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(American Journal of Pathology. 2007;170:818-829.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060547

Macrophage Depletion Impairs Wound Healing and Increases Left Ventricular Remodeling after Myocardial Injury in Mice

Machteld J. van Amerongen*, Martin C. Harmsen*, Nico van Rooijen{dagger}, Arjen H. Petersen* and Marja J.A. van Luyn*

From the Department of Pathology and Laboratory Medicine,* Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen; and the Department of Cell Biology and Immunology,{dagger} Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands

Macrophages have been suggested to be beneficial for myocardial wound healing. We investigated the role of macrophages in myocardial wound healing by inhibition of macrophage infiltration after myocardial injury. We used a murine cryoinjury model to induce left ventricular damage. Infiltrating macrophages were depleted during the 1st week after cryoinjury by serial intravenous injections of clodronate-containing liposomes. After injury, the presence of macrophages, which secreted high levels of transforming growth factor-ß and vascular endothelial growth factor-A, led to rapid removal of cell debris and replacement by granulation tissue containing inflammatory cells and blood vessels, followed by myofibroblast infiltration and collagen deposition. In macrophage-depleted hearts, nonresorbed cell debris was still observed 4 weeks after injury. Secretion of transforming growth factor-ß and vascular endothelial growth factor-A as well as neovascularization, myofibroblast infiltration, and collagen deposition decreased. Moreover, macrophage depletion resulted in a high mortality rate accompanied by increased left ventricular dilatation and wall thinning. In conclusion, infiltrating macrophage depletion markedly impairs wound healing and increases remodeling and mortality after myocardial injury, identifying the macrophage as a key player in myocardial wound healing. Based on these findings, we propose that increasing macrophage numbers early after myocardial infarction could be a clinically relevant option to promote myocardial wound healing and subsequently to reduce remodeling and heart failure.




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Copyright © 2007 by the American Society for Investigative Pathology.