038 Adenoviral overexpression of MCP‐2 induces macrophages and improves wound healing in diabetic rats

Abstract

The recruitment of leukocyte subsets is mainly driven by chemokines. Monocyte chemotactic protein‐2 (MCP‐2) belongs to the CC subfamily of chemokines, and it is especially a chemoattractant for monocytes. Of all CC subfamily members only MCP‐2 interacts with multiple receptors, and its N‐terminal truncated isoform is a natural chemokine inhibitor. Gene expression profiling in excisional wounds showed MCP‐2 was down‐regulated 40% in wild type mice and 69.2% in diabetic mice at 24 h after wounding. To determine the biological response to MCP‐2 during wound healing, we constructed an adenoviral vector (Ad‐MCP‐2). Ad‐MCP‐2 infected cell conditioned medium contained 460 ng/ml secreted MCP‐2 (ELISA) and had chemotactic activity similar to recombinant full‐length MCP‐2 but not to MCP‐2 N‐terminal 8–13aa peptides in a THP‐1cell migration assay. In an incisional wound model in STZ induced diabetic rats, the breaking strength of Ad‐MCP‐2 infected skin wounds increased by 43%(108 PFU, p < 0.05) and 30%(107 PFU, p < 0.05) at 7d after Ad‐MCP‐2 injection compared with Ad‐LacZ control. The wound closure strength of 107 PFU Ad‐MCP‐2 infected wounds still increased by 21%(p < 0.05) at 10d after injection. In normal rats, the breaking strength of Ad‐MCP‐2 and Ad‐Lacz infected wounds was not significantly different. In rats, we injected either Ad‐MCP‐2 or Ad‐LacZ (108 PFU) into each PVA sponge at 3d after implantation. Histological analyses revealed numerous ED‐1 positive macrophages infiltrating in the experimental granulation tissue at 7d after Ad‐MCP‐2 injection. Our data provide evidence that MCP‐2 improved wound healing in diabetic rats, and the recruitment of macrophages into the wound granulation tissues was the one of the mechanisms.