The inflammatory response in myocardial infarction.
One of the major therapeutic goals of modern cardiology is to design strategies aimed at minimizing myocardial necrosis and optimizing cardiac repair following myocardial infarction. However, a sound understanding of the biology is necessary before a specific intervention is pursued on a therapeutic basis. This review summarizes our current understanding of the cellular and molecular mechanisms regulating the inflammatory response following myocardial ischemia and reperfusion. Myocardial necrosis induces complement activation and free radical generation, triggering a cytokine cascade initiated by Tumor Necrosis Factor (TNF)-alpha release. If reperfusion of the infarcted area is initiated, it is attended by an intense inflammatory reaction. Interleukin (IL)-8 synthesis and C5a activation have a crucial role in recruiting neutrophils in the ischemic and reperfused myocardium. Neutrophil infiltration is regulated through a complex sequence of molecular steps involving the selectins and the integrins, which mediate leukocyte rolling and adhesion to the endothelium. Marginated neutrophils exert potent cytotoxic effects through the release of proteolytic enzymes and the adhesion with Intercellular Adhesion Molecule (ICAM)-1 expressing cardiomyocytes. Despite this potential injury, substantial evidence suggests that reperfusion enhances cardiac repair improving patient survival; this effect may be in part related to the inflammatory response. Monocyte Chemoattractant Protein (MCP)-1 is also markedly upregulated in the infarcted myocardium inducing recruitment of mononuclear cells in the injured areas. Monocyte-derived macrophages and mast cells may produce cytokines and growth factors necessary for fibroblast proliferation and neovascularization, leading to effective repair and scar formation. At this stage expression of inhibitory cytokines such as IL-10 may have a role in suppressing the acute inflammatory response and in regulating extracellular matrix metabolism. Fibroblasts in the healing scar undergo phenotypic changes expressing smooth muscle cell markers. Our previous review in this journal focused almost exclusively on reduction of the inflammatory injury. The current update is prompted by the potential therapeutic opportunity that the open vessel offers. By promoting more effective tissue repair, it may be possible to reduce the deleterious remodeling, that is the leading cause of heart failure and death. Elucidating the complex interactions and regulatory mechanisms responsible for cardiac repair may allow us to design effective inflammation-related interventions for the treatment of myocardial infarction.
Frangogiannis
Nikolaos G
NG
Section of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine and the DeBakey Heart Center, One Baylor Plaza M/S F-602, Houston, TX 77030, USA.
Smith
C Wayne
CW
Entman
Mark L
ML
D015815:Cell Adhesion Molecules / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D003167:Complement Activation; D016207:Cytokines / Q000378:metabolism*; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000276:immunology; D008407:Mast Cells / Q000276:immunology; D009203:Myocardial Infarction / Q000276:immunology*; D015428:Myocardial Reperfusion Injury / Q000276:immunology*; D009389:Neovascularization, Pathologic; D020556:Neutrophil Infiltration; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020257:Ventricular Remodeling
D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D016207:Cytokines; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha