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PubMed1994

PDGF and TGF-alpha act synergistically to improve wound healing in the genetically diabetic mouse.

Impaired wound healing results in significant morbidity for the surgical patient. The genetically diabetic (C57BL/KsJ-db/db) mouse is obese, hyperglycemic, insulin-resistant, and exhibits markedly impaired wound healing. Previous studies have demonstrated that the fibroblast mitogens, BB homodimer of platelet-derived growth factor (PDGF-BB) or basic fibroblast growth factor, plus insulin-like growth factor, act synergistically to enhance wound closure in the genetically diabetic mouse. The purpose of this study was to determine whether the keratinocyte mitogens, epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha), in combination with the fibroblast mitogen, PDGF-BB, would produce a similar synergistic enhancement in tissue repair. Full-thickness skin wounds created on the backs of diabetic mice received topical applications of vehicle (5% polyethylene glycol), PDGF-BB (10 micrograms), EGF (1 microgram), TGF-alpha (1 microgram), or the combination of PDGF (10 micrograms) and EGF (1 microgram) or TGF-alpha (1 microgram) for 5 consecutive days starting at wounding. Application of PDGF-BB or TGF-alpha alone to wounds in diabetic animals improved wound closure when compared to vehicle treatment. EGF did not affect healing and did not have any additive effects when combined with PDGF-BB. Significant improvements in wound closure were observed with the combination of PDGF-BB and TGF-alpha when compared to treatment with the individual growth factors. The PDGF-BB/TGF-alpha combination accelerated healing in the diabetic animals to a rate that was closer to that seen in nondiabetic mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Platelet-derived growth factor and wound contraction in the rat.

This experiment was undertaken for three purposes: (1) to determine a dose-response curve of acute steroid inhibition of wound contraction in the rat; (2) to confirm the results of our preliminary study that platelet-derived growth factor (PDGF) enhanced wound contraction in acutely steroid impaired rats; and (3) to examine the histology of the PDGF-treated wounds. To determine the dose-response of acute steroid inhibition of wound contraction, the rats were suppressed with daily doses of methylprednisolone and wound contraction was measured. Results demonstrated that significant glucocorticoid-induced inhibition of wound contraction begins with daily methylprednisolone doses of 2.0 mg/wound/day or 6.7 mg/kg/day. In an effort to confirm the results of our previous study of the effect of PDGF on wound contraction in acutely steroid-impaired rats and to study the histology of the PDGF-treated wounds, rats were suppressed with methylprednisolone or hydrocortisone and administered daily topical doses of rPDGF-BB. Wound contraction measurements revealed no improvement in the amount or rate of wound contraction. Histologically, the wounds were all very similar in the patterns of cellularity, granulation tissue maturity, collagen content, and epithelial migration. We have clarified the dose response of acute steroid inhibition of wound contraction in rats, data previously unavailable, and have concluded that PDGF in reasonable doses does not improve wound contraction in steroid-impaired rats nor does it alter the histology of the wounds.

Animals↗
PubMed1998

Release of PDGF-BB and bFGF by human endothelial cells seeded on expanded polytetrafluoroethylene vascular grafts.

BACKGROUND: The majority of endothelial cell (EC) seeded graft failures are due to anastomotic neointimal fibrous hyperplasia. We investigated the PDGF-BB and bFGF release in vitro by umbilical vein EC seeded on precoated expanded polytetrafluoroethylene (ePTFE) prostheses. MATERIALS: EC harvested from human umbilical veins were seeded into ePTFE (30 microns internodal distance, 1 cm2 in diameter) disks. ePTFE disks uncoated or precoated with collagen type I, fibronectin, and Matrigel were used, and EC seeded into plastic wells coated as ePTFE disks or uncoated plastic wells served as controls. Scanning electron microscopy study assessed EC coverage. The presence of bFGF and PDGF-BB in serum-free conditioned media from EC seeded into ePTFE grafts and EC seeded into wells was determined by the inhibition antibody-binding assay 72 h after seeding. RESULTS: EC coverage was similar in uncoated and coated ePTFE grafts. The release of PDGF-BB and bFGF by EC seeded into ePTFE grafts was significantly higher than that observed in EC seeded into plastic wells. The release of PDGF-BB and bFGF was independent from the various substrates used in the experiments in EC seeded into either ePTFE grafts or plastic wells. CONCLUSIONS: Our findings pointed out that in seeded ePTFE grafts, anastomotic smooth muscle cell proliferation and intimal thickening could take place underneath an intact endothelium because seeded EC may release several growth factors.

