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: 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
• 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

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）发生在所有移植的肝脏，外伤，震惊和选修中发生 向肝脏血液供应的手术暂时中断。 IRI最多导致早期移植的10％ 失败并可能导致急性和慢性拒绝的发生率明显更高。成千上万 患者每年在等待捐赠器官时死亡。这种令人沮丧的场景以及 肥胖症在人群中的显着患病率已导致使用次优的需求增加 根据对IRI的高敏感性，脂肪性障碍风险升高的移植中的脂肪肝肝脏。 在上一个资金期间，我们的结果表明特定基质金属蛋白酶9（MMP-9） 抑制作用可深度改善正常肝脏的IRI，并揭示了MMP-2和 肝损伤中的TIMP-1。该提案（i）探讨了MMP-9抑制的肝保护特性 边缘脂肪变性肝脏IRI和（ii）在IR诱导的损伤中剖析MMP-2和TIMP-1的功能 正常和脂肪肝肝脏。我们希望拟议的工作将提供有关的基本见解 关键MMP/TIMP的个体功能，导致新型治疗的发展 操纵可以最大程度地减少其有害影响的同时最大化其有益功能的操作 正常且在脂肪变性的肝脏IRI中。正常和脂肪变化的部分肝脏IRI的成熟模型 小鼠，外体冷肉毒肝脏缺血，然后是大鼠的同in-移植 解决以下目的：（1）剖析基质金属蛋白酶9特异性的机制 抑制作用会影响边缘脂肪变性肝脏的IRI结果。使用MMP-9 - / - 缺陷小鼠和特定 针对MMP-9的治疗操作，我们将剖析特定的MMP-9抑制（i）是否保护 I/R侮辱中的边缘脂肪变性肝脏（ii）干扰白细胞的交通和趋化因子释放/激活，以及 我们将（iii）确定导致脂肪变性肝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活性在正常情况下影响IRI结果的机制 并在脂肪肝肝脏中。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的表达改变，（iii）干扰白细胞的模式 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及其在正常和脂肪性肝脏IRI中的相对贡献； （3）通过 金属蛋白酶-1的哪种组织抑制剂会影响正常和脂肪分裂肝脏中的IRI。我们将 通过确定TIMP-1的影响，评估timp-1在正常和脂肪变性肝脏IRI中的功能 （i）肝功能/保存缺乏，（ii）肝脏再生和凋亡，（iii）MMP激活和 在（iii）白细胞募集和促炎网络上。此外，我们将评估 TIMP-1的过表达是部分肝脏IRI和脂肪变性OLT中的治疗方法。