Matrix metalloproteinase-8 overexpression prevents proper tissue repair

• Published in: Surgery Vol. 150; no. 5; pp. 897 - 906
• Main Authors: Danielsen, Patricia L., MD, PhD, Holst, Anders V., MD, Maltesen, Henrik R., MD, Bassi, Maria R., MSc, Holst, Peter J., MD, PhD, Heinemeier, Katja M., PhD, Olsen, Jørgen, MD, PhD, Danielsen, Carl C., MD, PhD, Poulsen, Steen S., MD, PhD, Jorgensen, Lars N., MD, DrMedSci, Ågren, Magnus S., DrMedSci
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01-11-2011; Elsevier
• Subjects: Adenoviridae - genetics; Animals; Biological and medical sciences; Cells, Cultured; Collagen - metabolism; Dermis - injuries; Dermis - pathology; Dermis - physiology; Disease Models, Animal; Fibroblasts - cytology; Fibroblasts - physiology; Gene Expression Regulation, Enzymologic - genetics; General aspects; Granulation Tissue - physiology; Macrophages - pathology; Male; Matrix Metalloproteinase 8 - genetics; Matrix Metalloproteinase 8 - metabolism; Medical sciences; Neutrophils - metabolism; Neutrophils - pathology; Prevention and actions; Public health. Hygiene; Public health. Hygiene-occupational medicine; Rats; Rats, Wistar; Surgery; Wound Healing - physiology; Matrix metalloproteinase 8; Enzyme; Gene overexpression; Metalloendopeptidases; Medicine; Prevention; Peptidases; Tissue; Treatment; Surgery; Neutrophil collagenase; Hydrolases; Repair
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/j.surg.2011.06.016

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 × 1010 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.