Archives of Pharmacal Research

, Volume 21, Issue 5, pp 487–495 | Cite as

Signal transduction in wound pharmacology

  • William June-Hyun Kim
  • George K. Gittes
  • Michael T. Longaker


Growth factors such as TGF-beta, PDGF and FGF are thought to play important roles in wound healing. However, their biological activity and signal transduction during wound repair remain poorly understood. Growth factors are often ligands for receptor tyrosine kinase and receptor serine/threonine kinases. With recent advances in signal transduction by receptor kinases, we are beginning to understand the underlying mechanism of how growth factors may regulate cutaneous wound repair. In this paper, we will describe the pharmacological effects of growth factors on wound healing, and discuss the potential underlying signaling mechanisms. Thus, we hope to provide the basis for designing more specific therapeutics for wound healing in the near future.

Key words

Growth factors Receptor kinases Signal transduction Wound healing Skin 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References Cited

  1. Abraham, J. A. and Klagsbrun, M., Modulation of wound rapair by members of the fibroblast growth factor family, In Clark, R. A. F. (ed.).The Molecular and Cellular Biology of Wound Repair 2nd Ed., Plenum Press, New York, pp. 195–248, 1996.Google Scholar
  2. Albertson, S., Hummel, R. P., Bresden, M. and Greenshalgh, D. G., PDGF and FGF reverse the healing impairment in protein-malnourished diabetic mice.Surgery, 11, 368–372 (1993).Google Scholar
  3. Azuma, T., Witke, W., Stossel, T. P., Hartwing, J. H. and Kwiatkowski, D. J., Gelsolin is a downstream effector of rac for fibroblast motility.EMBO J., 17, 1362–1370 (1998).PubMedCrossRefGoogle Scholar
  4. Barrandon, Y. and Green, H., Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-alpha and epidermal growth factor.Cell, 50, 1131–1137 (1987).PubMedCrossRefGoogle Scholar
  5. Beck, L. S., Deguzman, L., Lee, W. P., Xu, Y., Siegel, M. W. and Amento E. P., One systemic administration of TGF-beta 1 reverses age- or glucocorticoid-impaired wound healing.J. Clin. Invest., 93, 2841–2849 (1993).CrossRefGoogle Scholar
  6. Bement, W. M., Forscher, P. and Mooseker, M. S., A novel cytoskeletal structure involved in purse string wound closure and cell polarity maintenance.J. Cell Biol., 121, 565–578 (1993).PubMedCrossRefGoogle Scholar
  7. Bikfalvi, A., Klein, S., Pintucci, C. and Rifkin, D. B., Biological role of fibroblast growth factor-2.Endocrine Reviews, 18, 26–45 (1997).PubMedCrossRefGoogle Scholar
  8. Blotnick, S., Peoples, G. E., Freeman, M. R., Eberlein, T. J. and Klagsbrun, M., T lymphocytes synthesize and export heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor, mitogens for vascular cells and fibroblasts: differential production and release by CD4+ and CD8+ T cells.Proc. Natl. Acad. Sci. USA, 91, 2890–2894 (1994).PubMedCrossRefGoogle Scholar
  9. Brock, J., McCluskey, J., Baribault, H. and Martin, P., Perfect wound healing in the keratin 8 deficient mouse embryo.Cell Motil. Cytoskel., 35, 358–366 (1996).CrossRefGoogle Scholar
