Role of elevated plasma transforming growth factor-beta1 levels in wound healing - PubMed (original) (raw)

Role of elevated plasma transforming growth factor-beta1 levels in wound healing

M Shah et al. Am J Pathol. 1999 Apr.

Abstract

Transforming growth factor (TGF)-beta1 plays a central role in wound healing. Wounds treated with neutralizing antibody to TGF-beta1 have a lower inflammatory response, reduced early extracellular matrix deposition, and reduced later cutaneous scarring, indicating the importance of local tissue TGF-beta1. By contrast, increasing the local, tissue levels of TGF-beta1 increases the early extracellular matrix deposition but does not alter scar formation. Increased levels of plasma TGF-beta1 correlate with increased fibrogenesis in the lung, kidneys, and liver. The aim of the present study was to investigate the role of elevated systemic levels of TGF-beta1 on wound healing. We used transgenic mice that express high levels of active TGF-beta1 and have elevated plasma levels of TGF-beta1 and wild-type mice of the same strain as controls. Incisional wounds and subcutaneously implanted polyvinyl alcohol (PVA) sponges were analyzed. Surprisingly, cutaneous wounds in transgenic, TGF-beta1-overexpressing mice healed with reduced scarring accompanied by an increase in the immunostaining for TGF-beta3 and TGF-beta-receptor RII and a decrease in immunostaining for TGF-beta1 compared with wounds in control mice. By contrast, the PVA sponges showed the opposite response, with PVA sponges from transgenic mice demonstrating an enhanced rate of cellular influx and matrix deposition into the sponges accompanied 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-beta1 do not always result in increased expression or activity in selected target tissues such as the skin. The two wound models, subcutaneously implanted PVA sponges and cutaneous incisional wounds, differ significantly in terms of host response patterns. Finally, the data reinforce our previous observations that the relative ratios of the three TGF-beta isoforms is critical for control of scarring.

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Figures

Figure 1.

Figure 1.

Experimental model. Male transgenic mice line 25 containing the fusion gene (Alb/TGF-β1) consisting of a modified porcine TGF-β1 cDNA under the control of the regulatory elements of the mouse albumin gene were used for this investigation. Male wild-type mice of the same strain (C57B/L6J × CBA) were used as the control group. Four 0.75-cm, full-thickness, incisional wounds were made on the dorsum of the animal and left to heal by secondary intention (a). Two PVA sponges were implanted into subcutaneous pockets on the ventral surface of the animals, and the transverse wounds were sutured to prevent extrusion of the implants (b). Cutaneous wounds and PVA sponges were harvested on days 7, 14, and 80 after wounding.

Figure 2.

Figure 2.

Macroscopic appearance of cutaneous scars. At 80 days after wounding, there is a firm, raised obvious cutaneous scar (arrowheads) in the control mouse (a). By contrast, the wound in the transgenic mouse has healed with a very fine linear scar (arrowheads), which is barely discernible (b).

Figure 3.

Figure 3.

Microscopic appearance of cutaneous scars. Sections of wounds harvested 80 days after wounding were stained with picrosirius red and visualized through a polarized microscope. The architecture of the neodermis in the control wound (a) demonstrates parallel arrangement of the collagen fibers lacking the open basket-weave pattern of the normal dermis (b): scar formation. By contrast, the neodermis of wound in the transgenic mouse (c) more closely resembles the basket-weave pattern of normal dermis (d): better quality of scarring. Scale bar, 100 μm.

Figure 4.

Figure 4.

Immunostaining for TGF-β1. Sections of wounds and PVA sponges harvested 7 days after wounding were immunostained for TGF-β1 using the ABC technique (brown is positive staining). Surprisingly, the epidermis and neodermis of cutaneous wounds from transgenic mice (b) stained much less intensely for TGF-β1 than wounds from control mice (a). By contrast, PVA sponges from the transgenic mice (d) stained markedly more intensely than PVA sponges from control mice (c). Scale bar, 100 μm. Arrows indicate the wound site as determined microscopically from the divided panniculus carnosus and the differences between adjacent normal dermis and the wound.

Figure 5.

Figure 5.

Immunostaining for TGF-β2. Sections of wounds and PVA sponges harvested 7 days after wounding were immunostained for TGF-β2 using the ABC technique (brown is positive staining). Cutaneous wounds from transgenic mice (b) stained marginally more intensely for TGF-β2 than wounds from control mice (a), principally in the epidermis. By contrast, PVA sponges from the transgenic mice (d) stained markedly more intensely than PVA sponges from control mice (c). Scale bar, 100 μm. Arrows indicate the healing wound.

Figure 6.

Figure 6.

Immunostaining for TGF-β3. Sections of wounds and PVA sponges harvested 7 days after wounding were immunostained for TGF-β3 using the ABC technique (brown is positive staining). There was a marked increase in the immunostaining for TGF-β3 in both the cutaneous wounds (b) and the PVA sponges (d) from the transgenic mice compared with wounds (a) and PVA sponges (c) from control mice. Scale bar, 100 μm. Arrows indicate the healing wound.

Figure 7.

Figure 7.

Immunostaining for TGF-β receptor RI. Sections of wounds and PVA sponges harvested 7 days after wounding were immunostained for TGF-β receptor RI using the ABC technique (brown is positive staining). The cutaneous wounds from control (a) or transgenic (b) mice did not differ markedly in their immunostaining for RI. By contrast, immunostaining for RI was more marked in PVA sponges from transgenic mice (d) than from control mice (c). Scale bar, 100 μm. Arrows indicate the healing wound.

Figure 8.

Figure 8.

Immunostaining for TGF-β receptor RII. Sections of wounds and PVA sponges harvested 7 days after wounding were immunostained for TGF-β receptor RII using the ABC technique (brown is positive staining). There was a marked increase in the immunostaining for TGF-β receptor RII in both the cutaneous wounds (b) and the PVA sponges (d) from transgenic mice compared with wounds (a) and PVA sponges (c) from control mice. Scale bar, 100 μm. Arrows indicate the healing wound.

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