Becaplermin↗
PubMed1998

Temporal expression of TGF-beta1, EGF, and PDGF-BB in a model of colonic wound healing.

BACKGROUND: Dehiscence of colonic anastomoses is a multifactorial phenomenon. One mechanism by which this can occur is a deficiency of colonic submucosal collagen. Peptide growth factors (PGFs) have been shown to play a role in the synthesis, deposition, and maturation of collagen. Specifically, in tissues other than the colon, the transforming growth factor-beta (TGF-beta1) gene has been shown to be temporally associated with expression of the procollagen gene. This study examines the temporal expression of the TGF-beta1, epidermal growth factor (EGF), and platelet-derived growth factor B (PDGF-BB) genes and their temporal relationship to the expression of the procollagen type 1 (PROC I) gene. MATERIALS AND METHODS: Forty-eight Sprague-Dawley rats underwent transection of the descending colon with primary anastomosis. Perianastomotic colonic tissue was harvested on Day 0 and postoperative days 3, 5, 6, 7, and 14. Colonic tissue was analyzed using semiquantitative reverse transcriptase-polymerase chain reaction and primers specific for the TGF-beta1, EGF, and PDGF-B growth factors. Relative expression ratios of PGFs and PROC I genes were calculated versus a constitutive gene. RESULTS: The data show that although all three of the PGFs genes were expressed in healing postoperative colonic tissue, only TGF-beta1 showed a significant increase in its level of expression versus a constitutive gene from a mean ratio of 0.4 +/- 0. 08 on Day 0 to a mean ratio of 1.9 +/- 0.27 on Day 7 (P < 0.0001 by ANOVA). The PROC I gene also showed a significant increase in expression (P < 0.001 by ANOVA) in the postoperative period which temporally correlated with the increase in the expression of the TGF-beta1 gene (r = 0.89, P < 0.05). CONCLUSIONS: The temporal correlation between an increase in the gene expression of TGF-beta1 and PROC I is initial evidence that that TGF-beta1 plays a significant role in collagen metabolism in a healing colonic anastomosis.

Animals↗
PubMed2000

Initiating the inflammatory phase of incisional healing prior to tissue injury.

BACKGROUND: The time required for incisional healing accounts for the majority of postoperative pain and convalescence. Impaired healing prolongs the process further. If a method for accelerating acute incisional wound healing could be developed, patients would benefit from decreased wound failure and an earlier return to their premorbid condition. MATERIALS AND METHODS: In a rat dermal model, cytokine or vehicle infiltration prior to incision was performed using a single dose or four daily doses preincision. Planned incision sites were primed with the proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) or platelet-derived growth factor BB (PDGF-BB) in an effort to activate the inflammatory phase of healing prior to wounding. At the time of incision closure, one half of the incisions were treated with transforming growth factor beta(2) (TGF-beta(2)). Incisional sites were biopsied and stained with hematoxylin and eosin and immunohistochemistry for inflammatory cells and fibroblast populations and breaking strength was measured. RESULTS: Priming skin with GM-CSF or PDGF-BB mimicked the early inflammatory phase of wound healing. Macrophage staining (EB1) and fibroblast staining (vimentin) were significantly increased prior to incision. Inflammatory priming as well as priming coupled with TGF-beta(2) at the time of the incision closure synergistically improved breaking strength. CONCLUSION: This study demonstrates that sequential therapy consisting of priming of tissue with an inflammatory cytokine followed by application of a proliferative cytokine at the time of incision closure nearly doubles the breaking strength of an acute wound. By manipulating the inflammatory and early proliferative phases of wound healing with tissue growth factors, it may be possible to accelerate acute wound repair and shift the wound healing trajectory to the left.