  10. Brock, J., Midwinter, K., Lewis, J. and Martin, P., Healing of incisional wounds in the embryonic chick wing bud: characterization of the actin pursestring and demonstration of a requirement for Rho activation.J. Cell. Biol., 135, 1097–1107 (1996).PubMedCrossRefGoogle Scholar
  11. Brown, G. L., Curtsinger, L., Jurkiewicz, M. J., Nahai, F. and Schultz, G., Stimulation of healing of chronic wounds by epidermal growth factor.Plast. Reconstr. Surg., 88, 189–194 (1991).PubMedCrossRefGoogle Scholar
  12. Brown G. L., Curtsinger, L. 3d., Brightwell, J. R., Ackerman, D. M., Tobin, G. R., Polk, H. C. Jr., George-Nascimento, C., Valenzuela, P. and Schultz, G. S., Enhancement of epidermal regeneration by biosynthetic epidermal growth factor.J. Exp. Med., 163, 1319–1324 (1986).PubMedCrossRefGoogle Scholar
  13. Brown G. L., Nanney, L. B., Griffen, J., Cramer, A. B., Yancey, J. M., Curtsinger, L. J. 3d., Holtzin, L., Schultz, G. S., Jurkiewicz, M. J. and Lynch, J. B., Enhancement of wound healing by topical treatment with epidermal growth factor.New Engl. J. Med., 321, 76–79 (1989).PubMedGoogle Scholar
  14. Carney, D. H., Mann, R., Redin, W. R., Pernia, S. D., Berry, D., Heggers, J. P., Hayward, P. G., Robson, M. C., Christies, J. and Annable, C., Enhancement of incisional wound healing and neovascularization in normal rats by thrombin and synthetic thrombin receptor-activating peptides.J. Clin. Invest., 89, 1469–1477 (1992).PubMedCrossRefGoogle Scholar
  15. Carpenter, G. and Cohen, S., Epidermal growth factor.J. Biol. Chem., 265, 7709–7712 (1990).PubMedGoogle Scholar
  16. Chen, W. Y., Rogers, A. A. and Lydon, M. J., Characterization of biologic properties of wound fluid collected during early stages of wound healing.J. Invest. Dermatol., 99, 559–564 (1992).PubMedCrossRefGoogle Scholar
  17. Clark, R. A. F. (ed.),The Molecular and Cellular Biology of Wound Repair, 2nd Ed., Plenum Press, New York, 1996.Google Scholar
  18. Clark, R. A. F., Basics of cutaneous wound repair.J. Dermatol. Surg. Oncol., 19, 693–706 (1993).PubMedGoogle Scholar
  19. Cromack, D. T., Porras-Reyes, B., Purdy, J. A., Pierce, G. F. and Mustoe, T. A., Acceleration of tissue repair by TGF-beta 1: identification ofin vivo mechanism of action with radiotherapy-induced specific healing deficits.Surgery, 113, 36–42 (1993).PubMedGoogle Scholar
  20. Danilenko, D. M., Ring, B. D., Lu, J. Z., Tarpley, J. E., Chang, D., Liu, N., Wen, D. and Pierce, G. F., New differentiation factor upregulates epidermal migration and integrin expression in excisional wounds.J. Clin. Invest., 95, 842–851 (1995).PubMedCrossRefGoogle Scholar
  21. Davidson, J. M., Klagsbrun, M., Hill, K. E., Buckley, A., Sullivan, R., Brewer, P. S. and Woodard, S. C., Accelerated wound repair, cell proliferation, and collagen accumulation are produced by a cartilagederived growth factor.J. Cell. Biol., 100, 1219–1227 (1985).PubMedCrossRefGoogle Scholar
  22. Desmouliere, A., Geinoz, A., Gabbiani, F. and Gabbiani, G., Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts.J. Cell Biol., 122, 103–111 (1993).PubMedCrossRefGoogle Scholar
  23. Deuel, T. F., Kawahara, R., Mustoe, T. A. and Pierce, G. F., Role of PDGF in wound healing,J. Cell. Biochem., 45, 319–326 (1991).PubMedCrossRefGoogle Scholar
