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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（由申请人提供）：肝缺血再灌注损伤（IRI）发生在所有移植肝脏、创伤、休克和肝脏血液供应暂时中断的择期手术中。IRI导致高达10%的早期移植失败，并可能导致急性和慢性排斥反应的发生率显着增加。每年都有成千上万的病人在等待捐赠器官时死亡。这种令人沮丧的情况，加上肥胖在人群中的显著流行，导致在移植中使用次优脂肪变性肝脏的需求增加，基于其对IRI的高易感性，功能障碍的风险增加。在上一个资助期，我们的研究结果表明，特异性基质金属蛋白酶-9（MMP-9）抑制剂显著改善了正常肝脏的IRI，并揭示了MMP-2和TIMP-1在肝损伤中的潜在关键作用。该建议（i）探讨MMP-9抑制在边缘脂肪肝IRI中的保肝特性，以及（ii）剖析MMP-2和TIMP-1在正常和脂肪肝中IR诱导的损伤中的功能。我们希望这项工作将为关键MMPs/TIMPs的个体功能提供基本见解，从而开发新的治疗操作，可以最大限度地减少其有害影响，同时最大限度地提高其在正常和脂肪肝IRI中的有益功能。建立了正常和脂肪变性小鼠部分肝IRI模型，以及大鼠离体冷脂肪变性肝缺血后同种移植模型，目的如下：（1）分析基质金属蛋白酶-9特异性抑制影响边缘性脂肪变性肝IRI结果的机制。使用MMP-9-/-缺陷小鼠和针对MMP-9的特异性治疗操作，我们将剖析特异性MMP-9抑制是否（i）保护边缘性脂肪肝免受I/R损伤，（ii）破坏白细胞运输和趋化因子释放/活化，并且我们将（iii）鉴定导致脂肪肝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（MMP-2）活性影响正常肝和脂肪肝IRI预后的机制。我们将确定选择性MMP-2抑制是否（i）影响肝功能/保存，（ii）导致MMP-9表达的改变，（iii）干扰白细胞迁移和细胞因子/趋化因子活化的模式，此外，我们将（iv）鉴定MMP- 2的来源及其在正常和脂肪变性肝IRI中的相对作用;（3）探讨金属蛋白酶组织抑制剂-1（TIMP-1）对正常肝和脂肪肝IRI的影响机制。我们将通过确定TIMP-1缺乏对（i）肝功能/保存、（ii）肝再生和凋亡、（iii）MMP活化和（iii）白细胞募集和促炎网络的影响，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过表达作为部分肝脏IRI和脂肪变性奥尔特治疗方法的功能。

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。