Impaired Wound Contraction in Stromelysin-1–Deficient Mice : Annals of Surgery (original) (raw)

ORIGINAL ARTICLES

Bullard, Kelli M. MD*; Lund, Leif PhD†; Mudgett, John S. PhD‡; Mellin, Theodore N. PhD‡; Hunt, Thomas K. MD*; Murphy, Beth BS‡; Ronan, John BS‡; Werb, Zena PhD§; Banda, Michael J. PhD∥

From the Departments of *Surgery and §Anatomy, and the ∥Laboratory of Radiobiology and Environmental Health, University of California, San Francisco; the †Finsen Laboratory, Copenhagen, Denmark; and the ‡Departments of Immunology and Pharmacology, Merck Research Labs, Rahway, New Jersey

Correspondence: Kelli M. Bullard, MD, Box 0570, Fetal Treatment Center, Room HSW-1601, University of California, San Francisco, San Francisco, CA 94143-0570.

Supported by the Society for University Surgeons Surgical Research Fellowship and grants from NIH (AR 41118 and DE 10306), and a contract from OHER, U.S. Department of Energy DE-AC03-76-SF01012.

Accepted for publication January 5, 1999.

Abstract

Objective

To determine whether the deletion of stromelysin-1, a single metalloproteinase gene product, will alter the time course and quality of dermal wound repair in mice.

Summary Background Data

After dermal injury, a highly coordinated program of events is initiated by formation of a fibrin clot, followed by migration of keratinocytes, contraction of the dermis, recruitment of inflammatory macrophages, formation of granulation tissue with angiogenesis, and finally tissue remodeling. Matrix metalloproteinases are rapidly induced in the dermis and granulation tissue and at the leading edge of the epidermis in the healing wounds.

Methods

Incisional and circular full-thickness wounds 2 to 10 mm were made in the dermis of stromelysin-1–deficient and wild-type mice. The wounds were analyzed for rate of cellular migration and epithelialization. The wound contraction was examined by immunohistochemical staining for α-smooth muscle actin and fluorescent staining for fibrillar actin.

Results

Independent of the age of the animal, excisional wounds in stromelysin-1–deficient mice failed to contract and healed more slowly than those in wild-type mice. Cellular migration and epithelialization were unaffected in the stromelysin-1–deficient animals. The functional defect in these mice is failure of contraction during the first phase of healing because of inadequate organization of actin-rich stromal fibroblasts.

Conclusions

Excisional dermal wound healing is impaired in mice with a targeted deletion in the stromelysin-1 gene. Incisional wound healing is not affected. These data implicate stromelysin-1 proteolysis during early wound contraction and indicate that stromelysin-1 is crucial for the organization of a multicellular actin network.