In-Vitro Mechanisms of Cell Proliferation Induction: A Novel Bioactive Treatment for Accelerating Wound Healing
- 0 Comments
- 6962 reads
Over the past several years, much has been learned regarding the molecular and physiological bases of wound healing,1 as well as the causes of various chronic wounds, such as pressure ulcers. Recent cellular and molecular studies have substantially increased our understanding of the elegant cascade of signaling events necessary for the wound healing process.1–11 For example, several important biochemical mediators of cell migration and growth have been identified that are involved in tissue reformation.6,12,13 It is understood that, in many instances, these regulatory signals do not appear to be functioning properly in chronic, nonhealing wounds.14 There are distinct phases associated with the process of wound healing, and it is clear that fibroblasts and epithelial cells are two of several cell types critical to establishing and progressing through the wound healing process.1 For example, fibroblasts must proliferate and synthesize collagen to provide a strong matrix for vascularization and epithelial growth.
Growth factors have been considered candidate therapeutics for wound healing because they are synthesized by and stimulate cells required for tissue repair, they are deficient in chronic wounds, and there is evidence that pharmacological application enhances wound repair in a variety of animal models.14 Today, growth factors refer to an expanding class of molecules, sometimes with specificity for certain types of cells, that can have either pro- or antiproliferative effects under differing circumstances. Among the growth factors implicated in tissue repair are insulin-like growth factor (IGF),15 platelet-derived growth factor (PDGF),6 transforming growth factor-beta (TGF-b),16 and epidermal growth factor (EGF).17,18 These molecules and their receptors are the likely molecular substrates for tissue repair. Fibroblasts and endothelial cells and their surface growth factor receptors represent critical cellular targets for growth factors and related molecules associated with wound healing.1–3,8,15
Based on the hypothesis that defects in growth factor signaling contribute to the development and/or persistence of pressure ulcers, reinstitution or normalization of that signaling, whether by introducing new sources of growth factor molecules or by reinstituting appropriate receptor coupling to second messengers, should promote wound healing. However, the complexity and variability of clinical wounds have limited pharmacological approaches to accelerate wound healing, leaving dressings and nonpharmacological ancillary modalities to dominate a market associated with wound management. For example, while numerous studies have cited the in-vitro efficacy of growth factor-derived compounds in promoting cell proliferation,3,4,8,9,13–15 the use of these types of compounds in clinical trials of wound healing typically have not produced encouraging results. One notable exception is the current use of topically applied, platelet-derived growth factor (PDGF) in the treatment of diabetic foot ulcers.19 Although application of this growth factor has demonstrated efficacy in the healing of these and other chronic wounds, it requires a complicated treatment regimen to ensure effectiveness.20
As a result of this work, it has become apparent that focusing on a single growth factor or related compound or receptor site is not the most effective way to initiate and sustain the complex cascade of events needed to progress the wound healing process. Rather, what is required appears to be an appropriate sequential stimulation of multiple growth factor expression and secretion.
1. Schaffer CJ, Nanney LB. Cell biology of wound healing. Int Rev Cytol 1996;169:151–81.
2. Clark RA. Basics of cutaneous wound repair. J Dermatol Surg Oncol 1993;19(8):693–706.
3. Greenhalgh DG. The role of growth factors in wound healing. J Trauma 1996;41(1):159–67.
4. Levine JH, Moses HL, Gold LI, Nanney LB. Spatial and temporal patterns of immunoreactive transforming growth factor-beta 1, beta 2, and beta 3 during excisional wound repair. Am J Pathol 1993;143(2):368–80.
5. Maher PA. Nuclear translocation of fibroblast growth factor (FGF) receptors in response to FGF-2. J Cell Biol 1996;134(2):529–36.
6. Pierce GF, Tarpley JE, Tseng J, et al. Detection of platelet-derived growth factor (PDGF)-AA in actively healing human wounds treated with recombinant PDGF-BB and absence of PDGF in chronic, nonhealing wounds. J Clin Invest 1995;96(3):1336–50.
7. Shibuya M. Role of VEGF-flt receptor system in normal and tumor angiogenesis. Adv Cancer Res 1995;67:281–316.
8. Stachowiak MK, Moffett J, Joy A, et al. Regulation of bFGF gene expression and subcellular distribution of bFGF protein in adrenal medullary cells. J Cell Biol 1994;127(1):203–23.
