Matrix metalloproteinase-8 overexpression prevents proper tissue repair

Background. The collagenolytic matrix metalloproteinase-8 (MMP-8) is essential for normal tissue repair but is often. overexpressed in wounds with disrupted healing. Our aim was to study the impact of a local excess of this neutrophil-derived proteinase on wound healing using recombinant adenovirus-driven transduction of full-length Mmp8 (AdMMP-8). Methods. The effect of MMP-8 overexpression was evaluated in dermal fibroblasts and in two wound healing models in male Wistar rats: subcutaneously positioned ePTFE catheters and linear incisional skin wounds. Results. Fibroblasts transduced with AdMMP-8 secreted MMP-8 with type I collagenolytic activity that could be blocked by a selective MMP-8 inhibitor AdMMP-8 (5 x 10(10) viral particles) administered in homologous fibrin increased MMP-8 mRNA (P <.05) levels compared to parallel wounds treated with a control adenovirus expressing lacZ (AdLacZ). Impaired wound healing was demonstrated with AdMMP-8 by decreased collagen deposition and breaking strength of incisional wounds on day 7 compared to AdLacZ-treated wounds (P <.05). We found no significant effect of AdMMP-8 on mRNA levels of MMP-9, COL1A1, or COL3A1, but AdMMP-8 treatment decreased the number of neutrophils. in the incisional wounds, MMP-8 gene transfer was not associated with significant changes in macrophage numbers or amount of granulation tissue but did increase MMP-8 protein by 76% (P <.01) and decrease type I collagen protein by 29% (P <.05) compared with AdLacZ. Conclusion. These results demonstrate that superphysiologic levels of the proteinase MMP-8 can result in decreased collagen and lead to impaired wound healing. This observation makes MMP-8 a potential drug target in compromised human wound healing associated with MMP-8 overexpression. (Surgery 2011;150:897-906.)