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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online June 21, 2002 as doi:10.1096/fj.02-0103fje. |
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2
Departments of
* Biochemistry and Molecular Biology, and
Surgery, Saint Louis University School of Medicine, St. Louis, Missouri, USA;
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan;
Taiwan Pig Research Institute, Maioli and Pharmaceutical Chemistry Institute, China Medical College, Taichuang, Taiwan; and
|| Department of Plastic and Reconstructive Surgery, Chang Gun Memorial Hospital, Taoyuan, Taiwan
2Correspondence: Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1402 South Grand Bvd., St. Louis, MO 63104, USA. E-Mail: huangjs{at}slu.edu or huangss{at}slu.edu
SPECIFIC AIMS
Transforming growth factor ß (TGF-ß) is involved in the process of wound healing, but its exact roles are not well understood. The aim of this work was to determine the effects of a synthetic TGF-ß antagonist on wound re-epithelialization, contraction, and scarring in pig skin burn/excision and rabbit skin excision wound models.
PRINCIPAL FINDINGS
1. Accelerated re-epithelialization and reduced contraction and scarring in burn wounds treated with TGF-ß peptantagonist
We used the pig model to examine the ability of a synthetic TGF-ß peptide antagonist (peptantagonist) with an amino acid sequence identical to residues 41–65 of TGF-ß1 to affect wound healing in a standardized burn injury. Six thermal burns (110°C, 30 s, 
20 cm2, three on each side) were created on each pig. After wounding, two lesions were treated with a thin layer of IntraSite gel containing TGF-ß peptantagonist (1.5 mM); two received gel alone and two received no topical applications. The TGF-ß peptantagonist and vehicle were applied every 2 days for the first 10 days and twice a week for the next 30 days, at which time re-epithelialization and contraction of the wounds were measured and photographed. As shown in Fig. 1
A, B, the burn wounds showed significant re-epithelialization and contraction after postburn day 10. Wounds treated with TGF-ß peptantagonist exhibited rapid re-epithelialization and less contraction. The re-epithelialization appeared to be complete on postburn day 26 ± 2 (n=4) in wounds treated with TGF-ß peptantagonist whereas wounds treated with vehicle showed 70 ± 10% (n=4) re-epithelialization by this time (Fig. 1A
). Healing of wounds treated without TGF-ß peptantagonist or vehicle was similar to that of the vehicle-only group (data not shown). Wounds treated with TGF-ß peptantagonist exhibited less contraction than those treated with vehicle only (Fig. 1B
). On postburn day 33, cutaneous burns treated with TGF-ß peptantagonist and vehicle only exhibited 50 ± 4 (n=4) and 70 ± 2% (n=4) contraction, respectively (Fig. 1B
). On postburn day 34, the wounds treated with vehicle only exhibited a large area of open wound, whereas those treated with TGF-ß peptantagonist showed very little open wound (Fig. 1C, c, d
). On postburn day 41, less scarring was seen in wounds treated with TGF-ß peptantagonist than in the vehicle-only control wounds (Fig. 1C, e, f
). These results indicate that TGF-ß peptantagonist treatment accelerates re-epithelialization and reduces scarring in the pig burn injury model.
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2. Reduced contraction and scarring in excision wounds treated with TGF-ß peptantagonist
To test the effect of synthetic TGF-ß peptantagonist on scar formation after a different type of standardized injury, six full-thickness disks of skin (3x3 cm) were removed from the backs of four pigs. A thin layer of IntraSite gel containing TGF-ß peptantagonist (1.5 mM) or buffer was applied onto the wound immediately after the excision injury and every 2 days for the first 10 days and twice a week for the remaining experimental days. Dimensions of each wound were measured before each application of TGF-ß peptantagonist or vehicle. The TGF-ß peptantagonist treatment again attenuated contraction of the wound (Fig. 2
A). In contrast to burn injury, the excision injury wound exhibited near-complete horizontal (width of the healed wound) contraction by postexcision day 30 (Fig. 2A
). The wounds treated with TGF-ß peptantagonist showed less vertical (length of the healed wound) contraction than those treated with vehicle only (Fig. 2B, c, d
). On postexcision day 41, less scar formation was observed in the wounds treated with TGF-ß peptantagonist (Fig. 2B, c, d
). The near-complete horizontal contraction observed during wound healing in pigs is not observed in adult humans. We therefore examined the effect of the TGF-ß peptantagonist on scar formation after excision injury in the rabbit, another standard model. The TGF-ß peptantagonist treatment appeared to attenuate scar formation in rabbit ear excision injury on postexcision day 10 whereas the wounds treated with vehicle only and the no-treatment controls displayed large scars (data not shown).
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CONCLUSIONS AND SIGNIFICANCE
Intradermal injection of TGF-ß neutralizing antibodies has been shown to reduce scarring in rat incision wounds, but its effect on large-area wounds such as burn and excision wounds are unknown. Here we demonstrate that a synthetic TGF-ß peptantagonist is effective in accelerating wound healing and reducing scarring in pig skin burn, pig skin excision, and rabbit skin excision injury models (Fig. 3
). There were no apparent deleterious effects of TGF-ß peptantagonist or vehicle gel in the animals. We found no detectable antibodies to the TGF-ß peptantagonist in the plasma of treated animals during or after the experiments. The treatment of hypertrophic scarring with synthetic TGF-ß peptantagonist may have clinical applicability.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0103fje; to cite this article, use FASEB J. (June 21, 2002) 10.1096/fj.02-0103fje 
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