Commercially Available Topical Platelet-Derived Growth Factor as a Novel Agent to Accelerate Burn-Related Wound Healing
Taryn E TravisNeil A. MauskarMatthew J. MinoNick PrindezeLauren T. MoffattPhilip FidlerMarion H. JordanJeffrey W. Shupp
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The authors investigated whether the application of platelet-derived growth factor (PDGF) to donor site wounds would speed healing in a porcine model. In a red duroc pig model, three wounds that were 3 inches × 3 inches were created with a dermatome (0.06-inch depth) on one side of two different animals. These wounds were digitally and laser Doppler (LDI) imaged and biopsied immediately pre- and postwound creation and every 2 days for 2 weeks. A set of identical wounds were subsequently created on the opposite side of the same animals and treated with topical PDGF (becaplermin gel 0.01%, 4 g/wound) immediately on wounding. PDGF-treated wounds were imaged and biopsied as above. Digital images of wounds were assessed for epithelialization by clinicians using an ordinal scale. Perfusion units (PU) were evaluated by LDI. Wound healing was evaluated by hematoxylin and eosin histological visualization of an epithelium and intact basement membrane. First evidence of partial epithelialization was seen in control and PDGF-treated wounds within 7.7 ± 1.4 and 6.4 ± 1.1 days postwounding, respectively (P=.03). Completely epithelialized biopsies were seen in control and PDGF-treated wounds at 11.7 ± 2.6 and 9.6 ± 1.5 days, respectively (P=.02). Clinician evaluation of digital images showed that on day 9, control wounds were, on average, 48.3 ± 18.5% epithelialized vs 57.2 ± 20.2% epithelialized for PDGF-treated wounds. At day 16, control wounds showed an average of 72.9 ± 14.6% epithelialization and PDGF-treated wounds showed an average of 90 ± 11.8%epithelialization. Overall, PDGF-treated wounds had statistically significantly higher scores across all timepoints (P=.02). Average perfusion units as measured by LDI were similar for control and PDGF-treated wounds at time of excision (225 ± 81and 257 ± 100, respectively). On day 2 postwounding, average PU for control wounds were 803 and were 764 for PDGF-treated wounds. Control wounds maintained higher PU values compared with PDGF-treated wounds at all time points and returned to excision PU values by day 12.2 ± 1.1 postwounding. PDGF-treated wounds reached the same values by day 9.7 ± 2.3 (P=.03). The authors conclude that topical PDGF speeds time to epithelialization of partial-thickness wounds in a porcine model as evidenced by histology, clinical appearance, and time to return to prewounding vascularity.Keywords:
Platelet-derived growth factor
Platelet-derived growth factor (PDGF) is a family of isoforms that stimulate the growth, survival, and motility of fibroblasts, smooth muscle cells, and other cell types. PDGF was originally identified in human platelets and purified from this source; however, subsequent studies have shown that PDGF is synthesized by a number of different cell types. PDGF has important roles in the regulation of growth and differentiation of various mesenchymal cell types during embryonal development. In the adult, PDGF stimulates wound healing and also regulates the homeostasis of the connective tissue compartment. Overactivity of PDGF or constitutive activation of PDGF receptors has been implicated in several disorders, including malignancies, atherosclerosis, and fibrotic conditions. Therefore, much effort has recently been devoted to the development of specific and efficient PDGF antagonists. This review will focus on the validation of PDGF antagonists in animal models and on the initial clinical studies in which PDGF antagonists have been used to treat patients.
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Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in mediating smooth muscle cell (SMC) growth after vascular injury. Studies examining TGF-beta-induced growth of cultured SMC have identified only modest mitogenic effects which are largely dependent on autocrine production of platelet-derived growth factor-AA (PDGF-AA). Recent studies have suggested, however, that TGF-beta also may have delayed growth effects independent of PDGF-AA. The aims of the present studies were to examine the effects of TGF-beta on chronic growth responses of cultured SMC. Results demonstrated that TGF-beta elicited a delayed growth response (24 fold increase in 3H-TdR incorp. from 48-72 h) and enhanced SMC production of PDGF-AA (eightfold increase at 24 h). Neutralizing antibodies to PDGF-AA, however, inhibited only 10-40% of delayed TGF-beta-induced growth. Co-treatment with TGF-beta transiently delayed epidermal growth factor (EGF)-, basic fibroblast growth factor (bFGF)-, or PDGF-BB-induced entry into S phase but enhanced the delayed growth responses to these growth factors by 16.0-, 5.8-, or 4.2-fold, respectively. Neutralizing antibodies to PDGF-AA had no effect on these synergistic responses and exogenous PDGF-AA did not increase growth responses to EGF, bFGF, or PDGF-BB. In summary, TGF-beta induces marked delayed growth responses, alone and in combination with EGF, bFGF or PDGF-BB, that are largely independent of PDGF-AA.