  24. Eriksson, A., Siegbahn, A., Westermark, B., Helding, C. H. and Claesson-Welsh, L., PDGF alpha- and beta-receptors activate unique and common signal transduction pathways.EMBO J., 11, 543–550 (1992).PubMedGoogle Scholar
  25. Falanga, V., Eaglstein, W. H., Bucalo, B., Katz, M. H., Harris, B. and Carson, P., Topical use of human recombinant epidermal growth factor (h-EGF) in venous ulcers.J. Dermatol. Sugr. Oncol., 18, 604–606 (1992),Google Scholar
  26. Fanger, G. R., Johson, N. L. and Johnson, G. L., MEK kinases and regulated by EGF and selectively interact with Rac/Cdc42.EMBO J., 16, 4961–4972 (1997).PubMedCrossRefGoogle Scholar
  27. Ferguson, M. W. J., Growth factors and antagonists: their role in wound healing. In abstracts,4 th Annual Meeting of the European Tissue Repair Society, Oxford, p. 136 (1994).Google Scholar
  28. Ffrench-Constant, C., Van de Water, H. F., Dvorak, L. and Hynes, R. O., Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat.J. Cell. Biol., 109, 903–914 (1989).PubMedCrossRefGoogle Scholar
  29. Fischer, E. H., Charbonneau, H. and Tonks, N. K., Protein tyrosine phosphatase: a diverse family of intracellular and transmembrane enzymes.Science, 253, 401–406 (1991).PubMedCrossRefGoogle Scholar
  30. Frank, S., Madlener, M. and Werner, S., Transforming growth factors beta 1, beta 2 and beta 3 and their receptors are differentially regulated during normal and impaired wound healing.J. Biol. Chem., 271, 10188–10193 (1996).PubMedCrossRefGoogle Scholar
  31. Frost, J. A., Steen, H., Shapiro, P., Lewis, T., Ahn, N., Shaw, P. E. and Cobb, M. H., Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins.EMBO J., 16, 6426–6438 (1997).PubMedCrossRefGoogle Scholar
  32. Gibran, N. S., Isik, F. F., Heimbach, D. M. and Gordon, D., Basic fibroblast growth factor in the early human burn wound.J. Surg. Res. 56, 226–234 (1994).PubMedCrossRefGoogle Scholar
  33. Glaser, B. M., Michels, R. G., Kuppermann, B. D., Sjaarda, R. N. and Pena, R. A., TGF-beta 2 for the treatment of full-thickness macular holes. A prospective randomized study.Opthalmology, 99, 1162–1173 (1992).Google Scholar
  34. Greenhalgh, D. G., Sprugel, K. H., Murray, M. J. and Ross, R., PDGF and FGF stimulate wound healing in the genetically diabetic mouse.Am. J. Pathol., 136, 1235–1246 (1990).PubMedGoogle Scholar
  35. Greenhalgh, D. G., The role of growth factors in wound healing.J. Trauma., 41, 159–167 (1996).PubMedCrossRefGoogle Scholar
  36. Greiling, D. and Clark, R. A. F., Fibronectin provides a conduit for fibroblast transmigration from collagenous stroma into fibrin clot provisional matrix.J. Cell. Sci., 110, 861–870 (1997).PubMedGoogle Scholar
  37. Grinnell, F., Fibroblasts, myofibroblasts, and wound contraction.J. Cell. Biol., 124, 401–404 (1994).PubMedCrossRefGoogle Scholar
  38. Grotendorst, G. R., Okochi, H. and Hayashi, N., A novel transforming growth factor gene.Cell Growth Differ., 7, 469–480 (1996).PubMedGoogle Scholar
  39. Guo, L., Degenstein, L., Dowling, J., Yu, Q. C., Wollmann, R., Perman, B. and Fuchs, E., Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neuroligic degeneration.Cell, 81, 233–243 (1995).PubMedCrossRefGoogle Scholar
  40. Hart, C. E., Forstrom, J. W., Kelly, J. D., Seifert, R. A., Smith, R. A., Ross, R., Murray, M. J. and Bowen-Pope, D. F., Two classes of PDGF receptor recognize different isoforms of PDGF.Science, 240, 1529–1531 (1988).PubMedCrossRefGoogle Scholar
