A key component of cardiac remodeling after acute myocardial infarction (MI) is the inflammatory response, which modulates cardiac tissue repair. The purpose of this study was to investigate the relationship between the monocytic inflammatory response and left ventricular remodeling after MI using mice deficient in CC chemokine receptor 2 (CCR2), the primary receptor for the critical regulator of CC chemokine ligand 2. Immunohistochemical analysis revealed rapid infiltration of macrophages into infarcted tissue within 7 days in wild-type (WT) mice. However, this process was greatly impaired in CCR2-deficient (CCR2(-/-)) mice. Echocardiography demonstrated beneficial effects of CCR2 deficiency on left ventricular remodeling at 7 and 28 days after MI. In situ zymography showed augmented gelatinolytic activity in WT mice within 7 days after MI, whereas gelatinolytic activity was barely detectable in CCR2(-/-) mice. Moreover, the distribution of gelatinolytic activity in serial sections was very similar to the distribution of macrophages rather than neutrophils. Expression of matrix metalloproteinases and tumor necrosis factor-alpha mRNAs was up-regulated in infarcted regions from WT mice compared to CCR2(-/-) mice at 3 days after MI. Direct inhibition of CCR2 functional pathway might contribute to the attenuation of left ventricular remodeling after MI.

Macrophage infiltration is implicated in various types of pulmonary fibrosis. One important pathogenetic process associated with pulmonary fibrosis is injury to basement membranes by matrix metalloproteinases (MMPs) that are produced mainly by macrophages. In this study, C-C chemokine receptor 2-deficient (CCR2-/-) mice were used to explore the relationship between macrophage infiltration and MMP activity in the pathogenesis of pulmonary fibrosis, using the bleomycin-induced model of this disease process. CCR2 is the main (if not only) receptor for monocyte chemoattractant protein-1/C-C chemokine ligand 2 (MCP-1/CCL2), which is a critical mediator of macrophage trafficking, and CCR2 -/- mice demonstrate defective macrophage migration. Pulmonary fibrosis was induced in CCR2-/- and wild-type (CCR2+/+) mice by intratracheal instillation of bleomycin. No significant differences in the total protein concentration in bronchoalveolar lavage (BAL) fluid, or in the degree of histological lung inflammation, were observed in the two groups until day 7. Between days 3 and 21, however, BAL fluid from CCR2-/- mice contained fewer macrophages than BAL fluid from CCR2+/+ mice. Gelatin zymography of BAL fluid and in situ zymography revealed reduced gelatinolytic activity in CCR2-/- mice. Immunocytochemical staining showed weaker expression of MMP-2 and MMP-9 in macrophages in BAL fluid from CCR2-/- mice at day 3. Gelatin zymography of protein extracted from alveolar macrophages showed reduced gelatinolytic activity of MMP-2 and MMP-9 in CCR2-/- mice. At days 14 and 21, lung remodelling and the hydroxyproline content of lung tissues were significantly reduced in CCR2-/- mice. These results suggest that the CCL2/CCR2 functional pathway is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis and that CCR2 deficiency may improve the outcome of this disease by regulating macrophage infiltration and macrophage-derived MMP-2 and MMP-9 production.

No abstract

arly coronary reperfusion limits myocardial damage and improves survival after myocardial infarction. However, growing evidence indicates that reperfusion itself can cause damage to the ischemic myocardium; this damage is known as post-ischemic myocardial reperfusion injury. 1 Local and systemic inflammatory reactions play a key role in the extension of myocardial tissue injury and adverse effects during left ventricular (LV) recovery. 2 Some experimental studies have demonstrated the importance of monocyte/macrophage infiltration after myocardial infarction. 3,4 Monocyte chemoattractant protein-1 (MCP-1) belongs to the CC chemokine subfamily with 2 adjacent cysteine residues, and serves as a chemotactic and activating factor for the recruitment of monocytes. 5 MCP-1 is secreted by various types of cells, such as monocytes/macrophages, T lymphocytes, endothelial cells, vascular smooth muscle cells and myocytes. [5][6][7] Many experimental and clinical studies have demonstrated up-regulation of MCP-1 after myocardial infarction, with recruitment of monocytes/macrophages to the ischemic myocardium. 8,9 CC chemokine receptor 2 (CCR2) is a major receptor for MCP-1 and MCP-1 appears to bind solely to CCR2. 5 We have previously reported improvement in LV remodeling after myocardial infarction in mice deficient in the gene encoding CCR2 by inhibiting matrix metalloproteinase (MMP) activity. 10 Recently, Dewald et al also reported that MCP-1 -/-mice attenuated LV remodeling after myocardial ischemia followed by reperfusion. 11 In addition to the effects on MMP activity and the release of pro-inflammatory cytokines, macrophages may cause oxidative stress. 12-14 Increased oxidative stress has been implicated in the cell death associated with cardiovascular diseases including ischemia-reperfusion injury. 15 Macrophages have been shown to produce peroxynitrite (ONOO -), a highly reactive oxygen species that can cause cell injury. 16 Several studies have implicated peroxynitrite as a major cause of injury in the heart subjected to ischemiareperfusion or cytokines. 17,18 However, it is not clear whether the inhibition of the CCR2 pathway may attenuate oxidative stress induced by myocardial ischemia-reperfusion in mice. We hypothesized that the inhibition of the MCP-1/CCR2 pathway may contribute to the attenuation of infarct size after myocardial ischemia-reperfusion via inhibition of macrophage-related oxidative stress and MMP.Thus, the purpose of the present study was to investigate the relationship between the monocytic inflammatory response and myocardial ischemia-reperfusion injury by using mice deficient in the CCR2 gene. Background Monocyte chemoattractant protein-1 (MCP-1) and its major receptor, CC chemokine receptor 2 (CCR2), have been shown to contribute to left ventricular remodeling after myocardial infarction. However, it is unknown whether CCR2 deficiency protects the myocardium after myocardial ischemia-reperfusion. The purpose of the present study was to investigate the effects of CCR2 deficiency on myocardial...

No abstract