Severe injury to the epidermal barrier often results in scarring and life-long functional deficits, the outcome worsening with a number of factors including time taken to heal. We have investigated the potential of exogenous metallothionein IIA (Zn-7-MT-IIA), a naturally occurring small cysteine-rich protein, to accelerate healing of burn wounds in a mouse model. Endogenous MT-I/II expression increased in basal keratinocytes concurrent with reepithelialization after a burn injury, indicating a role for MT-I/II in wound healing. In vitro assays of a human keratinocyte cell line indicated that, compared with saline controls, exogenous Zn-7-MT-IIA significantly increased cell viability by up to 30% (p < 0.05), decreased apoptosis by 13% (p < 0.05) and promoted keratinocyte migration by up to 14% (p < 0.05), all properties that may be desirable to promote rapid wound repair. Further in vitro assays using immortalized and primary fibroblasts indicated that Zn7-MT-IIA did not affect fibroblast motility or contraction (p > 0.05). Topical administration of exogenous Zn-7-MT-IIA (2 mu g/mL) in vivo, immediately postburn accelerated healing, promoted faster reepithelialization (3 days: phosphate-buffered saline (PBS), 8.9 +/- 0.3 mm diameter vs. MT-I/II, 7.1 +/- 0.7 mm; 7 days: PBS 5.8 +/- 0.98 mm vs. MT-I/II, 3.6 +/- 1.0 mm, p < 0.05) and reduced epidermal thickness (MT-I/II: 45 +/- 4 mu m vs. PBS: 101 +/- 19 mu m, p < 0.05) compared with controls. Our data suggest that exogenous Zn-7-MT-IIA may prove a valuable therapeutic for patients with burns and other skin injuries.