Elsevier

Human Pathology

Volume 33, Issue 3, March 2002, Pages 355-364
Human Pathology

Original Contributions
Ectopic localization of matrix metalloproteinase-9 in chronic cutaneous wounds*,**

https://doi.org/10.1053/hupa.2002.32221Get rights and content

Abstract

It has been hypothesized that excessive activity of matrix metalloproteinases (MMPs), in particular the gelatinases MMP-9 and MMP-2, contributes to poor healing of chronic skin ulcers. We compared MMP-9 and MMP-2 in wound margin biopsies of standardized acute partial-thickness wounds in healthy volunteers (n = 6) and in venous leg ulcer patients (n = 12) with those of chronic wounds of different etiologies (n = 34) by a combination of specific analyses of activity and protein localization. We also studied MMP-14 by immunohistochemistry and in situ hybridization in parallel. Neither MMP-9 (P =.814) nor MMP-2 (P =.742) endogenous activities differed significantly between acute and chronic wound tissues. Acute wound healing was characterized by induction of MMP-9 in the advancing epithelium. In chronic wounds, prominent MMP-9 immunostaining was seen in neutrophils and macrophages in the ulcer bed, but virtually no MMP-9 was detected in wound edge keratinocytes. MMP-2 was increased and activated with acute wound age. MMP-2 was found abundantly in dermal fibroblasts and endothelial cells beneath, but not in new epithelium of acute and chronic wounds. MMP-14 mRNA or protein was detected solely in the stroma of both acute and chronic wounds. In conclusion, the overall activity of gelatinases MMP-9 and MMP-2 was not increased in chronic wounds compared to normally healing wound tissues. Chronic nonhealing wounds may not be caused by excessive gelatinase activity, but are distinguished from healing wounds by an unfavorable distribution and persistance of MMP-9. HUM PATHOL 33:355-364. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

Patients

The local ethics committees of University of Copenhagen (KF 01-072/94) and University of Helsinki (TIA 4014) approved the study, and patients participated only after giving their written consent.

Wound healing

The acute wounds healed uneventfully. The dermatome partial-thickness wounds decreased by 58 ± 10% (mean ± SEM) in surface area over the 1-week postwounding period. The pinch graft donor wounds were completely healed in 6 to 9 days. The chronic wounds showed no or minimal healing tendency and decreased in size by at most 4% per week.

MMP-9 and MMP-2 activities in acute and chronic wounds

The endogenous activities of MMP-9 and MMP-2 were determined in normal skin and in wound margin biopsies of 6 acute dermatome wounds postwounding days 1 and 7. The

Discussion

The role of MMPs in normal wound healing is well documented,10 but the role of MMPs in nonhealing chronic wounds is less clear. Contrary to the general assumption, MMP-9 activities did not differ significantly between chronic and standardized acute wounds, but its localization did. In chronic wounds, MMP-9 was concentrated in inflammatory cells of the ulcer bed, whereas in normal wounds, MMP-9 was predominantly expressed by advancing epithelium. Keratinocytes at the wound margins of chronic

Acknowledgements

The authors thank Dr Jouko Lohi for the MMP-14 plasmid, Alli Tallqvist for skillful technical assistance, and Annie Høj for the smear counts. Drs Lawrence T. Kim and J. Frederick Woessner Jr reviewed the manuscript.

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    *

    Supported by grants from Helsinki University Central Hospital Research Funds (EVO), the Academy of Finland and Sigrid Jusélius Foundation, and the Malmö University Hospital, University of Lund, Sweden. Coloplast A/S, Denmark funded the dermatome study.

    **

    Address correspondence and reprint requests to Ursula Mirastschijski, MD, Sørens Allé 4B, DK-3050 Humlebæk, Denmark. E-mail: [email protected].

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