  41. Hartwing, J. H. H., Bokoch, G. M., Carpenter, C. L., Janmey, P. A., Taylor, L. A., Toker, A. and Stossel, T. P. Thrombin receptor ligation and activated Rac uncap actin filament barbed ends through phosphoinositide synthesis in permeabilized human platelets.Cell, 82, 643–653 (1995).CrossRefGoogle Scholar
  42. Heldin, C. H. and Westermark, B., Role of PDGFin vivo, In Clark, R. A. F. (ed.),The Molecular and Cellular Biology of Wound Repair, 2nd Ed., Plenum Press, New York, pp. 249–274, 1996.Google Scholar
  43. Hertle, M. D., Jones, P. H., Groves, R. W., Hudson, D. L. and Watt, F. M., Integrin expression by human epidermal keratinocytes can be modulated by interferon-gamma, transforming growth factor-beta, tumor necrosis factor-alpha, and culture on a dermal equivalent.J. Invest. Dermato., 104, 206–265 (1995).Google Scholar
  44. Hopkinson-Woolley, J., Hughes, D., Gordon, S. and Martin, P., Macrophage recruitment during limb development and wound healing in the embryonic and foetal mouse.J. Cell Sci., 107, 1159–1167 (1994).PubMedGoogle Scholar
  45. Hubner, G., Hu, Q., Smola, H. and Werner, S., Strong induction of activin expression after injury suggests an important role of activin in wound repair.Dev. Biol., 173, 490–498 (1996).PubMedCrossRefGoogle Scholar
  46. Ignotz, R. A. and Massague, J., TGF-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix.J. Biol. Chem., 261, 4337–4345 (1986).PubMedGoogle Scholar
  47. Kim, W. J. H., Studies on protein tyrosine phosphatases in growth factor receptor signal transduction. Ph. D. thesis, New York University, 1996.Google Scholar
  48. Kretzschmar, M. and Massague, J., SMADs: mediators and regulators of TGF-beta signaling.Curr. Opin. Genet. Dev., 8, 103–111 (1998).PubMedCrossRefGoogle Scholar
  49. Ksander, G. A., Ogawa, Y., Chu, G. H., McMullin, H., Rosenblatt, J. S. and McPherson, J. M., Exogenous TGF-beta 2 enhances connective tissue formation and wound strength in guinea pig dermal wounds healing by secondary intent.Ann. Sugr., 211, 288–294 (1989).Google Scholar
  50. Kucukcelebi, A., Hui, P. S. and Sahara, K., The effect of IL-1 beta on the inhibition of contraction of excisional wounds caused by bacterial contamination.Surg. Forum, 43, 715–716 (1992).Google Scholar
  51. Kurita, Y., Tsuboi, R., Ueki, R., Rifkin, D. B. and Ogawa, H., Immunohistochemical localization of basic fibroblast growth factor in wound healing sites of mouse skin.Arch. Dermotol. Res., 284, 193–197 (1992).CrossRefGoogle Scholar
  52. Legrand, E. K., Burke, J. F., Costa, D. E. and Kiorpes, T. C., Dose response effects of PDGF-BB, PDGF-AA EGF and bFGF on granulation tissue in a guinea pig partial thickness skin excision model.Growth Factor, 8, 307–314 (1993).CrossRefGoogle Scholar
  53. Levine, J. H., Moses, H. L., Gold, L. I. and Nanney, L. B., Spatial and temporal patterns of immunoreactive transforming growth factor beta 1, beta 2 and beta 3 during excisional wound repair.Am. J. Pathol., 143, 368–380 (1993).PubMedGoogle Scholar
  54. Li, W., Nishimura, R., Kashishian, A., Batzer, A. G., Kim, W. J., Cooper, J. A. and Schlessinger, J., A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase.Mol. Cell. Biol., 14, 509–517 (1994).PubMedGoogle Scholar
