Selective effects of tumor necrosis factor-alpha on wound healing in rats

Many growth factors are believed to act simultaneously in wounds. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine released by activated macrophages. In various concentrations it has inflammatory, cytolytic, mitogenic, antitumor, and possibly angiogenic or antiangiogenic effects; therefore it is likely to affect wound healing. With stainless steel wire mesh wound cylinders implanted in rats, we tested topical TNF-alpha in wounds, alone and in combination with platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta). The cylinders were injected daily for a total of 12 days, after which we measured the accumulation of protein, DNA, and hydroxyproline in each cylinder. TNF-alpha had little effect by itself; it inhibited the growth-promoting effects of TGF-beta, but it did not influence the effects of PDGF. These results agree with the in vitro studies showing synergism of TNF-alpha and PDGF and antagonism between TGF-beta and TNF-alpha. They also suggest that TGF-beta may have a negligible role in normal healing and emphasize that interaction of growth factors must be understood before appropriate clinical use can be planned.