Animals↗
PubMed2000

Nicotine reorganizes cytoskeleton of vascular endothelial cell through platelet-derived growth factor BB.

BACKGROUND: Cigarette smoking has been directly linked to atherosclerosis formation and vascular graft failures but the role of nicotine in these processes is not yet completely understood. We investigated the release of platelet-derived growth factor BB (PDGF BB) by the bovine aortic endothelial cell (EC) after nicotine administration at concentrations similar to those found in plasma of active and passive smokers and the role of PDGF BB, autocrinally released, in EC cytoskeletal modification. METHODS: EC were stimulated in a serum-free medium for 72 h with (-)-nicotine (from 6 x 10(-4) to 6 x 10(-8) M). The release of PDGF BB was assessed by inhibition antibody-binding assay and confirmed by Western blotting. Mitogenic activity of nicotine on EC was also determined. The EC cytoskeleton was studied with specific antibodies anti-alpha-actin fibers and anti-vimentin and the modification induced by PDGF BB was assessed by blocking PDGF BB activity with specific antibodies. RESULTS: The greatest PDGF BB release was noted at a (-)-nicotine concentration of 6 x 10(-6) M (P < 0.001). The addition of antibody anti-PDGF BB to EC exposed to (-)-nicotine decreased tritiated thymidine uptake by 20% (P < 0.001). EC exposed to (-)-nicotine concentrations of 6 x 10(-6) and 6 x 10(-8) M had a significant alteration in the expression of alpha-actin fibers and vimentin as compared with control. Administration of the antibody anti-PDGF BB in the culture medium reversed cytoskeletal alteration. CONCLUSIONS: Nicotine enhanced the release of PDGF BB by EC which in turn caused an alteration in cytoskeletal organization.

Actins↗
PubMed2001

Rat aortic smooth muscle cell density affects activation of MAP kinase and Akt by menadione and PDGF homodimer BB.

Mitogen-activated protein kinases (MAPK) and protein kinase B (PKB or Akt) are major signal transduction molecules regulating cell proliferation, differentiation, and apoptosis. We examined how cultured rat aortic vascular smooth muscle cells (VSMC) at different cell densities respond to selected stimuli and how this is reflected in the two distinct (MAPK and Akt) and yet cross-talking signaling pathways. VSMC were cultured to 100% confluence, reaching contact inhibition, and to 60-70% confluence, as sparse, proliferating cells. They were treated with menadione (an intracellular generator of O(-2)) and/or platelet-derived growth factor homodimer BB (PDGF). In sparse cells, menadione or PDGF alone activated ERK, and together the effect was synergistic, whereas in confluent cells menadione's and PDGF's activations of ERK were, at most, additive. Activation of the upstream ERK kinase (MEK-1) paralleled ERK activation except in sparse cells in which the synergistic effects of menadione and PDGF on ERK could not be fully accounted for by MEK-1 activation. Another member of the MAPK family, p38, did not show significant changes. Akt activation by PDGF alone was present under both cell culture conditions; Akt activation is blocked by menadione. Co-incubation with the reducing agent dithiothreitol or calcium chelators (EDTA/EGTA) inhibited partially or completely menadione's effects on MEK/ERK and Akt pathways, as well as menadione's effects on PDGF-induced ERK and Akt activations. These data suggest that in VSMC, the state of cell confluence determines how distinct pathways of MAPK activation cross talk. In addition while PDGF may function as a survival factor by inducing Akt activation, menadione could promote apoptosis by inhibiting PDGF-induced Akt activation independent of cell density. The effects of menadione, but not those of PDGF, are more dependent on the cellular redox status and extracellular calcium.

Animals↗
PubMed2002

PDGF(BB) increases myocardial production of VEGF: shift in VEGF mRNA splice variants after direct injection of bFGF, PDGF(BB), and PDGF(AB).

BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis. We hypothesized that a combination of recombinant angiogenic proteins might induce myocardial VEGF production and cause a shift in the mRNA signal produced. MATERIALS AND METHODS: The left ventricles of New Zealand white rabbits were injected with 500 microL of saline, basic fibroblast growth factor (bFGF), platelet-derived growth factor-AB (PDGF(AB)), platelet-derived growth factor-BB (PDGF(BB)), bFGF + PDGF(AB), or bFGF + PDGF(BB). Myocardial VEGF production was analyzed by ELISA while mRNA splice variants were analyzed by RT-PCR 3 and 7 days after injection. RESULTS: PDGF(BB) alone caused the most pronounced induction of VEGF. Three days after injection the induction of VEGF by PDGF(BB) was significant compared to all treatment groups, except the bFGF + PDGF(BB) group. Induction of VEGF by PDGF(BB) was associated with a decrease in mRNA production of VEGF(121) within the myocardium. CONCLUSIONS: Injection of PDGF(BB) induces significant production of VEGF within the myocardium. This induction of VEGF production is associated with a shift toward other, less soluble forms of VEGF. These findings may allow more precise regulation of the myocardial response to therapeutic angiogenesis.

Animals↗
PubMed1998

The neuron-glia signal beta neuregulin induces sustained CREB phosphorylation on Ser-133 in cultured rat Schwann cells.

beta neuregulins (also called NDF, GGF, ARIA, and heregulins) are neuron-derived molecules that are likely to be responsible for Schwann cell precursor survival, proliferation, and maturation in vivo and in vitro. Although the receptors to which beta neuregulins bind have been defined, little is known about the transcription factors these important ligands activate. Using antibodies, quantitative imaging methods and Western blotting, we show that beta neuregulin induces a high level of phosphorylation of the transcription factor cyclic AMP response element binding protein (CREB) on Ser-133 in cultured rat Schwann cells and that the phosphorylation is prolonged over several hours. In contrast, neurotrophins, CNTF, FGF-2, EGF, and TGF beta induce little or no phosphorylation of CREB despite the fact that receptors for these factors are present on Schwann cells. As expected CREB phosphorylation was detected following cAMP elevation, and it was also induced by elevation of cytoplasmic Ca2+, endothelin 1, and PDGF-BB. The signal was lower than that seen in response to beta neuregulin, and transient, unlike the sustained CREB activation induced by beta neuregulin. Our results suggest that the sustained phosphorylation of CREB on Ser-133 may contribute to the broad spectrum of effects that beta neuregulins have on cells of the Schwann cell lineage and that the CREB pathway may be important for transduction of neuregulin signals in Schwann cells.

Animals↗
PubMed1994

Platelet-derived growth factor exerts trophic effects on rat striatal DARPP-32-containing neurons in culture.

The objective of the present study was to determine if either of the two isoforms of platelet-derived growth factor (PDGF), PDGF-AA and PDGF-BB, exerts trophic effects in vitro on developing rat strial neurons. Striatal neurons were identified using immunocytochemistry for dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein with a molecular weight of 32 kilodalton (DARPP-32). In control cultures without PDGF, the mean number of DARPP-32-positive neurons decreased by 47% at days 3 to 5 in vitro. PDGF-BB, but not PDGF-AA, significantly increased the number of DARPP-32-positive neurons both at day 3 (by 42%) and day 5 (by 149%). Total cell number was similar in control and PDGF-BB-treated cultures, suggesting that, in striatal cultures, the action of PDGF-BB is relatively specific for DARPP-32-positive neurons. The DARPP-32-positive neurons in PDGF-BB-treated cultures had longer neurites and larger soma areas than those in control and in PDGF-AA-treated cultures. Our data provide evidence that PDGF-BB exerts a trophic action on striatal DARPP-32-positive neurons in vitro by promoting cell survival and morphological differentiation, although a stimulatory effect on intraneuronal DARPP-32 levels also is possible. The findings raise the possibility that PDGF-BB might also be involved in the development and maintenance of striatal neurons in vivo, and could be used to counteract striatal degeneration in models of Huntington's disease.

Animals↗
PubMed1994

Fibronectin and the basement membrane components laminin and collagen type IV influence the phenotypic properties of subcultured rat aortic smooth muscle cells differently.

