The Effect of Topically Applied Recombinant Human Growth Hormone on Wound Healing in Pigs

6/1/2009
0 Comments
8321 reads

Author(s):

Suk Hwa Kim, MD; Eun Ju Heo, BS; Sang Woo Lee, MD

A score of 1 to 5 was assigned to each parameter (1 = weakly stained, 5 = strongly stained).

Statistical evaluation. Statistical assessment of the changes in wound size and staining intensity in both groups was performed using the Wilcoxon test; P < 0.05 was considered significant.

Results

Healing time. A significant reduction in the wound sizes of the GH-treated group was observed as compared with the control group (P < 0.05). The wound size of the experimental group decreased significantly more than the control group each week. In the later weeks, the ratio of wound area reduction between the two groups increased. The healing rate in the GH-treated group was faster than that of the control group (Figure 3).

Histological and immunohistochemical examination. To compare IGF-1 levels, the initial (week 1) biopsies of both groups were reviewed, because the healing might be most actively processed. To examine collagen production, the third week biopsies were compared because the healing process was almost finished and the collagen deposition would be most abundant.

Immunostaining for IGF-1 revealed that in GH-treated group, production of IGF-1 increased significantly more than that of the control group, meaning that locally administered GH promoted IGF-1 production within the wound.

Immunostaining for collagen 1 revealed that collagen production in the GH-treated group was greater than that of the control group. This means that locally administered GH can produce IGF-1 in the wound area, and IGF-1 can stimulate granulation tissue growth. But immunohistochemical analysis in collagen 3 showed no significant difference in staining intensity (Figures 4, 5).

Discussion

The foremost role of IGF-1 is its insulin-like metabolic effects; it can stimulate the growth of target tissues such as the liver, adipose tissue, muscle, cartilage, and fibroblasts.^8,9IGF-1 can enhance protein production, cell proliferation, and migration, which is essential in the wound-healing process.^15,16 IGF-1 expression is increased in subcutaneous¹⁷ and incisional¹⁸ wounds, and in post-burn injuries.¹⁹ Some studies have shown that the administration of exogenous IGF-I enhanced protein synthesis in severely burned experimental animals.²⁰ However, recent data have demonstrated that administered IGF-1 did not improve wound healing, and only the IGF-1 produced locally by fibroblasts and macrophages contributed to the regulation of wound healing.^10,11

To enhance the wound healing process, especially in chronic wounds, many growth factors were tested and are now clinically applied. If the systemic IGF-1 was ineffective in wound healing, topical administration of IGF-1 can be considered as other growth factors such as EGF, TGF-β, etc. Unfortunately, topical administration of growth factors has some shortcomings. The cost to produce growth factors is significantly high as it is difficult to keep and transport; hence, increasing IGF-1 production locally by GH administration is superior to administration of IGF-1 itself.

It has been reported that systemic application of GH has a positive effect on wound healing. Systemic GH can increase the collagen production and mechanical strength of wounds.^6,21 Ghofrani et al¹⁴ reported that systemic GH could accelerate the split-thickness skin defect in pigs.

References:

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.