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

• 批准号: 8078969
• 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
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078969
• 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; public health relevance; tumor

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. PUBLIC HEALTH RELEVANCE: Thousands of patients die every year while waiting for a donor organ; this serious situation has led to an increased use of suboptimal steatotic livers in transplantation. However, it is widely accepted that steatotic livers present very high risks of primary non-function, or dysfunction, based on their increased susceptibility to ischemia and reperfusion injury (IRI). We expect that our proposed work will lead to critical insights on the individual functions of key matrix metalloproteinases (MMPs), leading to the development of novel therapeutic manipulations that, by reducing the detrimental effects of MMPs while keeping their beneficial functions in hepatic IRI, will allow the successful utilization of suboptimal donors in transplantation.

描述（由申请人提供）：肝缺血再灌注损伤（IRI）发生在所有移植的肝脏中，受创伤，休克和选修手术中，肝脏向肝脏血液供应暂时中断。 IRI最多会导致早期移植失败的10％，并可能导致急性和慢性拒绝的发生率明显更高。每年等待捐赠器官时，成千上万的患者死亡。这种令人沮丧的情况，加上肥胖症在人群中的显着流行，导致人们越来越需要根据对IRI的高敏感性，以较高的功能障碍的风险来移植下次优的肝脏进行移植。在上一个资金期间，我们的结果表明，特定的基质金属蛋白酶-9（MMP-9）抑制作用可深度缓解正常肝脏的IRI，并在肝损伤中揭示了MMP-2和TIMP-1的潜在关键作用。该提议（i）探讨了边缘脂肪变性肝脏IRI中MMP-9抑制的肝保护性能，并（ii）剖析了MMP-2和TIMP-1在正常和脂肪性肝脏中IR诱导的损伤中的功能。我们预计拟议的工作将为关键MMP/TIMP的个体功能提供基本见解，从而发展出新型的治疗操作，从而最大程度地减少其有害影响，同时最大程度地提高其在正常和脂肪性肝脏IRI中的有益功能。正常和脂肪变性小鼠中部分肝脏IRI的建立良好的模型，以及在大鼠大鼠中的同时冷脂肪变性肝脏缺血，然后在大鼠中进行同学转移，以解决以下目的：（1）解剖机制，以使基质蛋白酶9特异性抑制会影响Marginal Steteatectoction Marginal Steateateational cocuntic contical cocy contical cocy contical cocy contotic contotic cocy cocy cocuntic cocuntic cocuntic cocuntic cocuntic cocuntim coctoction cocuret coctotic。 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）分析基质金属蛋白酶-2活性影响正常和脂肪分裂肝脏中的IRI结果的机制。我们将确定选择性MMP-2抑制（i）是否影响肝功能/保存，（ii）导致MMP-9的表达改变，（iii）会干扰白细胞迁移的模式以及细胞因子/趋化因子激活以及此外，我们将确定（IV）（IV）（IV）确定MMP-2-2的来源及其相对贡献IRI IRI IRI IRI IRI IRVIE infri IRI IRVIR IRI IRVIR IRI IRVIR IRI IRVIR IRI IRVIR IRI IRVIR IRI IRVIR IRVIR IRVIR IRICET infri IRI IRVIR IRVIR IRI; （3）剖析金属蛋白酶1的组织抑制剂1在正常和脂肪肝肝脏中影响IRI的机制。我们将通过确定TIMP-1缺乏症对（i）肝功能/保存，（ii）肝脏再生和凋亡，（III）MMP激活以及（III）白细胞招募和促疾病网络的影响，评估TIMP-1在正常和脂肪变性肝脏IRI中的功能。此外，我们将评估TIMP-1过表达的功能，作为部分肝脏IRI和Steatotic OLT中的治疗方法。 公共卫生相关性：等待捐赠器官时，每年成千上万的患者死亡；这种严重的情况导致在移植中增加了次优肝肝脏的使用。然而，人们普遍认为，脂肪肝肝脏对原发性无功能或功能障碍的高风险具有很高的敏感性（IRI）。我们预计我们的拟议工作将导致对关键基质金属蛋白酶（MMP）的个别功能的重要见解，从而导致新型治疗操作的发展，通过减少MMP的有害作用，同时保持其在肝IRI中的有益功能，从而可以成功地利用替代供体的供应量。