  55. Lin, Y. C. and Grinnell, F., Decreased level of PDGF-stimulated receptor autophosphorylation by fibroblasts in mechanically relaxed collagen matrices.J. Cell Biol., 122, 663–672 (1993).PubMedCrossRefGoogle Scholar
  56. Maciag, T., Zhan, X., Garfinkel, S., Friedman, S., Prudovsky, I., Jackson, A., Wessendorf, J., Hu, X., Gamble, S. and Shi, J., Novel mechanisms of fibroblast growth factor I function.Recent. Prog. Horm. Res., 49, 105–123 (1994).PubMedGoogle Scholar
  57. Madlener, M., Mauch, C., Conca, W., Brauchle, M., Parks, W. C. and Werner, S., Regulation of the expression of stromelysin-2 by growth factors in keratinocytes: implications for normal and impaired wound healing.Biochem. J., 320, 659-? (1996).PubMedGoogle Scholar
  58. Marks, M. G., Doillon, C. and Silver, F. H., Effects of fibroblasts and basic fibroblast growth factor on facilitation of dermal wound healing by type I collagen matrices.J. Biomed. Mater. Res., 25, 683–696 (1991).PubMedCrossRefGoogle Scholar
  59. Martin, P. and Lewis, J., Actin cables and epidermal movement in embryonic wound healing.Nature, 360, 179–183 (1992).PubMedCrossRefGoogle Scholar
  60. Martin, P., Dickson, M. C., Millan, F. A. and Akhurst, R. J., Rapid induction and clearance of TGF beta 1 is an early response to wounding in the mouse embryo.Dev. Genet., 14, 225–238 (1993).PubMedCrossRefGoogle Scholar
  61. Martin, P., Wound healing-aiming for perfect skin regeneration.Science, 276, 75–81 (1997).PubMedCrossRefGoogle Scholar
  62. Massague, J. and Polyak, K., Mammalian antiproliferative signals and their targets.Curr. Opin. Genet. Dev., 5, 91–96 (1995).PubMedCrossRefGoogle Scholar
  63. Massague, J. and Weis-Garcia, F., Serine/threonine kinase receptors: mediators of TGF beta family signals.Cancer Surv., 27, 41–64 (1996).PubMedGoogle Scholar
  64. Massague, J., TGF beta signaling: receptors, transducers, and Mad proteins.Cell, 28, 947–950 (1996).CrossRefGoogle Scholar
  65. McClain, S. A., Simon, M., Jones, E., Nandi, A., gailit, J. O., Tonnesen, M. G., Newman, D. and Clark, R. A., Mesenchymal cell activation is the rate-limiting step of granulation tissue induction.Am. J. Pathol., 149, 1257–1270 (1996).PubMedGoogle Scholar
  66. McGee, G. S., Davidson, J. M., Buckley, A., Sommer, A., Woodward, S. C., Aquino, A. M., Barbour, R. and Demetriou, A. A., Recombinant basic fibroblast growth factor accelerates wound healing.J. Surg. Res., 45, 145–153 (1998).CrossRefGoogle Scholar
  67. McGluskey, J. and Martin, P., Analysis of the tissue movements of embryonic wound healing-Dil studies in the limb bud stage mouse embryo.Dev. Biol., 170, 102–114 (1995).CrossRefGoogle Scholar
  68. Montesano, R., Vassalli, J.-D., Baired, A., Guillemin, R. and Orci, L., Basic fibroblast growth factor induces angiogenesisin vitro.Proc. Natl. Acad. Sci. USA, 83, 7297–7301 (1986).PubMedCrossRefGoogle Scholar
  69. Mustoe, T. A., Pierce, G. F., Morishima, C. and Deuel, T. F., Growth factor induced acceleration of tissue repair through direct and inductive activities.J. Clin. Invest., 87, 694–703 (1991).PubMedCrossRefGoogle Scholar