A substrate of the extracellular matrix protein fibronectin has previously been found to promote the modulation of freshly isolated rat aortic smooth muscle cells from a contractile to a synthetic phenotype early in primary culture. In contrast, substrates of the basement membrane proteins laminin and collagen type IV were found to retain the cells in a contractile phenotype. Here, we have studied whether rat aortic smooth muscle cells tht have already adopted a synthetic phenotype are also affected differently by these proteins. For this sake, subcultured cells were detached with trypsin, seeded on substrates of either fibronectin or laminin plus collagen type IV, and incubated in a serum-free medium for one to three days. RNA blot and immunoblot analyses indicated that cells grown on laminin plus collagen type IV expressed smooth muscle alpha-actin transcripts and protein at higher levels than cells grown on fibronectin. Moreover, immunocytochemical and electron-microscopic analyses revealed that cells positively stained for smooth muscle alpha-actin and cells with a cytoplasm dominated by large microfilament bundles were more numerous on laminin plus collagen type IV than on fibronectin. Finally, thymidine autoradiography showed that the DNA synthetic response to stimulation with platelet-derived growth factor or serum was weaker in cells grown on laminin plus collagen type IV than in cells grown on fibronectin. These findings confirm the notion that a substrate of laminin and collagen type IV stimulates the in vitro expression of differentiated smooth muscle traits at a higher level than does a substrate of fibronectin.(ABSTRACT TRUNCATED AT 250 WORDS)

Actin Cytoskeleton↗
PubMed1997

Proliferative response of cultured human tenon's capsule fibroblasts to platelet-derived growth factor isoforms.

BACKGROUND: Although platelet-derived growth factor (PDGF) has been thought to be critical in the wound-healing response of Tenon's capsule fibroblasts after glaucoma filtration surgery, no information is currently available concerning the proliferative effect of PDGF isoforms on this cell type. The aim of the present study was to evaluate the proliferative effect of PDGF-AB heterodimer and PDGF-AA and -BB homodimers on cultured human Tenon's capsule fibroblasts. METHODS: Human Tenon's capsule fibroblasts, cultured under serum-free conditions, were stimulated with PDGF-AA, -AB and -BB isoforms in concentrations ranging from 1 to 100 ng/ml. Cell numbers were determined on days 1, 3, 5 and 7, using a cell counter. RESULTS: Addition of PDGF-AB and -BB led to a dose-dependent increase in cell proliferation. A maximal response (79.9% over control) was obtained after 7 days with 30 ng/ml of PDGF-BB, with an EC50 of 8.9 ng/ml. The maximal increase in cell proliferation caused by PDGF-AB (30 ng/ml) was 54.9%, with an EC50 of 12.5 ng/ml. Stimulation with PDGF-AA revealed a significant effect only with concentrations higher than 30 ng/ml. CONCLUSION: Our results indicate that PDGF-AB and -BB isoforms are potent stimulators of proliferation of human Tenon's capsule fibroblasts, suggesting that PDGF-AB and -BB isoforms play an important role in the wound-healing response after glaucoma filtration surgery.

Anticoagulants↗
PubMed1997

The in vitro effect of platelet-derived growth factor isoforms on the proliferation of bovine corneal stromal fibroblasts depends on cell density.

