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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：
8635968
负责人：
Ana J. Coito
金额：
$ 38.12万
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：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8635968
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 Human In Vitro Incidence Individual Infiltration Inflammatory 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 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 acute liver injury base chemokine cytokine high risk inhibitor/antagonist insight liver function liver injury liver ischemia liver transplantation migration mouse model neutralizing antibody novel therapeutics overexpression public health relevance tumor

项目摘要

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：肝脏缺血再灌注损伤(IRI)发生在所有移植肝脏、创伤、休克和肝脏供血暂时中断的择期手术中。IRI导致高达10%的早期移植失败，并可能导致显著更高的急性和慢性排斥反应发生率。每年有数以千计的患者在等待器官捐赠者的过程中死亡。这种悲观的前景，加上肥胖在人群中的显著流行，导致了在移植中使用次理想脂肪变性肝脏的需求增加，基于其对IRI的高度易感性，功能障碍的风险增加。在之前的资金支持期间，我们的研究结果表明，抑制特定的基质金属蛋白酶-9(MMP9)可以显著改善正常肝脏的IRI，并揭示了MMP2和TIMP-1在肝损伤中的潜在关键作用。本研究探讨了基质金属蛋白酶-9在边缘脂肪变性肝脏缺血再灌注损伤中的保肝作用，以及基质金属蛋白酶-2和组织金属蛋白酶组织抑制蛋白-1在肝脏缺血再灌注损伤中的作用。我们期望这项拟议的工作将为关键的MMPs/TIMP的个体功能提供基本的见解，导致开发新的治疗操作，使其有害影响最小化，同时在正常和脂肪变性肝脏IRI中最大限度地发挥其有益功能。已建立的正常和脂肪变性小鼠部分肝脏IRI模型以及大鼠体外冷脂肪变性肝缺血后同种异体移植模型将用于解决以下目的：(1)剖析基质金属蛋白酶-9特异性抑制影响边缘脂肪变性肝脏IRI结局的机制。利用MMP9缺陷小鼠和针对MMP9的特定治疗操作，我们将剖析特定的MMP9抑制是否(I)保护边缘脂肪变性肝脏免受I/R损伤，(Ii)扰乱白细胞的运输和趋化因子的释放/激活，以及(Iii)确定导致脂肪变性肝IRI中MMP9表达的细胞内信号机制；(2)分析基质金属蛋白酶-2活性影响正常和脂肪变性肝脏IRI结局的机制。我们将确定选择性抑制基质金属蛋白酶-2是否影响肝脏的功能/保存，(Ii)导致基质金属蛋白酶-9的表达改变，(Iii)干扰白细胞迁移和细胞因子/趋化因子的激活模式，此外，我们将(Iv)确定正常和脂肪变性肝脏IRI中基质金属蛋白酶-2的来源和它们的相对贡献；以及(3)剖析正常和脂肪变性肝脏中金属蛋白酶组织抑制因子-1影响IRI的机制。我们将通过确定TIMP-1缺乏对(I)肝功能/保存、(Ii)肝再生和细胞凋亡、(Iii)基质金属蛋白酶激活以及(Iii)白细胞募集和促炎网络的影响来评估TIMP-1在正常和脂肪变性肝IRI中的功能。此外，我们将评估TIMP-1过表达作为部分肝IRI和脂肪变性原位肝移植的治疗方法的作用。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fibronectin-α4β1 interactions in hepatic cold ischemia and reperfusion injury: regulation of MMP-9 and MT1-MMP via the p38 MAPK pathway.

DOI：
10.1111/j.1600-6143.2012.04161.x
发表时间：
2012-10
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
0
作者：
Duarte S;Shen XD;Fondevila C;Busuttil RW;Coito AJ
通讯作者：
Coito AJ

MMP-9 deficiency shelters endothelial PECAM-1 expression and enhances regeneration of steatotic livers after ischemia and reperfusion injury.

DOI：
10.1016/j.jhep.2013.12.022
发表时间：
2014-05
期刊：
JOURNAL OF HEPATOLOGY
影响因子：
25.7
作者：
Kato, Hiroyuki;Kuriyama, Naohisa;Duarte, Sergio;Clavien, Pierre-Alain;Busuttil, Ronald W.;Coito, Ana J.
通讯作者：
Coito, Ana J.

Fibronectin-alpha4beta1 integrin interactions modulate p42/44 MAPK phosphorylation in steatotic liver cold ischemia-reperfusion injury.

纤连蛋白-α4β1 整合素相互作用调节脂肪肝冷缺血再灌注损伤中的 p42/44 MAPK 磷酸化。