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The expression of platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β, and connective tissue growth factor (CTGF) and the effect of imatinib, an agent inhibiting PDGF receptors, were assessed in a porcine bronchial transplantation model of obliterative bronchiolitis (OB). Up-regulation of PDGF-A, PDGF receptors α and β, and TGF-β expression occurred in allografts, whereas PDGF-B and CTGF expression was similar in allo- and autografts. Imatinib modified the inflammatory responses and expression patterns of PDGF-A and PDGF receptors. This study further confirms PDGF and TGF-β as mediators of OB and supports the concept of the importance of the pathways signaled through PDGF receptors in post-transplant OB.
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Platelet-derived growth factor (PDGF) is a potent mitogen for cells of mesenchymal origin. We previously demonstrated that PDGF is produced by osteogenic sarcoma cells. We report here that normal human bone-derived cells produce PDGF and that these cells have an osteoblastic phenotype. This was demonstrated by use of a double immunofluorescent technique and by examining cloned human adult osteoblasts. Northern blot analysis indicates that PDGF production is accounted for by expression of the PDGF-A gene. PDGF-AA and PDGF-BB generally stimulated thymidine incorporation in normal human bone explants to a similar extent. All of the cloned human osteoblasts responded to PDGF-BB while the response to PDGF-AA varied. Similarly, five cloned osteoblastic cell populations were shown to produce PDGF while one did not. This result supports the hypothesis that there are different osteoblastic cell populations that differ in their growth factor responses or in the production of growth factors. Our results suggest that PDGF-BB has the potential to act as a paracrine factor for normal human osteoblasts because all of the osteoblastic cell populations responded to PDGF-BB. None of the osteoblastic cell populations expressed the PDGF-B gene, indicating that it would not act as an autocrine factor. Although not definitive, our results suggest that PDGF-AA has the potential to act as an autocrine factor because osteoblastic bone cell populations were shown to express the PDGF-A gene and respond to PDGF-AA.
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<i>Background:</i> Smooth muscle cell (SMC) proliferation in atherosclerosis is regulated through the interaction of growth factors like platelet-derived growth factor-BB (PDGF-BB) and insulin-like growth factor-1 (IGF-1) and their receptors (R). We hypothesized that serum starvation of SMCs may affect PDGFβ-R and IGF-1-R expression and, consequently, the effect of their cognate ligands on SMC survival/proliferation. <i>Methods and Results:</i> Serum starvation significantly increases PDGFβ-R but not IGF-1-R mRNA and protein expression in SMCs. PDGF-BB stimulates cell survival but not proliferation in serum-starved SMCs of the synthetic phenotype, whereas SMCs of the contractile phenotype respond to PDGF-BB by a significant increase in proliferation. Immunohistochemical analysis of coronary atherosclerotic lesions reveals PDGFβ-R expression in SMCs in the lamina fibromuscularis, but not in the media and in healthy parts of the arterial wall. No such differential expression was observed for IGF-1-R. <i>Conclusions:</i> Differential regulation of PDGFβ-R and IGF-1-R expression by serum starvation might represent a mechanism for the control of SMC survival/proliferation in atherogenesis and restenosis. The distribution of PDGFβ-Rs and IGF-1-Rs in atherosclerotic lesions may indicate an effect of serum starvation on SMCs in the arterial wall.
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A polypeptide acting as a systemic and local regulator of tissue growth. Its function is similar to FGF. It stimulates the replication of osseous cells and collagen synthesis. The synthesis of locally produced PDGF is regulated by growth factors.
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