PURPOSE: Recently, it has been shown that corneal stromal fibroblasts express the mRNA for PDGF-beta-type receptors, while corneal epithelial cells express the mRNA for the PDGF B-chain, suggesting a role of PDGF isoforms in the regulation of corneal homeostasis and wound healing via an unidirectional epithelial to stromal paracrine interaction. The purpose of this study was to characterize the proliferative response of cultured bovine corneal stromal fibroblasts to PDGF isoforms. METHODS: Bovine corneal stromal fibroblasts were seeded at a cell density of 60 cells/mm2 (low density) and 120 cells/mm2 (high density) and were cultured under serum-free conditions. Except for corresponding controls, PDGF AA, BB and AB (obtained by separate expression of cloned genes in E. coli) were added in concentrations ranging from 3.125 to 100 ng/ml. Cell numbers were determined after an incubation period of 6 days using a cell counter. RESULTS: Stromal fibroblasts, when cultured at a high density, revealed constant cell numbers during the whole incubation period. Under these culture conditions, stimulation with PDGF AA, BB and AB led to a significant dose-dependent increase in cell proliferation. When cultured at a low cell density, stromal fibroblasts revealed a significant reduction of cell numbers after 6 days of incubation. This reduction was prevented by PDGF AA and AB isoforms in a dose-dependent manner. In contrast, PDGF BB was not effective. CONCLUSION: The results of the "high-density" assays suggest that PDGF isoforms act as mitogens for stromal fibroblasts during wound healing, when density of fibroblasts is high. The results of the "low-density" assays support the idea that PDGF AA and AB can prevent cell loss during corneal homeostasis when density of keratocytes is low.

Animals↗
PubMed1995

Plasma platelet-derived growth factor-B chain is elevated in patients with extensively large brain tumour.

The plasma concentration of the platelet-derived growth factor (PDGF)-B chain and the plasma platelet factor 4 (PF4) levels were measured in 17 healthy controls and 55 brain tumour patients. In the 17 normal controls, the plasma PDGF-B and PF4 levels were 523 +/- 157 pg/ml (mean +/- SD) and 84 +/- 37 ng/ml, respectively. In the brain tumour patients, these values were 881 +/- 854 pg/ml and 93 +/- 64 ng/ml, respectively. The plasma PDGF-B concentration was elevated above the upper limit of normal individuals in 12 (22%) of the 55 patients. However, since the corresponding PF4 levels suggested the platelet activation, the increased plasma PDGF-B may have originated from platelets. To address this, platelet releasing experiments were performed on citrated blood samples from 5 normal individuals. The plasma PDGF-B and PF4 levels from the 17 normal controls and those observed in the platelet releasing experiments correlated with a regression line of Y = 240 + 4.86X (Y:PDGF, X:PF4). There were only 6 (11%) patients whose plasma PDGF-B level was elevated above the 95% confidence limit estimated from the corresponding PF4 value. In these patients, the tumour volumes were extensively large, and those elevated PDGF-B values decreased after treatment and became elevated again in three patients with recurrent glioblastoma. Although the plasma tumour-derived PDGF-B was detected only in an extensively large brain tumour, it might be a useful plasma marker evaluating the effects of therapy and prognosis in such patients.

Adolescent↗
PubMed1998

Engineering the healing of the rabbit medial collateral ligament.

A biological approach to improve healing of the medial collateral ligament (MCL) was investigated by exploring the use of therapeutic growth factors based on in vitro and in vivo experiments. The in vitro cell culture studies involved screening a variety of growth factors to select those that exhibit the most positive effects on cell proliferation and extracellular matrix synthesis. The selected growth factors were applied in vivo to a rabbit model where the MCL was ruptured. Biomechanical and histological evaluations are performed to determine whether the selected growth factors can enhance the properties of the healed MCL, whether these improvements are dose dependent, and whether combinations of growth factors can enhance MCL healing to a greater extent than individual growth factors. In vitro studies showed that epidermal growth factor (EGF) and platelet derived growth factor-BB (PDGF-BB) have the greatest effect on ligament fibroblast proliferation, whereas transforming growth factor-beta 1 (TGF-beta 1) superiorly promotes extracellular matrix synthesis. These growth factors were then applied in vivo at different dosages, in isolation and in combination, and the ligaments were evaluated six weeks post-operatively. Tensile testing of the femur-MCL-tibia complexes (FMTCs) revealed that the specimens treated with a high dose of PDGF-BB have ultimate load, ultimate elongation and energy absorbed to failure values that are significantly greater than those from the other groups. The high dose of PDGF-BB was more effective than the low dose, indicating a dose dependency. The addition of TGF-beta 1 to PDGF-BB did not lead to any further increases in the structural properties of the FMTC. These encouraging results suggest that PDGF-BB may be a potential growth factor to enhance the quality of the healing ligament.

Animals↗