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(American Journal of Pathology. 2001;159:2147-2157.)
© 2001 American Society for Investigative Pathology

Regular Article

Healing of Burn Wounds in Transgenic Mice Overexpressing Transforming Growth Factor-ß1 in the Epidermis

Liju Yang^*, Teddy Chan^*, Jack Demare^*, Takashi Iwashina^*, Aziz Ghahary^*, Paul G. Scott and Edward E. Tredget^*

From the Department of Surgery,^*
Division of Plastic and Reconstructive Surgery, Wound Healing Research Group, and the Division of Critical Care Medicine
and Department of Biochemistry,
University of Alberta, Edmonton, Alberta, Canada

Transforming growth factor-ß (TGF-ß) isoforms are multifunctional cytokines that play an important role in wound healing. Transgenic mice overexpressing TGF-ß in the skin under control of epidermal-specific promoters have provided models to study the effects of increased TGF-ß on epidermal cell growth and cutaneous wound repair. To date, most of these studies used transgenic mice that overexpress active TGF-ß in the skin by modulating the latency-associated-peptide to prevent its association with active TGF-ß. The present study is the first to use transgenic mice that overexpress the natural form of latent TGF-ß1 in the epidermis, driven by the keratin 14 gene promoter to investigate the effects of locally elevated TGF-ß1 on the healing of partial-thickness burn wounds made on the back of the mice using a CO₂ laser. Using this model, we demonstrated activation of latent TGF-ß after wounding and determined the phenotypes of burn wound healing. We found that introduction of the latent TGF-ß1 gene into keratinocytes markedly increases the release and activation of TGF-ß after burn injury. Elevated local TGF-ß significantly inhibited wound re-epithelialization in heterozygous (42% closed versus 92% in controls, P < 0.05) and homozygous (25% versus 92%, P < 0.01) animals at day 12 after wounding. Interestingly, expression of type I collagen mRNA and hydroxyproline significantly increased in the wounds of transgenic mice, probably as a result of a paracrine effect of the transgene.

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