Skip to main content
NCBI home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1994 Dec;145(6):1399–1410.

Tissue repair processes in healing chronic pressure ulcers treated with recombinant platelet-derived growth factor BB.

G F Pierce 1, J E Tarpley 1, R M Allman 1, P S Goode 1, C M Serdar 1, B Morris 1, T A Mustoe 1, J Vande Berg 1
PMCID: PMC1887508  PMID: 7992843

Abstract

Cellular and molecular mechanisms responsible for the observed vulnerary effects of recombinant human platelet-derived growth factor BB (rP-DGF-BB) in man have not been elucidated. In a double-blinded trial, patients having chronic pressure ulcers were treated topically with either rPDGF-BB or placebo for 28 days. To explore how rPDGF-BB may induce chronic wounds to heal, biopsies were taken from the ulcers of a cohort of 20 patients from the trial and evaluated in a blinded fashion by light microscopy for 1), fibroblast content, 2) neovessel formation, and 3), collagen deposition. Electron microscopy also was used to assess fibroblast activation and collagen deposition. Before initiation of therapy most wounds had few fibroblasts and most of those present were not activated. When mean scores for the total active treatment phase (days 8, 15, and 29) for rPDGF-BB-treated ulcers were compared with the scores for placebo-treated ulcers, fibroblast content was significantly higher for the rPDGF-BB-treated ulcers (P = 0.03, Kruskal-Wallis test). More significant differences in fibroblast and neovessel content were observed when six nonhealing wounds were eliminated from the analysis (three placebo, three treatment). Thus, in all healing wounds, rPDGF-BB therapy significantly increased fibroblast (P = 0.0007) and neovessel (P = 0.02) content. These results were correlated with increased collagen fibrillogenesis by fibroblasts from healing rPDGF-BB-treated wounds, as assessed by intracellular procollagen type I immunostaining, and by electron microscopy, and were concordant with clinical measurements (eg, area of ulcer opening and ulcer volume) which showed greater healing in rPDGF-BB-treated wounds. These results suggest induction of fibroblast proliferation and differentiation is one mechanism by which rPDGF-BB can accelerate wound healing and that rPDGF-BB can augment healing responses within a majority of, but not all, nonhealing chronic pressure ulcers in man.

Full text

PDF
1399

Images in this article

1401Figure 1
on p.1401
1402Figure 4
on p.1402
1403Figure 5
on p.1403
1404Figure 6
on p.1404
1405Figure 7
on p.1405
1406Figure 8
on p.1406
1406Figure 9
on p.1406
1408Figure 10
on p.1408

