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PubMedDate not supplied

Effect of recombinant platelet-derived growth factor (Regranex) on wound closure in genetically diabetic mice.

Burns, especially those involving large surface areas, represent a complex wound healing problem. Platelet-derived growth factor (PDGF) is released by activated platelets to recruit inflammatory cells toward the wound bed. It has effects on promoting angiogenesis and granulation tissue formation. However, the effectiveness of topical PDGF on wound closure is variable, ranging from little improvement observed in pig models to dramatic improvement reported in a diabetic mouse model. Here, we sought to determine the effectiveness of commercially sold PDGF-BB (Regranex) on wound closure in genetically diabetic mice. C57BL/KsJ db+/db+ mice and its host strain bearing dorsal 1.5-cm wounds were divided into groups (n = 8 in each group) receiving topical application of either Regranex (10 microg/wound) or vehicle for 5 consecutive days after wounding. The rate of wound closure was analyzed using computerized planimetry. The amount of granulation tissue was determined histologically. Our data indicate that diabetic mice exhibit a significant delay in wound closure when compared with their host strain. Topical application of Regranex did not improve the time to wound closure but did significantly increase the amount of granulation tissue. Our current study using commercially available Regranex failed to reproduce the previously reported finding that PDGF improved wound closure in healing impaired genetically diabetic mice.

Administration, Topical↗
PubMed2004

Influence of endothelin receptor antagonism on smooth muscle cell proliferation after chronic renal failure.

Uremic patients suffer from an accelerated development of atherosclerosis. In uremia the angiotensin-aldosterone-endothelin system is activated. It is not known, however, whether endothelin receptor antagonism inhibits atherosclerosis in uremia. An experimental model of mild renal insufficiency is subtotal nephrectomy in rats. The aim of this study was to assess the proliferative response of vascular smooth muscle cells from rats that have undergone subtotal nephrectomy and are treated with an endothelin-A or combined endothelin-A/endothelin-B receptor antagonist to the proatherogenic growth factors platelet-derived growth factor-BB and basic fibroblast growth factor. For 12 weeks 5/6-nephrectomized rats were treated with the endothelin-A receptor antagonist LU 302146 or the combined endothelin-A/endothelin-B receptor antagonist LU 302872 (10 mg/kg bodyweight)or received no medication (subtotal nephrectomy). Aortal smooth muscle cells were isolated and cultivated. After incubation with platelet-derived growth factor-BB (10(-13)-10(-9) mol/L for 5 days) or basic fibroblast growth factor (10(-14)-10(-10) mol/L for 7 days) proliferation was measured using bromodeoxyuridine enzyme-linked immunosorbent assay. Both growth factors increased proliferation in vascular smooth muscle cells from untreated subtotally nephrectomized rats (platelet-derived growth factor-BB10(-9) mol/L: 487%, basic fibroblast growth factor 10(-10) mol/L:175%). Treatment with the endothelin-A receptor antagonist resulted in a reduced proliferation (platelet-derived growth factor-BB: 137%, basic fibroblast growth factor: 109%). After treatment with the combined endothelin-A/endothelin-B receptor antagonist findings were similar (platelet-derived growth factor-BB: 123%,basic fibroblast growth factor: 110%). These data demonstrate that chronic endothelin-A and combined endothelin-A/endothelin-B receptor antagonism inhibits vascular smooth muscle cell proliferation in rats treated with subtotal nephrectomy. This indicates a regulatory influence of these drugs on gene transcription and supports the importance of early treatment to inhibit coronary artery disease in uremic patients.

Animals↗
PubMed2003

Platelet derived growth factor-BB is a potent mitogen for rat ureteral and human bladder smooth muscle cells: dependence on lipid rafts for cell signaling.