  70. Mustoe, T. A., Pierce, G. F., and Thomason, A., Accelerated healing of incisional wounds in rats induced by transforming growth factor type beta.Science, 347, 1333–1336 (1987).CrossRefGoogle Scholar
  71. Mustose, T. A., Purdy, J., Gramates, P., Deuel, T. F., Thomason, A. and Pierce, G. F., Reversal of impaired wound healing in irradiated rats by PDGFBB: requirement of an active bone marrow.Am. J. Surg., 158, 345–350 (1989).CrossRefGoogle Scholar
  72. Nanney, L. B. and King, L. E., Epidermal growth factor and transforming growth factor-alpha, In Clark, R. A. F. (ed.).The Molecular and Cellular Biology of Wound Repair, 2nd Ed., Plenum Press, New York, pp. 171–194, 1996.Google Scholar
  73. Nilsson, J., Von Euler, A. and Dalsgaard, C. J., Stimulation of connective tissue cell growth by substance P and substrance K.Nature, 315, 61–63 (1985).PubMedCrossRefGoogle Scholar
  74. Nimni, M. E., Polypeptide growth factors: targeted delivery systems.Biomaterials, 18, 1201–1225 (1997).PubMedCrossRefGoogle Scholar
  75. Nobes, C. D. and Hall, A., Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia.Cell, 81, 53–62 (1995).PubMedCrossRefGoogle Scholar
  76. Paladini, R. D., Takahashi, K., Bravo, N. S. and Coulombe, P. A., Onset of re-epithelialization after skin injury correlates with a reorganization of keratin filaments in wound edge keratinocytes: defining a potential role for keratin 16,J. Cell Biol., 132, 381–397 (1996).PubMedCrossRefGoogle Scholar
  77. Pawson, T., Protein modules and signaling networks,Nature, 373, 573–580 (1995).PubMedCrossRefGoogle Scholar
  78. Phillips, L. G., Abdullah, K. M., Geldner, P. D., Dobbins, S., Ko, F., Linares, H. A., Broemeling, L. D. and Robson, W. C., Application of basic fibroblast growth factor may reverse diabetic wound healing impairment.Ann. Plast. Surg., 31, 331–334 (1993).PubMedCrossRefGoogle Scholar
  79. Pierce, G. F. and Mustoe, T. A., Lingelbach, J., Masakowski, V. R., Griffin, G. L., Senior, R. M. and Deuel, T. F., PDGF and TGF-beta enhance tissue repair activities by unique mechanisms.J. Cell Biol., 109, 429–440 (1989).PubMedCrossRefGoogle Scholar
  80. Pierce, G. F. and Mustose, T. A., Pharmacologic enhancement of wound healing.Ann. Rev. Med., 46, 467–481 (1995).PubMedCrossRefGoogle Scholar
  81. Pierce, G. F., Tarpley J. E., Allman, R. M., Goode, P. S., Serder, C. M., Morris, B., Mustoe, T. A. and Vande Berg, J., Tissue repair processes in chronic pressure ulcers treated with recombinant PDGF-BB.Am. J. Pathol., 145, 1399–1410 (1994).PubMedGoogle Scholar
  82. Pierce, G. F., Tarpley J. E., Tseng, J., Bready, J., Chang, D., Kenney, W. C., Rudolph, R., Robson, M. C., Vande-Berg, J. and Reid, P., Detection of increased levels of PDGF-AA in actively healing human wounds treated with recombinant PDGF-BB and absence of PDGF in chronic nonhealing wounds.J. Clin. Invest., 96, 1336–1350 (1995).PubMedCrossRefGoogle Scholar
  83. Pierce, G. F., Tarpley, J. E., Yanagihara, D., Mustoe, T. A., Fox, G. M. and Thomason, A., PDGF (BB homodimer) TGF-beta 1, and basic FGF in dermal wound healing. Neovessel and matrix formation and cessation of repair.Am. Pathol., 140, 1375–1388 (1992).Google Scholar