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allman R. M. Pressure ulcers among the elderly. N Engl J Med. 1989 Mar 30;320(13):850–853. doi: 10.1056/NEJM198903303201307. [DOI] [PubMed] [Google Scholar]
  2. Beitz J. G., Kim I. S., Calabresi P., Frackelton A. R., Jr Human microvascular endothelial cells express receptors for platelet-derived growth factor. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):2021–2025. doi: 10.1073/pnas.88.5.2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bennett N. T., Schultz G. S. Growth factors and wound healing: Part II. Role in normal and chronic wound healing. Am J Surg. 1993 Jul;166(1):74–81. doi: 10.1016/s0002-9610(05)80589-6. [DOI] [PubMed] [Google Scholar]
  4. Blatti S. P., Foster D. N., Ranganathan G., Moses H. L., Getz M. J. Induction of fibronectin gene transcription and mRNA is a primary response to growth-factor stimulation of AKR-2B cells. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1119–1123. doi: 10.1073/pnas.85.4.1119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brown L. F., Dubin D., Lavigne L., Logan B., Dvorak H. F., Van de Water L. Macrophages and fibroblasts express embryonic fibronectins during cutaneous wound healing. Am J Pathol. 1993 Mar;142(3):793–801. [PMC free article] [PubMed] [Google Scholar]
  6. Clark R. A. Regulation of fibroplasia in cutaneous wound repair. Am J Med Sci. 1993 Jul;306(1):42–48. doi: 10.1097/00000441-199307000-00011. [DOI] [PubMed] [Google Scholar]
  7. Daltrey D. C., Rhodes B., Chattwood J. G. Investigation into the microbial flora of healing and non-healing decubitus ulcers. J Clin Pathol. 1981 Jul;34(7):701–705. doi: 10.1136/jcp.34.7.701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Deuel T. F., Kawahara R. S., Mustoe T. A., Pierce A. F. Growth factors and wound healing: platelet-derived growth factor as a model cytokine. Annu Rev Med. 1991;42:567–584. doi: 10.1146/annurev.me.42.020191.003031. [DOI] [PubMed] [Google Scholar]
  9. Falanga V., Grinnell F., Gilchrest B., Maddox Y. T., Moshell A. Workshop on the pathogenesis of chronic wounds. J Invest Dermatol. 1994 Jan;102(1):125–127. doi: 10.1111/1523-1747.ep12371745. [DOI] [PubMed] [Google Scholar]
  10. Goode P. S., Allman R. M. The prevention and management of pressure ulcers. Med Clin North Am. 1989 Nov;73(6):1511–1524. doi: 10.1016/s0025-7125(16)30613-7. [DOI] [PubMed] [Google Scholar]
  11. Greenhalgh D. G., Sprugel K. H., Murray M. J., Ross R. PDGF and FGF stimulate wound healing in the genetically diabetic mouse. Am J Pathol. 1990 Jun;136(6):1235–1246. [PMC free article] [PubMed] [Google Scholar]
  12. Grotendorst G. R., Martin G. R., Pencev D., Sodek J., Harvey A. K. Stimulation of granulation tissue formation by platelet-derived growth factor in normal and diabetic rats. J Clin Invest. 1985 Dec;76(6):2323–2329. doi: 10.1172/JCI112243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Heldin P., Laurent T. C., Heldin C. H. Effect of growth factors on hyaluronan synthesis in cultured human fibroblasts. Biochem J. 1989 Mar 15;258(3):919–922. doi: 10.1042/bj2580919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hermansson M., Nistér M., Betsholtz C., Heldin C. H., Westermark B., Funa K. Endothelial cell hyperplasia in human glioblastoma: coexpression of mRNA for platelet-derived growth factor (PDGF) B chain and PDGF receptor suggests autocrine growth stimulation. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7748–7752. doi: 10.1073/pnas.85.20.7748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Herrick S. E., Sloan P., McGurk M., Freak L., McCollum C. N., Ferguson M. W. Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. Am J Pathol. 1992 Nov;141(5):1085–1095. [PMC free article] [PubMed] [Google Scholar]
  16. Juhasz I., Murphy G. F., Yan H. C., Herlyn M., Albelda S. M. Regulation of extracellular matrix proteins and integrin cell substratum adhesion receptors on epithelium during cutaneous human wound healing in vivo. Am J Pathol. 1993 Nov;143(5):1458–1469. [PMC free article] [PubMed] [Google Scholar]
  17. Khouri R. K., Hong S. P., Deune E. G., Tarpley J. E., Song S. Z., Serdar C. M., Pierce G. F. De novo generation of permanent neovascularized soft tissue appendages by platelet-derived growth factor. J Clin Invest. 1994 Nov;94(5):1757–1763. doi: 10.1172/JCI117523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Levine J. H., Moses H. L., Gold L. I., 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. 1993 Aug;143(2):368–380. [PMC free article] [PubMed] [Google Scholar]
  19. Lynch S. E., Colvin R. B., Antoniades H. N. Growth factors in wound healing. Single and synergistic effects on partial thickness porcine skin wounds. J Clin Invest. 1989 Aug;84(2):640–646. doi: 10.1172/JCI114210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lynch S. E., Nixon J. C., Colvin R. B., Antoniades H. N. Role of platelet-derived growth factor in wound healing: synergistic effects with other growth factors. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7696–7700. doi: 10.1073/pnas.84.21.7696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Marikovsky M., Breuing K., Liu P. Y., Eriksson E., Higashiyama S., Farber P., Abraham J., Klagsbrun M. Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury. Proc Natl Acad Sci U S A. 1993 May 1;90(9):3889–3893. doi: 10.1073/pnas.90.9.3889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. McDonald J. A., Broekelmann T. J., Matheke M. L., Crouch E., Koo M., Kuhn C., 3rd A monoclonal antibody to the carboxyterminal domain of procollagen type I visualizes collagen-synthesizing fibroblasts. Detection of an altered fibroblast phenotype in lungs of patients with pulmonary fibrosis. J Clin Invest. 1986 Nov;78(5):1237–1244. doi: 10.1172/JCI112707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. McDonald J. A., Kelley D. G., Broekelmann T. J. Role of fibronectin in collagen deposition: Fab' to the gelatin-binding domain of fibronectin inhibits both fibronectin and collagen organization in fibroblast extracellular matrix. J Cell Biol. 1982 Feb;92(2):485–492. doi: 10.1083/jcb.92.2.485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mustoe T. A., Cutler N. R., Allman R. M., Goode P. S., Deuel T. F., Prause J. A., Bear M., Serdar C. M., Pierce G. F. A phase II study to evaluate recombinant platelet-derived growth factor-BB in the treatment of stage 3 and 4 pressure ulcers. Arch Surg. 1994 Feb;129(2):213–219. doi: 10.1001/archsurg.1994.01420260109015. [DOI] [PubMed] [Google Scholar]
