Matrix Metalloproteinases in Hepatic Ischemia and Reperfusion Injury

肝脏缺血和再灌注损伤中的基质金属蛋白酶

基本信息

批准号：
8040076
负责人：
Ana J. Coito
金额：
$ 2.83万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2010-05-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8040076
关键词：
Acute Address Affect Animals Antibodies Apoptosis Basement membrane Binding Biological Preservation Biological Process Bone Marrow Cells Chronic Clinical Data Development Event Extracellular Matrix Failure Free Radicals Functional disorder Funding Gelatinase A Gelatinase B Gelatinases Gene Transfer Grant Hepatic Human In Vitro Incidence Individual Infiltration Inflammatory Injury Lead Leukocyte Trafficking Leukocytes Link Liver Liver Regeneration Liver diseases Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Mediator of activation protein Modeling Mus Natural regeneration Obesity Operative Surgical Procedures Organ Donor Outcome Patients Pattern Peptide Hydrolases Peptides Physiological Pilot Projects Play Population Predisposition Prevalence Process Property Proteolysis Public Health Rattus Regulation Relative (related person)Reperfusion Injury Risk Role Shock Signal Transduction Source Staging System Testing Therapeutic Tissue Inhibitor of Metalloproteinase-1 Tissue Inhibitor of Metalloproteinases Transplantation Trauma Vascular blood supply Work base chemokine cytokine high risk inhibitor/antagonist insight liver function liver ischemia liver transplantation migration mouse model neutralizing antibody novel therapeutics overexpression tumor

项目摘要

Hepatic ischemia reperfusion injury (IRI) occurs in all transplanted livers, in trauma, shock, and in elective surgery where blood supply to the liver is temporary interrupted. IRI causes up to 10% of early transplant failures and can lead to significantly higher incidence of acute and chronic rejections. Thousands of patients die every year while waiting for a donor organ. This gloomy scenario, together with the significant prevalence of obesity in the population, has led to an increased need of using suboptimal steatotic livers in transplantation at elevated risks of dysfunction based on their high susceptibility to IRI. In the previous funding period, our results demonstrated that specific matrix metalloproteinase-9 (MMP-9) inhibition profoundly ameliorates IRI in normal livers, and unveiled potential key roles for MMP-2 and TIMP-1 in liver injury. This proposal (i) explores the hepatoprotective properties of MMP-9 inhibition in marginal steatotic liver IRI and (ii) dissects the functions of MMP-2 and TIMP-1 in IR-induced damage in both normal and steatotic livers. We expect that the proposed work will provide fundamental insights on the individual functions of key MMPs/TIMPs, leading to the development of novel therapeutic manipulations that can minimize their detrimental effects while maximizing their beneficial functions in normal and in steatotic liver IRI. Well-established models of partial liver IRI in normal and in steatotic mice, and of ex vivo cold steatotic liver ischemia followed by iso-transplantation in rats will be used to address the following aims: (1) To dissect mechanisms by which Matrix Metalloproteinase-9 specific inhibition affects the IRI outcome in marginal steatotic livers. Using MMP-9-/- deficient mice and specific therapeutic manipulations against MMP-9, we will dissect whether specific MMP-9 inhibition (i) protects marginal steatotic livers from the I/R insult, (ii) disrupts leukocyte traffic and chemokine release/activation, and we will (iii) identify intracellular signaling mechanisms leading to MMP-9 expression in steatotic hepatic IRI; (2) To analyze mechanisms by which Matrix Metalloproteinase-2 activity affects the IRI outcome in normal and in steatotic livers. We will determine whether selective MMP-2 inhibition (i) affects liver function/preservation, (ii) results in altered expression of MMP-9, (iii) interferes with patterns of leukocyte migration and of cytokine/chemokine activation and, furthermore, we will (iv) identify the sources of MMP- 2 and their relative contribution in normal and steatotic liver IRI; and (3) To dissect the mechanisms by which tissue inhibitor of metalloproteinases-1 affects IRI in normal and in steatotic livers. We will assess the function of TIMP-1 in normal and in steatotic liver IRI by determining the impact of TIMP-1 deficiency on (i) liver function/preservation, (ii) liver regeneration and apoptosis, (iii) MMP activation, and on (iii) leukocyte recruitment and pro-inflammatory networks. Moreover, we will assess the function of Timp-1 overexpression as a therapeutic approach in partial liver IRI and in steatotic OLT.

肝缺血再灌注损伤 (IRI) 发生在所有移植肝脏、创伤、休克和选择性移植中暂时中断肝脏血液供应的手术。 IRI 导致高达 10% 的早期移植失败并可能导致急性和慢性排斥反应的发生率显着升高。数千个每年都有患者在等待捐赠器官时死亡。这种悲观的情景，加上肥胖在人口中的显着流行，导致使用次优的需求增加移植中的脂肪肝由于对 IRI 高度易感性而具有较高的功能障碍风险。在之前的资助期间，我们的结果表明特定基质金属蛋白酶-9 (MMP-9) 抑制可显着改善正常肝脏中的 IRI，并揭示了 MMP-2 和 TIMP-1在肝损伤中的作用。该提案 (i) 探讨了 MMP-9 抑制的肝保护特性边缘性脂肪变性肝 IRI 和 (ii) 剖析 MMP-2 和 TIMP-1 在 IR 诱导损伤中的功能正常肝脏和脂肪变性肝脏。我们期望拟议的工作将为以下方面提供基本见解：关键 MMP/TIMP 的个体功能，导致新型治疗方法的开发可以最大限度地减少其有害影响，同时最大限度地发挥其有益功能的操作正常和脂肪肝 IRI。正常和脂肪变性部分肝脏 IRI 的完善模型小鼠和离体冷脂肪肝缺血随后进行大鼠同种移植将用于解决以下目标：（1）剖析 Matrix Metallo Proteinase-9 特异性的机制抑制会影响边缘脂肪肝的 IRI 结果。使用 MMP-9-/- 缺陷小鼠和特定针对 MMP-9 的治疗操作，我们将剖析特异性 MMP-9 抑制 (i) 是否可以保护 I/R 损伤造成的边缘脂肪变性肝脏，(ii) 扰乱白细胞运输和趋化因子释放/激活，以及我们将 (iii) 确定导致脂肪肝 IRI 中 MMP-9 表达的细胞内信号传导机制； (2) 分析基质金属蛋白酶 2 活性影响正常人 IRI 结果的机制和脂肪肝。我们将确定选择性 MMP-2 抑制 (i) 是否影响肝脏功能/保存，(ii) 导致 MMP-9 表达改变，(iii) 干扰白细胞模式迁移和细胞因子/趋化因子激活，此外，我们将 (iv) 确定 MMP-的来源 2 及其在正常和脂肪肝 IRI 中的相对贡献； (3) 剖析机制金属蛋白酶-1 的组织抑制剂影响正常肝脏和脂肪变性肝脏中的 IRI。我们将通过确定 TIMP-1 的影响来评估 TIMP-1 在正常和脂肪肝 IRI 中的功能 (i) 肝功能/保存、(ii) 肝再生和细胞凋亡、(iii) MMP 激活和 (iii)白细胞募集和促炎症网络。此外，我们将评估 Timp-1 过表达作为部分肝 IRI 和脂肪变性 OLT 的治疗方法。