  84. Pierce, G. F., Tarpley, J. E., Yanagihara, D., Mustoe, T. A., Fox, G. M. and Thomason, A., PDGF-BB, TGF-beta 1, and basic FGF in dermal wound healing: neoveseel and matrix formation and cessation of repair.Am. J. Pathol., 140, 1375–1388 (1992).PubMedGoogle Scholar
  85. Pierce, G. F., Yanagihara, D., Klopchin, K., Danilenko, D. M., Hsu, E., Kenney, W. C. and Morris, C. F., Stimulation of all epithelial elements during skin regeneration by keratinocyte growth factor.J. Exp. Med., 179, 831–840 (1994).PubMedCrossRefGoogle Scholar
  86. Quaglino, D. Jr., Nanney, L. B., Kennedy, R. and Davidson, J. M., TGF-beta stimulates wound healing and modulates extracellular matrix gene expression in pig skin. I. Excisional wound model.Lab. Invest., 63, 307–319 (1990).PubMedGoogle Scholar
  87. Ridley, A. J., Comoglio, P. M. and Hall, A., Regulation of scatter factor/hepatocyte growth factor responses by Res, Rac, and Rho in MDCK cells.Mol. Cell. Biol., 15, 1110–1122 (1995).PubMedGoogle Scholar
  88. Roberts, A. B. and Sporn, M. B., Transforming growth factor-beta, In Clark, R. A. F. (ed.).The Molecular and Cellular Biology of Wound Repair, 2nd Ed., Plenum Press, New York, pp. 275–310, 1996.Google Scholar
  89. Robson, M. C., Phillips, L. G., Lawrence, W. T., Bishop, J. B., Youngerman, J. S., Hayward, P. G., Broemeling, L. D. and Heggers, J. P., The safety and effect of topically applied recombinant basic fibroblast growth factor on the healing of chronic pressure sores.Ann. Surg., 216, 401–408 (1992).PubMedCrossRefGoogle Scholar
  90. Schlessinger, J. and Ullrich, A., Growth factor signaling by receptor tyrosine kinases.Neuron, 9, 383–391 (1992).PubMedCrossRefGoogle Scholar
  91. Schlessinger, J. and Lax, I., and Lemmon, M., Regulation of growth factor activation by proteoglycans: what is the role of the low affinity receptors?Cell, 83, 357–360 (1995).PubMedCrossRefGoogle Scholar
  92. Schlessinger, J., Direct binding and activation of receptor tyrosine kinases by collagen.Cell, 91, 869–972 (1997).PubMedCrossRefGoogle Scholar
  93. Schlessinger, J., Lax, I. and Lemmon, M., Regulation of growth factor activation by proteoglycans: what is the role of the low affinity receptors?Cell, 83, 357–360 (1995).PubMedCrossRefGoogle Scholar
  94. Schmid, P., Cox, D., Bilbe, G., McMaster, G., Morrison, C., Stahelin, H., Luscher, N. and Seiler, W., TGF-betas and TGF-beta type II receptor in human epidermis: differential expression in acute and chronic skin wounds.J. Pathol., 171, 191–197 (1993a).PubMedCrossRefGoogle Scholar
  95. Schmid, P., Kunz, S., Cerletti, N., McMaster, G. and Cox, D., Injury induced expression of TGF-beta 1 mRNA is enhanced by exogenously applied TGF-beta.Biochem. Biophys. Res. Commun., 194, 399–406 (1993b).PubMedCrossRefGoogle Scholar
  96. Schultz, G. S., White, M., Mitchell, R., Brown, G., Lynch, J., Twardzik, D. R. and Todaro, G. J., Epithelial wound healing enhanced by transforming growth factor-alpha and vaccina growth factor.Science, 235, 350–352 (1987).PubMedCrossRefGoogle Scholar
  97. Shah, M., Foreman, D. M. and Ferguson, M. W., Control of scarring in adult wounds by neutralizing antibody to TGF-beta.Lancet, 339, 213–214 (1992).PubMedCrossRefGoogle Scholar
  98. Shah, M. Foreman, D. M. and Ferguson, M. W., Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring.J. Cell Sci., 108, 985–1002 (1995).PubMedGoogle Scholar
  99. Slavin, J., Hunt, J. A., Nash, J. R., Williams, D. F. and Kingsnorth, A. N., Recombinant basic FGF in red blood cell ghosts accelerates incisional wound healing.Br. J. Surg., 79, 918–921 (1992).PubMedCrossRefGoogle Scholar
  100. Spivak-Kroizman, T., Lemmon, M. A., Dikic, I., Ladbury, J. E., Pinchasi, D., Hung, J., Jaye, M., Crumley, G., Schlessinger, J. and Lax, I., Heparin-induced oligomerization or FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation.Cell, 79, 1015–1024 (1994).PubMedCrossRefGoogle Scholar
  101. Sporn M. B. and Roberts, A. B., A major advance in the use of growth factors to enhance wound healing.J. Clin. Invest., 92, 2565–2566 (1993).PubMedCrossRefGoogle Scholar
  102. Stenberg, B. D., Phillips, L. G., Hokanson, J. A., Heggers, J. P. and M. C. Robson, M. C., Effect of bFGF on the inhibition of contraction caused by bacteria.J. Surg, Res., 50, 47–50 (1991).CrossRefGoogle Scholar
  103. Tsuboi, R. and Rifkin, D. B., Recombinant basic fibroblast growth factor stimulates wound healing in healing-impaired db/db mice.J. exp. Med., 172, 245–251 (1990).PubMedCrossRefGoogle Scholar
  104. Tsuboi, R., Sato, C., Kurita, Y., Ron, D., Rubin, J. S. and Ogawa, H., Keratinocyte growth factor (FGF-7) stimulates migration and plasminogen activator activity of normal human keratinocytes.J. Invest. Dermatol., 101, 49–53 (1993).PubMedCrossRefGoogle Scholar
  105. Tsuboi, R., Shi, C. M., Rifkin, D. B. and Ogawa, H. A., Wound healing model using healing-impaired diabetic mice.J. Dermatol., 19, 673–675 (1992).PubMedGoogle Scholar
  106. Werner, S., Peters K. G., Longaker, M. T., Fuller-Pace, F., Banda, M. J. and Williams, L. T., Large induction of kerationcyte growth factor expression in the dermis during wound healing.Proc. Natl. Acad. Sci. USA, 89, 6896–6900 (1992).PubMedCrossRefGoogle Scholar
  107. Werner, S., Smola, H., Liao, X., Longaker, M. T., Krieg, T., Hofschneider, P. H. and Williams, L. T., The function of KGF in morphogenesis of epithelium and reepithelialization of wounds.Science, 266, 819–822 (1994).PubMedCrossRefGoogle Scholar
  108. Witke, W., Sharpe, A. H., Hartwing, J. H., Azuma, T., Stossel, T. P. and Kwiatkowski, D. J., Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin.Cell, 81, 41–51 (1995).PubMedCrossRefGoogle Scholar
  109. Wrana, J. and Pawson, T., Signal transduction. Med about SMADsNature, 388, 28–29 (1997).PubMedCrossRefGoogle Scholar
  110. Wrana, J. L., Attisano, L., Wieser, R., Ventura, F. and Massague, J., Mechanism of activation of the TGF-beta receptor.Nature, 370, 341–347 (1994).PubMedCrossRefGoogle Scholar
  111. Xu, J. and Clark, R. A. F., Extracellular matrix alters PDGF regulation of fibroblast integrins.J. Cell Biol., 132, 239–249 (1996).PubMedCrossRefGoogle Scholar
  112. Zhou, P., Byrne, C., Jacobs, J. and Fuchs, E., Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate.Genes Dev., 9, 700–713 (1995).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 1998

Authors and Affiliations

  • William June-Hyun Kim
    • 1
  • George K. Gittes
    • 1
  • Michael T. Longaker
    • 1
  1. 1.Laboratory of Developmental Biology and Repair, Room H-169New York University Medical CenterNew YorkU.S.A.

Personalised recommendations