  25. Mustoe T. A., Pierce G. F., Morishima C., Deuel T. F. Growth factor-induced acceleration of tissue repair through direct and inductive activities in a rabbit dermal ulcer model. J Clin Invest. 1991 Feb;87(2):694–703. doi: 10.1172/JCI115048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mustoe T. A., Purdy J., Gramates P., Deuel T. F., Thomason A., Pierce G. F. Reversal of impaired wound healing in irradiated rats by platelet-derived growth factor-BB. Am J Surg. 1989 Oct;158(4):345–350. doi: 10.1016/0002-9610(89)90131-1. [DOI] [PubMed] [Google Scholar]
  27. Paulsson Y., Hammacher A., Heldin C. H., Westermark B. Possible positive autocrine feedback in the prereplicative phase of human fibroblasts. Nature. 1987 Aug 20;328(6132):715–717. doi: 10.1038/328715a0. [DOI] [PubMed] [Google Scholar]
  28. Pierce G. F., Brown D., Mustoe T. A. Quantitative analysis of inflammatory cell influx, procollagen type I synthesis, and collagen cross-linking in incisional wounds: influence of PDGF-BB and TGF-beta 1 therapy. J Lab Clin Med. 1991 May;117(5):373–382. [PubMed] [Google Scholar]
  29. Pierce G. F., Mustoe T. A., Altrock B. W., Deuel T. F., Thomason A. Role of platelet-derived growth factor in wound healing. J Cell Biochem. 1991 Apr;45(4):319–326. doi: 10.1002/jcb.240450403. [DOI] [PubMed] [Google Scholar]
  30. Pierce G. F., Mustoe T. A., Lingelbach J., Masakowski V. R., Griffin G. L., Senior R. M., Deuel T. F. Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms. J Cell Biol. 1989 Jul;109(1):429–440. doi: 10.1083/jcb.109.1.429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pierce G. F., Mustoe T. A., Senior R. M., Reed J., Griffin G. L., Thomason A., Deuel T. F. In vivo incisional wound healing augmented by platelet-derived growth factor and recombinant c-sis gene homodimeric proteins. J Exp Med. 1988 Mar 1;167(3):974–987. doi: 10.1084/jem.167.3.974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pierce G. F., Tarpley J. E., Yanagihara D., Mustoe T. A., Fox G. M., Thomason A. Platelet-derived growth factor (BB homodimer), transforming growth factor-beta 1, and basic fibroblast growth factor in dermal wound healing. Neovessel and matrix formation and cessation of repair. Am J Pathol. 1992 Jun;140(6):1375–1388. [PMC free article] [PubMed] [Google Scholar]
  33. Pierce G. F., Vande Berg J., Rudolph R., Tarpley J., Mustoe T. A. Platelet-derived growth factor-BB and transforming growth factor beta 1 selectively modulate glycosaminoglycans, collagen, and myofibroblasts in excisional wounds. Am J Pathol. 1991 Mar;138(3):629–646. [PMC free article] [PubMed] [Google Scholar]
  34. Robson M. C., Phillips L. G., Thomason A., Altrock B. W., Pence P. C., Heggers J. P., Johnston A. F., McHugh T. P., Anthony M. S., Robson L. E. Recombinant human platelet-derived growth factor-BB for the treatment of chronic pressure ulcers. Ann Plast Surg. 1992 Sep;29(3):193–201. doi: 10.1097/00000637-199209000-00001. [DOI] [PubMed] [Google Scholar]
  35. Robson M. C., Phillips L. G., Thomason A., Robson L. E., Pierce G. F. Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet. 1992 Jan 4;339(8784):23–25. doi: 10.1016/0140-6736(92)90143-q. [DOI] [PubMed] [Google Scholar]
  36. Rossi P., Karsenty G., Roberts A. B., Roche N. S., Sporn M. B., de Crombrugghe B. A nuclear factor 1 binding site mediates the transcriptional activation of a type I collagen promoter by transforming growth factor-beta. Cell. 1988 Feb 12;52(3):405–414. doi: 10.1016/s0092-8674(88)80033-3. [DOI] [PubMed] [Google Scholar]
  37. Sato N., Beitz J. G., Kato J., Yamamoto M., Clark J. W., Calabresi P., Raymond A., Frackelton A. R., Jr Platelet-derived growth factor indirectly stimulates angiogenesis in vitro. Am J Pathol. 1993 Apr;142(4):1119–1130. [PMC free article] [PubMed] [Google Scholar]
  38. Seiler W. O., Stähelin H. B. Recent findings on decubitus ulcer pathology: implications for care. Geriatrics. 1986 Jan;41(1):47-50, 53-7, 60. [PubMed] [Google Scholar]
  39. Sprugel K. H., McPherson J. M., Clowes A. W., Ross R. Effects of growth factors in vivo. I. Cell ingrowth into porous subcutaneous chambers. Am J Pathol. 1987 Dec;129(3):601–613. [PMC free article] [PubMed] [Google Scholar]
  40. Stricklin G. P., Li L., Jancic V., Wenczak B. A., Nanney L. B. Localization of mRNAs representing collagenase and TIMP in sections of healing human burn wounds. Am J Pathol. 1993 Dec;143(6):1657–1666. [PMC free article] [PubMed] [Google Scholar]
  41. Welch M. P., Odland G. F., Clark R. A. Temporal relationships of F-actin bundle formation, collagen and fibronectin matrix assembly, and fibronectin receptor expression to wound contraction. J Cell Biol. 1990 Jan;110(1):133–145. doi: 10.1083/jcb.110.1.133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Werner S., Peters K. G., Longaker M. T., Fuller-Pace F., Banda M. J., Williams L. T. Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6896–6900. doi: 10.1073/pnas.89.15.6896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wysocki A. B., Grinnell F. Fibronectin profiles in normal and chronic wound fluid. Lab Invest. 1990 Dec;63(6):825–831. [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES