The Effect of Topically Applied Recombinant Human Growth Hormone on Wound Healing in Pigs
- 0 Comments
- 9940 reads
Abstract: The beneficial wound healing effect of the systemic growth hormone (GH) mediated by insulin-like growth factor 1 (IGF-1) has been widely reported. Recent studies have suggested that GH facilitates wound healing not by circulating IGF-1, but by local IGF-1 produced in the wound itself. The aim of this study was to define whether the locally administered GH could accelerate the wound-healing rate. Full-thickness skin defects (diameter 4 cm) were made in the back of micropigs, and GH (2.5 IU/L) was applied every other day for 3 weeks (11 times total). Control wounds were given the vehicle only. The wound sizes were measured weekly by planimetry and biopsies were taken. The wound sizes were significantly reduced in the GH-treated groups as compared with the control group (P < 0.05) each week. Histological and immunohistochemical examination revealed that the production of IGF-1 and collagen 1 in the experimental group increased more than in the control group. The present results suggest that local treatment with GH effectively accelerates wound healing.
Address correspondence to:
Sang Woo Lee, MD
Department of Plastic and Reconstructive Surgery
Seoul National University, Bundang Hospital
166 Gumiro, Bundang, Seongnam, Gyeonggi
Phone: +82 11 264 0674
Recombinant growth hormone (GH) has been used as an anabolic treatment in burn and postoperative patients.1,2 More recently, growth hormone has been increasingly used in experiments and has shown promise in the acceleration of wound healing in several studies.3,4 Growth hormone stimulates granulation tissue formation, increases collagen deposition, and facilitates epithelialization.5,6 It can also accelerate donor site healing in patients with burns3 and bone healing.7
Many studies have shown that insulin-like growth factor-1 (IGF-1) mediates the action of GH in wound healing. However, it has not yet been determined whether IGF-1 affects the wound through endocrine action or through paracrine and autocrine action. In the past, it was discovered that GH could have a positive effect on wound healing by stimulating the production of IGF-1 in the liver to increase circulating IGF-1 concentration.8,9 More recently, many evidences have been reported that circulating IGF-1 does not affect the wound, but that IGF-1 produced locally by fibroblasts, macrophages, and endothelial cells contribute to wound healing.10,11 And topically applied GH increases the concentration of IGF-1 mRNA in the granulation tissue in vivo.12
If the effect of IGF-1 by GH on wound healing is produced locally within the wound, then topical administration of GH can facilitate wound healing. The present study tested the contribution of topically applied GH on wound healing.
Materials and Methods
Recombinant human growth hormone and other ingredients for cream formulation were obtained from LG Household & Health Care Ltd (Seoul, Korea). White petrolatum, cod-liver oil, glycerin, bisabolol, and propylparaben were used to formulate a GH cream base. To yield 2.5 IU/L of GH cream, GH powder was dissolved in warm water and then mixed with the other ingredients.
GH concentration. The concentration of GH was determined through a preliminary study. Growth hormone stimulates fibroblast proliferation, which is an integral step in the wound healing process.13 When GH was applied, the fibroblast proliferation increased significantly (P < 0.05; paired t-test). Cell proliferation was measured by tetrazolium-based colorimetric assay (MTT cell growth assay kit, Millipore, Temecula, Calif).
1. Hernandez MJ, Fernandez OC, Gallego FC. Recombinant growth hormone in total parenteral nutrition. Farm Clin. 1995;12:112.
2. Vara-Thorbeck R, Guerrero JA, Rosell J, Ruiz-Requena E, Capitán JM. Exogenous growth hormone: effects on the catabolic response to surgically produced acute stress and on postoperative immune function. World J Surg. 1993;17(4):530–538.
3. Losada F, García-Luna PP, Gómez-Cía T, et al. Effects of human recombinant growth hormone on donor-site healing in burned adults. World J Surg. 2002;26(1):2–8.
4. Rasmussen LH, Karlsmark T, Avnstorp C, Peters K, Jorgensen M, Jensen LT. Topical human growth hormone treatment of chronic leg ulcers. Phlebol. 1991;6:23–30.
5. Rasmussen LH, Garbarsch C, Schuppan D, et al. Influence of human growth hormone on granulation tissue formation, collagen deposition, and the aminoterminal propeptide of collagen type III in wound chambers in rats. Wound Repair Regen. 1994;2(1):31–36.
6. Jørgensen PH, Oxlund H. Growth hormone increases the biomechanical strength and collagen deposition rate during the early phase of skin wound healing. Wound Repair Regen. 1996;4(1):40–47.
7. Kolbeck S, Bail H, Schmidmaier G, et al. Homologous growth hormone accelerates bone healing—a biomechanical and histological study. Bone. 2003;33(4):628–637.
8. Scott CD, Martin JL, Baxter RC. Production of insulin-like growth factor I and its binding protein by adult rat hepatocytes in primary culture. Endocrinology. 1985;116(3):1094–1101.
9. Pell JM, Bates PC. Differential actions of growth hormone and insulin-like growth factor-I on tissue protein metabolism in dwarf mice. Endocrinology. 1992;130(4):1942–1950.
10. Robertson JG, Walton PE, Dunshea F, Dunaiski V, Ballard FJ. Growth hormone but not insulin-like growth factor-I improves wound strength in pigs. Wound Repair Regen. 1997;5(2):168–174.
11. Dunaiski V, Belford DA. Contribution of circulating IGF-1 to wound repair in GH-treated rats. Growth Horm IGF Res. 2002;12(6):381–387.
12. Steenfos HH, Jansson JO. Growth hormone stimulates granulation tissue formation and insulin-like growth factor-I gene expression in wound chambers in the rat. J Endocrinol. 1992;132(2):293–298.
13. Li JX, Liu XS, Tang H, Zhou X, Huang YS. Influence of some topical antibiotics and FGF2, EGF and rhGH on the biological characteristics of fibroblasts in vitro. Zhonghua Shao Shang Za Zhi. 2006;22(1):33–37.
14. Ghofrani A, Höller D, Schuhmann K, Saldern S, Messmer BJ. The influence of systemic growth hormone administration on the healing time of skin graft donor sites in a pig model. Plast Reconstr Surg. 1999;104(2):470–475.
15. Ando Y, Jensen PJ. Epidermal growth factor and insulin-like growth factor I enhance keratinocyte migration. J Invest Dermatol. 1993;100(5):633–639.
16. Lee YR, Oshita Y, Tsuboi R, Ogawa H. Combination of insulin-like growth factor (IGF)-1 and IGF-binding protein-1 promotes fibroblast-embedded collagen gel contraction. Endocrinology. 1996;137(12):5278–5283.
17. Bitar MS. Insulin-like growth factor-1 reverses diabetes-induced wound healing impairment in rats. Horm Metab Res. 1997;29(8):383–386.
18. Gartner MH, Benson JD, Caldwell MD. Insulin-like growth factors I and II expression in the healing wound. J Surg Res. 1992;52(4):389–394.
19. Ghahary A, Shen YJ, Wang R, Scott PG, Tredget EE. Expression and localization of insulin-like growth factor-1 in normal and post-burn hypertrophic scar tissue in human. Mol Cell Biochem. 1998;183(1-2):1–9.
20. Strock LL, Singh H, Abdullah A, Miller JA, Herndon DN. The effect of insulin-like growth factor I on postburn hypermetabolism. Surgery. 1990;108(2):161–164.
21. Jørgensen PH, Andreassen TT. A dose-response study of the effects of biosynthetic human growth hormone on formation and strength of granulation tissue. Endocrinology. 1987;121(5):1637–1641.