A salient feature of normal wound healing is the development and resolution of an acute inflammatory response. Although much is known about the function of inflammatory cells within wounds, little is known about the chemotactic and activation signals that influence this response. As the CC chemokines macrophage inflammatory protein-1alpha (MIP-1alpha) and monocyte chemotactic protein-1 (MCP-1) are abundant in acute wounds, wound repair was examined in MIP-1alpha(-/-) and MCP-1(-/-) mice. Surprisingly, wound re-epithelialization, angiogenesis, and collagen synthesis in MIP-1alpha(-/-) mice was nearly identical to wild-type controls. In contrast, MCP-1(-/-) mice displayed significantly delayed wound re-epithelialization, with the greatest delay at day 3 after injury (28 +/- 5% versus 79 +/- 14% re-epithelialization, P < 0.005). Wound angiogenesis was also delayed in MCP-1(-/-) mice, with a 48% reduction in capillary density at day 5 after injury. Collagen synthesis was impeded as well, with the wounds of MCP-1(-/-) mice containing significantly less hydroxyproline than those of control mice (25 +/- 3 versus 50 +/- 8 microg/wound at day 5, P < 0.0001). No change in the number of wound macrophages was observed in MCP-1(-/-) mice, suggesting that monocyte recruitment into wounds is independent of this chemokine. The data suggest that MCP-1 plays a critical role in healing wounds, most likely by influencing the effector state of macrophages and other cell types.
At sites of injury, macrophages secrete growth factors and proteins that promote tissue repair. While this central role of the macrophage has been well studied, the specific stimuli that recruit macrophages into sites of injury are not well understood. This study examines the role of macrophage inflammatory protein 1 ␣ (MIP-1 ␣ ), a C-C chemokine with monocyte chemoattractant capability, in excisional wound repair. Both MIP-1 ␣ mRNA and protein were detectable in murine wounds from 12 h through 5 d after injury. MIP-1 ␣ protein levels peaked 3 d after injury, coinciding with maximum macrophage infiltration. The contribution of MIP-1 ␣ to monocyte recruitment into wounds was assessed by treating mice with neutralizing anti-MIP-1 ␣ antiserum before injury. Wounds of mice treated with anti-MIP-1 ␣ antiserum had significantly fewer macrophages than control (41% decrease, P Ͻ 0.01). This decrease in wound macrophages was paralleled by decreased angiogenic activity and collagen synthesis. When tested in the corneal micropocket assay, wound homogenates from mice treated with anti-MIP-1 ␣ contained significantly less angiogenic activity than control wound homogenates (27% positive for angiogenic activity versus 91% positive in the control group, P Ͻ 0.01). Collagen production was also significantly reduced in the wounds from anti-MIP-1 ␣ treated animals (29% decrease, P Ͻ 0.05). The results demonstrate that MIP-1 ␣ plays a critical role in macrophage recruitment into wounds, and suggest that appropriate tissue repair is dependent upon this recruitment. (
Previous studies suggest that normal wound repair requires the regulated production of monocyte and macrophage chemoattractants. The current study examines the role of monocyte chemoattractant protein-1 (MCP-1) in coordinating monocyte recruitment into sites of injury. MCP-1 protein was detected in both incisional and excisional murine wounds, with a peak concentration occurring slightly before maximum macrophage infiltration. Compared to wounds treated with control antibody, wounds treated with a neutralizing monoclonal anti-MCP-1 antibody contained significantly fewer macrophages (8.2 +/- 0.9 vs. 14 +/- 1.7 macrophages per high power field, p < 0.05). Conversely, the addition of recombinant MCP-1 to wounds resulted in a substantial increase in the number of macrophages (107% to 124% increase over untreated wounds, p < 0.01). Because macrophages promote wound healing, the effect of recombinant MCP-1 on the wound healing process was examined. Incisional wounds (n = 12) were either left untreated or treated with vehicle alone, 5 ng recombinant MCP-1 in vehicle, or 50 ng recombinant MCP-1 in vehicle. Wound disruption strength was determined on days 7, 14, 21, and 28 for each group. Wounds treated with MCP-1 exhibited a slight increase in wound disruption strength at nearly all time points but this increase did not reach statistical significance. Addition of 100 ng of MCP-1 to excisional wounds did not have any significant effect on wound reepithelialization. Taken together, the results show that MCP-1 is produced within wounds at physiologic concentrations, and is an important positive regulator of macrophage recruitment into sites of injury. Addition of exogenous MCP-1 to wounds of normal mice yields only modest enhancement of the repair process.
Angiogenesis, the formation of new capillaries from existing vasculature, plays an essential role in tissue repair. The rapid onset and predominance of proangiogenic factors optimizes healing in damaged tissues. One factor that directly mediates wound vessel angiogenesis is vascular endothelial growth factor (VEGF). Although much is known about the biology of VEGF and its cognate receptors, VEGFR1 and VEGFR2, the role of a recently identified co-receptor for VEGF, neuropilin-1, is not well understood. Using a murine model of dermal wound repair, we found that neuropilin-1 was abundantly expressed on new vasculature in healing wounds. Moreover, mice treated with anti-neuropilin-1 antibodies exhibited a significant decrease in vascular density within these wounds (67% decrease, P = 0.0132). In in vitro assays, VEGF induced formation of endothelial cord-like structures on collagen gel and endothelial cell migration toward VEGF was inhibited by antibodies directed against neuropilin-1. These results provide both in vitro and in vivo evidence for a critical role of neuropilin-1 in wound angiogenesis.
A series of novel water-soluble PEGylated dibenzosilole-based conjugated polymers were prepared as ultra-bright fluorescent labels for biomolecules. Due to their superior solubility and brightness, antibody conjugates labeled with functionalized polymers showed significantly enhanced signal and sensitivity relative to traditional fluorophores in functional flow cytometry applications.
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