Resolution of inflammation in healing myocardial infarcts

缓解心肌梗塞中的炎症

• 批准号: 7365283
• 负责人: Nikolaos G Frangogiannis
• 金额: $ 34.54万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7365283
• 关键词: Affect; Angiogenesis Inhibitors; Area; Attenuated; Cardiac; Cells; Characteristics; Cicatrix; Containment; Defect; Deposition; Development; Disruption; Down-Regulation; Endothelial Cells; Enzymes; Equilibrium; Event; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Genes; Goals; Granulation Tissue; Healed; Heart; In Vitro; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injection of therapeutic agent; Injury; Lead; Left Ventricular Remodeling; Leukocytes; Localized; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Molecular; Mus; Myocardial Infarction; Myocardium; Myofibroblast; Pathogenesis; Pathway interactions; Peptides; Play; Proteolysis; Protocols documentation; Recombinant Proteins; Regulation; Repression; Resistance; Resolution; Role; Series; Signal Pathway; Signal Transduction; Testing; Therapeutic Intervention; Thrombospondin 1; Time; Tissues; Transforming Growth Factor beta; Transglutaminases; base; chemokine; concept; crosslink; cytokine; healing; in vivo; interstitial; leukocyte activation; migration; prevent; repaired; research study; response; wound

DESCRIPTION (provided by applicant): Effective repair of the infarcted heart depends on mechanisms that suppress the inflammatory response after granulation tissue formation has occurred, and that limit expansion of fibrosis to the non-infarcted myocardium. Our project examines the mechanisms responsible for resolution of post-infarction inflammation and transition to fibrous tissue deposition. Our preliminary experiments suggest that Thrombospondin (TSP)-1, a potent angiostatic mediator and crucial TGF-2 activator, and the matrix crosslinking enzyme tissue transglutaminase (tTG), are selectively induced in the infarct border zone and that TSP-1 plays a key role in suppression of the chemokine response and resolution of the inflammatory infiltrate in healing infarcts. The selective localization of TSP-1 and tTG suggests that, through its unique composition, the infarct border zone may serve as a barrier preventing expansion of granulation tissue formation into the non- infarcted myocardium. Specific aim 1 will examine the role of TSP-1 in suppression and containment of the post-infarction inflammatory response. In vivo experiments examining activation of TGF-2 signaling pathways and neovessel formation, in vitro studies using endothelial cells and infarct myofibroblasts isolated from TSP-1 -/- and WT mice and injections of peptides that restore specific actions of the TSP-1 molecule will be used to examine the mechanistic basis of the TSP-1-mediated effects. Specific aim 2 will test the hypothesis that tTG may protect the non-infarcted myocardium by locally activating TGF- beta and by forming a "barrier" composed of proteolysis-resistant matrix, preventing leukocyte migration. In vivo studies using tTG -/- mice and in vitro experiments using infarct myofibroblasts and endothelial cells from WT and tTG -/- mice will be performed. Specific aim 3 will explore the signaling pathways responsible for the distinct effects of TGF-2 in suppressing inflammation by repressing chemokine and cytokine expression in endothelial cells, and in promoting fibrosis, by inducing extracellular matrix proteins and by altering the MMP:TIMP balance in cardiac fibroblasts. The importance of Smad- dependent and Smad-independent pathways in post-infarction inflammation and fibrous tissue deposition will be examined using myocardial infarction experiments and in vitro studies on isolated endothelial cells and fibroblasts. These studies may lead to therapeutic interventions aimed at optimizing cardiac repair by preventing prolongation and extension of the inflammatory injury.

描述（由申请人提供）：梗死心脏的有效修复取决于在肉芽组织形成后抑制炎症反应的机制，以及限制纤维化向非梗死心肌扩展的机制。我们的项目研究了负责解决梗死后炎症和过渡到纤维组织沉积的机制。我们的初步实验表明，血栓反应蛋白（TSP）-1，一种有效的血管生成抑制介质和关键的TGF-2激活剂，和基质交联酶组织转氨酶（tTG），选择性地诱导在梗死边缘区，TSP-1起着关键作用，抑制趋化因子反应和解决炎症浸润愈合梗死。TSP-1和tTG的选择性定位表明，通过其独特的组成，梗死边缘区可以作为防止肉芽组织形成扩展到非梗死心肌中的屏障。具体目标1将检查TSP-1在抑制和遏制梗死后炎症反应中的作用。检查TGF-2信号传导途径的激活和新血管形成的体内实验、使用从TSP-1 -/-和WT小鼠分离的内皮细胞和梗塞肌成纤维细胞的体外研究以及恢复TSP-1分子的特异性作用的肽的注射将用于检查TSP-1介导的作用的机制基础。具体目标2将检验以下假设：tTG可通过局部激活TGF-β和形成由抗蛋白水解基质组成的“屏障”，防止白细胞迁移，从而保护非梗死心肌。将进行使用tTG -/-小鼠的体内研究和使用来自WT和tTG -/-小鼠的梗死肌成纤维细胞和内皮细胞的体外实验。具体目标3将探索负责TGF-2在通过抑制内皮细胞中的趋化因子和细胞因子表达来抑制炎症，以及通过诱导细胞外基质蛋白和通过改变心脏成纤维细胞中的MMP：TIMP平衡来促进纤维化中的不同作用的信号传导途径。将使用心肌梗死实验和对分离的内皮细胞和成纤维细胞的体外研究来检查梗死后炎症和纤维组织沉积中Smad依赖性和Smad非依赖性途径的重要性。这些研究可能导致旨在通过防止炎性损伤的延长和扩展来优化心脏修复的治疗干预。