9. Thomas KA. Vascular endothelial growth factor, a potent and selective angiogenic agent. J Biol Chem 1996;271(2):603–6.
10. Weiner HL. The role of growth factor receptors in central nervous system development and neoplasia. Neurosurgery 1995;37(2):179–93.
11. Yakovchenko E, Whalin M, Movsesyan V, Guroff G. Insulin-like growth factor I receptor expression and function in nerve growth factor-differentiated PC12 cells. J Neurochem 1996;67(2):540–8.
12. Stachowiak MK, Maher PA, Joy A, et al. Nuclear localization of functional FGF receptor 1 in human astrocytes suggests a novel mechanism for growth factor action. Brain Res Mol Brain Res 1996;38(1):1615.
13. Stachowiak MK, Moffett J, Maher P, et al. Growth factor regulation of cell growth and proliferation in the nervous system: A new intracrine nuclear mechanism. Mol Neurobiol 1997;15(3):257–83.
14. Pierce GF, Mustoe TA. Pharmacologic enhancement of wound healing. Annu Rev Med 1995;46:467–81.
15. Rotwein P. Structure, evolution, expression, and regulation of insulin-like growth factors I and II. Growth Factors 1991;5(1):3–18.
16. Schmid P, Cox D, Bilbe G, et al. TGF-beta s and TGF-beta type II receptor in human epidermis: Differential expression in acute and chronic skin wounds. J Pathol 1993;171(3):191–7.
17. Cohen S. The epidermal growth factor (EGF). Cancer 1983;51(10):1787–91.
18. Gonul B, Soylemezoglu T, Yanicoglu L, Guvendik G. Effects of epidermal growth factor on serum zinc and plasma prostaglandin E2 levels of mice with pressure sores. Prostaglandins 1993;45(2):153–7.
19. Robson MC, Mustoe TA, Hunt TK. The future of recombinant growth factors in wound healing. Am J Surg 1998;176(2A Suppl):80S–82S.
20. Rees RS, Robson MC, Smiell JM, Perry BH. Becaplermin gel in the treatment of pressure ulcers: A phase II, randomized, double-blind, placebo-controlled study. Wound Repair Regen 1999;7(3):141–7.
21. George FR, Lukas RJ, Li R, et al. Cell proliferation induction (CPI): Pulse parameters for maximal induction of fibroblast proliferation in vitro. FASEB J 1999;13(4):351.
22. Li R, Ritz MC, Lukas RJ, et al. Cell proliferation induction (CPI): Dose- and time-dependent effects on fibroblast proliferation in vitro. FASEB J 1999;13(4):351.
23. Gilbert TL, Griffin N, Moffett J, et al. The Provant Wound Closure System induces activation of p44/42 MAP kinase in normal cultured human fibroblasts. Ann NY Acad Sci 2002;961(May):in press.
24. Gillies RJ, Didier N, Denton M. Determination of cell number in monolayer cultures. Anal Biochem 1986;159(1):109–13.
25. Ritz MC, Gallegos R, Canham MB, et al. Provant Wound Closure System accelerates closure of pressure wounds in a randomized, double-blind, placebo-controlled trial. Ann NY Acad Sci 2002;961(May):in press.
26. Liburdy RP, Callahan DE, Harland J, et al. Experimental evidence for 60Hz magnetic fields operating through the signal transduction cascade: Effects on calcium influx and c-MYC mRNA induction. FEBS Lett 1993;334(3):301–8.
27. Phillips JL, Haggren W, Thomas WJ, et al. Magnetic field-induced changes in specific gene transcription. Biochim Biophys Acta 1992;1132(2):140–4.
28. Bourguignon GJ, Jy W, Bourguignon LY. Electric stimulation of human fibroblasts causes an increase in Ca2+ influx and the exposure of additional insulin receptors. J Cell Physiol 1989;140(2):379–85.
29. Murray JC, Farndale RW. Modulation of collagen production in cultured fibroblasts by a low-frequency, pulsed, magnetic field. Biochim Biophys Acta 1985;838(1):98–105.
30. Weiss DS, Kirsner R, Eaglstein WH. Electrical stimulation and wound healing. Arch Dermatol 1990;126(2):222–5.
31. Yen-Patton GP, Patton WF, Beer DM, Jacobson BS. Endothelial cell response to pulsed electromagnetic fields: Stimulation of growth rate and angiogenesis in vitro. J Cell Physiol 1988;134(1):37–46.