缺陷的 bmEos 无法改善 肝脏修复。我们还发现嗜酸性粒细胞缺陷小鼠中 EGFR 激活减少，HB-EGF 水平降低。 总之，这些发现支持了我们的假设，即嗜酸性粒细胞衍生的 IL-4 和/或 IL-13 通过 诱导 HB-EGF 产生，在促进肝 IR 损伤后的组织修复中发挥重要作用。 我们提出三个具体目标：(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IR损伤后肝脏修复的机制，（3）探索 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

Interleukin-33 facilitates liver regeneration through serotonin-involved gut-liver axis.

Interleukin-33 通过涉及血清素的肠-肝轴促进肝脏再生。

• 发表时间: 2023-05-01
• 作者: Wen, Yankai;Emontzpohl, Christoph;Xu, Long;Atkins, Constance L;Jeong, Jong;Yang, Yang;Kim, Kangho;Wu, Chuan;Akira, Shizuo;Ju, Cynthia
• 通讯作者: Ju, Cynthia

article : the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease

文章：肠道微生物组作为慢性肝病发病机制和治疗的治疗靶点

• DOI: 10.1002/9781118982907.ch15
• 发表时间: 2024-09-14
• 期刊: Current opinion in pharmacology
• 影响因子: 4
• 作者: C. Woodhouse;V. Patel;A. Singanayagam;D. Shawcross
• 通讯作者: D. Shawcross

Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners.

部分肝切除术后库普弗细胞的恢复主要是由局部细胞以IL-6依赖性自分泌和旁分泌方式增殖驱动的。

• 发表时间: 2021-09
• 影响因子: 24.1
• 作者: Ait Ahmed, Yeni;Fu, Yaojie;Rodrigues, Robim M;He, Yong;Guan, Yukun;Guillot, Adrien;Ren, Ruixue;Feng, Dechun;Hidalgo, Juan;Ju, Cynthia;Lafdil, Fouad;Gao, Bin
• 通讯作者: Gao, Bin

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

肝缺血再灌注损伤的免疫细胞基础的更新。

• 发表时间: 2023-09-30
• 影响因子: 3.8
• 作者: Heo, Mi Jeong;Suh, Ji Ho;Poulsen, Kyle L;Ju, Cynthia;Kim, Kang Ho
• 通讯作者: Kim, Kang Ho

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

几丁质酶 3-like-1 通过促进肝血小板募集而导致对乙酰氨基酚诱导的肝损伤。

• 发表时间: 2021-06-10
• 影响因子: 7.7
• 作者: Shan, Zhao;Li, Leike;Atkins, Constance Lynn;Wang, Meng;Wen, Yankai;Jeong, Jongmin;Moreno, Nicolas F;Feng, Dechun;Gui, Xun;Zhang, Ningyan;Lee, Chun Geun;Elias, Jack A;Lee, William M;Gao, Bin;Lam, Fong Wilson;An, Zhiqiang;Ju, Cynthia
• 通讯作者: Ju, Cynthia