Impaired cutaneous wound healing with excess granulation tissue formation in TNFα-null mice

We examined the effects of lacking tumor necrosis factor alpha (TNF alpha) on the healing process of a cutaneous wound in mice using TNF alpha-deficient mice. A full-thickness circular cutaneous wound 5.0 mm in diameter was produced in the dorsal skin of wild-type (WT) or TNF alpha-null (KO) mice. After specific intervals of healing, the healing pattern was evaluated by macroscopic observation, histology, immunohistochemistry, or real-time reverse transcription-polymerase chain reaction. Effect of Smad7 gene transfer on the healing phenotype of KO mice was also examined. The results showed that loss of TNF alpha promotes granulation tissue formation and retards reepithelialization in a circular wound in mouse dorsal skin. Immunohistochemistry showed that distribution of macrophages and myofibroblasts in newly generated granulation tissue seemed similar between WT and KO mice. However, lacking TNF alpha enhanced mRNA expression of TGF beta 1 and collagen I alpha 2 in such tissue. Smad7 gene transfer counteracted excess granulation tissue formation in KO mice. In conclusion, lacking TNF alpha potentiates Smad-mediated fibrogenic reaction in healing dermis and retards reepithelialization in a healing mouse cutaneous wound.