Role of elevated plasma transforming growth factor-beta 1 levels in wound healing

Transforming growth factor (TGF)-beta 1 plays a central role in wound heali ng. Wounds treated with neutralizing antibody to TGF-beta 1 have a lower in flammatory response, reduced early extracellular matrix deposition, and red uced later cutaneous scarring, indicating the importance of local tissue TG F-beta 1. By contrast, increasing the local, tissue levels of TGF-beta 1 in creases the early extracellular matrix deposition but does not alter scar f ormation. Increased levels of plasma TGF-beta 1 correlate with increased fi brogenesis in the lung, kidneys, and liver. The aim of the present study wa s to investigate the role of elevated systemic levels of TGF-beta 1 on woun d healing. We used transgenic mice that express high levels of active TGF-b eta 1 and have elevated plasma levels of TGF-beta 1 and wild-type mice of t he same strain as controls. Incisional wounds and subcutaneously implanted polyvinyl alcohol (PVA) sponges were analyzed. Surprisingly, cutaneous woun ds in transgenic, TGF-beta 1-overexpressing mice healed with reduced scarri ng accompanied by an increase in the immunostaining for TGF-beta 3 and TGF- beta-receptor RII and a decrease in immunostaining for TGF-beta 1 compared with wounds in control mice. By contrast, the PVA sponges showed the opposi te response, with PVA sponges from transgenic mice demonstrating an enhance d rate of cellular influx and matrix deposition into the sponges accompanie d by an increase in the immunostaining for all three TGF-beta isoforms and their receptors compared with PVA sponges from control mice. Together, the data demonstrate that increased circulating levels of TGF-beta 1 do not alw ays result in increased expression or activity in selected target tissues s uch as the skin. The two wound models, subcutaneously implanted PVA sponges and cutaneous incisional wounds, differ significantly in terms of host res ponse patterns. Finally, the data reinforce our previous observations that the relative ratios of the three TGF-beta isoforms is critical for control of scarring.