PURPOSE: Fibromuscular tissues of the detrusor/bladder body (B), trigone (T) and ureter (U) display distinct patterns of tissue remodeling in pathologic contexts, however the mechanisms underlying these observations are unknown. In this study we asked whether B, T and U smooth muscle cells (SMC) respond to several SMC growth factors and explored the role of caveolae/lipid raft membrane microdomains in signaling by one of these factors, PDGF-BB. MATERIALS AND METHODS: SMC were isolated and cultured from B, T and U from newborn rats and from human bladder detrusor. Responses to growth factors were assessed by cell proliferation, DNA synthesis, and immunoblot methods. Cholesterol was depleted from cell membranes in select experiments using cyclodextrin and the cholesterol synthesis inhibitor lovastatin. High-affinity PDGF receptor (PDGFR) sites were measured by 125I-PDGF-BB binding assay. RESULTS: PDGF-BB increased DNA synthesis rate in U and T SMC, with U SMC being highly responsive; in contrast, B SMC did not respond to this growth factor. Two other mitogens, HB-EGF and FGF-2, marginally stimulated DNA synthesis in all lineages. Human detrusor (hD) SMC were also highly responsive to PDGF-BB. Differences in responses to PDGF-BB correlated with translocation of PDGFRs into the caveolae/lipid raft membrane fraction following stimulation, but not with the number of high affinity PDGF binding sites. Cholesterol depletion from cell membranes reduced the response of U and hD SMC to PDGF-BB. CONCLUSIONS: These findings indicate that 1) PDGF-BB is likely to be a physiologically relevant stimulator of mitogenic signaling in certain types of urinary tract SMC, 2) there are significant and unanticipated regional differences in the ability of urinary tract SMC to respond to muscle mitogens, and 3) lipid raft membrane microdomains mediate, in part, the ability of urinary tract SMC to respond to PDGF-mediated signals.

Animals↗
PubMed2003

Signaling through PI3K/Akt mediates stretch and PDGF-BB-dependent DNA synthesis in bladder smooth muscle cells.

PURPOSE: Smooth muscle cells (SMC) of the bladder undergo hypertrophy and hyperplasia following exposure to sustained mechanical overload. Although superficial similarities in the response of the heart and bladder to hypertrophic stimuli suggest that similar molecular mechanisms may be involved, this remains to be demonstrated. In this study we compared signal transduction pathway activation in primary culture bladder SMC and cardiac myofibroblasts in response to cyclic stretch. The effects of growth factor stimulation on pathway activation in bladder SMC were also investigated. MATERIALS AND METHODS: Primary culture rodent bladder SMC or cardiac myofibroblasts were subjected to cyclic stretch-relaxation in the absence or presence of pharmacologic inhibitors of the phosphoinositide-3-kinase, (PI3K)/Akt, extracellular signal-regulated kinase-mitogen activated protein kinase (Erk-MAPK) or the p38 stress-activated protein kinase-2 (SAPK2) pathways. In parallel experiments human bladder SMC were treated with platelet-derived growth factor-BB (PDGF-BB), heparin-binding EGF-like growth factor (HB-EGF) or fibroblast growth factor-2 (FGF-2). In each case the extent of DNA synthesis was determined by uptake of tritiated thymidine, and activation of specific signaling intermediates was determined by immunoblot analysis using antibodies to the non-phosphorylated and phosphorylated (activated) forms of Akt, p38 and Erk1/2. RESULTS: Akt and p38 were rapidly phosphorylated in stretched bladder SMC and cardiac myofibroblasts, and stretch-induced DNA synthesis in these cells was ablated with inhibitors of PI3K or p38 but not Erk-MAPK. Similarly, PDGF-BB up-regulated DNA synthesis in bladder SMC in a p38 and Akt-dependent manner. CONCLUSIONS: We conclude that distinct stimuli, such as mechanical stretch and PDGF-BB, promote DNA synthesis in bladder SMC through shared downstream signaling pathways. Furthermore, phenotypically similar cells from the bladder and heart show comparable pathway activation in response to stretch. These findings suggest that similar molecular mechanisms underlie the altered growth responses of the bladder and heart to mechanical overload. This study also provides the first report of Akt activation in bladder SMC and suggests that Akt, consistent with its pivotal role in cardiac hypertrophy, may also be a key regulator of remodeling in the SMC compartment of the bladder exposed to hypertrophic/hyperplastic stimuli in vivo.

Animals↗
PubMed2003

Connective tissue growth factor participates in scar formation of crescentic glomerulonephritis.

Glomerular crescents are a major determinant of progression in various renal diseases. Some types of growth factors are known to be involved in the evolution of crescents and the subsequent scar formation. Although glomerular parietal epithelial cells (PECs) are the major component of cellular crescents, the influence of growth factors on PECs is unknown. We performed immunohistochemical studies and in situ hybridization to examine alterations in connective tissue growth factor (CTGF) expression and to identify CTGF-synthesizing cells in crescents in the crescentic glomerulonephritis model of Wistar Kyoto rats. In addition, we examined the roles of fibroblast growth factor (FGF)-2, platelet-derived growth factor (PDGF)-BB, transforming growth factor (TGF)-beta, and CTGF in cell proliferation and matrix synthesis in an established rat PEC cell line (PEC line). In an acute phase of rat crescentic glomerulonephritis, a major component of the crescents were macrophages, which did not express CTGF mRNA. However, in the advanced phase, crescents strongly expressed CTGF mRNA and the epithelial marker pan-cadherin but did not express the macrophage marker ED1, suggesting that PECs synthesized the CTGF. In the PEC line, FGF-2 predominantly promoted [(3)H]thymidine incorporation compared with PDGF-BB. Both TGF-beta and PDGF-BB strongly stimulated extracellular matrix synthesis in association with up-regulation of endogenous CTGF, but TGF-beta showed a predominant role. FGF-2 had a minor effect on it. In addition, blockade of endogenous CTGF using an antisense oligodeoxynucleotide significantly attenuated both TGF-beta- and PDGF-BB-induced extracellular matrix synthesis. These results suggest that several growth factors promote cell proliferation and matrix production in PECs. CTGF-mediated matrix production via the TGF-beta or PDGF-BB pathway in PECs may, in part, play a role in the progression of scar formation in crescents.

Animals↗
PubMed2003

Human embryonic stem cells as an in vitro model for human vascular development and the induction of vascular differentiation.

Early embryonic blood vessels are typically composed of fragile tubes of endothelial cells encircled by vascular smooth muscle cells. Early human vasculogenesis was explored in spontaneous and directed differentiation models derived from human embryonic stem (HES) cells. In a 3-dimensional (3D) model, HES cells were studied for their potential for vascular differentiation during the spontaneous formation of embryoid bodies. Directed differentiation was investigated by means of a 2-dimensional (2D) differentiation method to promote vascular differentiation from HES cells (without the formation of embryoid bodies). Using this latter approach, up-regulation of early lineage markers of endothelial progenitors were induced. Additional culture under strict conditions and exposure to angiogenic growth factors resulted in a prolonged differentiation pathway into mature endothelial cells and up-regulation of vascular smooth muscle cell markers. The use of 3D collagen gels and Matrigel assays for the induction and inhibition of human vascular sprouting in vitro further established the vascular potential of the cells generated by the 2D differentiation system. Our study shows that HES cells can provide useful models to study early differentiation and development of blood vessels. Moreover, the 2D differentiation model facilitates both the production of vascular lineage cells from HES cells for various potential therapeutic applications and also provides a model for studying the mechanisms involved in early human embryonic blood vessel development.

Becaplermin↗
PubMed2005

Differential and synergistic effects of platelet-derived growth factor-BB and transforming growth factor-beta1 on activated pancreatic stellate cells.

OBJECTIVE: The cytokines platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta1 are major factors influencing the transformation from the quiescent to the activated phenotype of pancreatic stellate cells (PSC), a process involved in the pathogenesis of chronic pancreatitis. Albeit much effort has been made to study the effects of PDGF and TGF-beta1 on PSCs, their interaction is still unclear, because these cytokines show both differential and synergistic effects as outlined by this study. METHODS: Culture-activated PSCs of rats were treated with PDGF-BB and TGF-beta1. Subsequent changes of cell proliferation and migration were determined by cell counting, (+)-bromo-2'-deoxyuridine enzyme-linked immunosarbant assay (ELISA), and migration assay. Gene expression, synthesis of proteins, and activation of kinases were further studied by reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, ELISA, and Western blot. RESULTS: PDGF-BB increased PSC proliferation and migration, accompanied by elevated expression of matrix metalloproteinases (MMP)-13 and MMP-3. The mRNA amount of procollagen alpha2(I), alpha-smooth muscle actin (alpha-SMA), tissue inhibitor of metalloproteinase (TIMP)-1, and TGF-beta1 was also increased by PDGF-BB. In contrast, PDGF-BB reduced collagen type I in culture medium and synthesis of alpha-SMA. Treatment of PSC with TGF-beta1 decreased proliferation, had no significant effect on migration and MMP expression, but increased expression and synthesis of procollagen alpha2(I) and alpha-SMA. Both cytokines induced phosphorylation of extracellular signal regulated kinase (ERK)-1/2 and p38, but only PDGF-BB activated the protein kinase B signaling pathway. CONCLUSION: PDGF-BB augments effects of TGF-beta1 on the mRNA level presumably because of up-regulation of TGF-beta1 synthesis and common signaling pathways of the 2 cytokines. However, at the protein level, PDGF-BB impairs typical TGF-beta1 effects such as increased synthesis of collagen (type I) and alpha-SMA. Moreover, PDGF-BB facilitates degradation of extracellular matrix proteins by enhancement of MMP synthesis, but MMP activity was probably limited because of elevated tissue inhibitor of metalloproteinase 1 expression.

Actins↗
PubMed2004

Platelet quantification and growth factor analysis from platelet-rich plasma: implications for wound healing.

Growth factors released from activated platelets initiate and modulate wound healing in both soft and hard tissues. A recent strategy to promote the wound-healing cascade is to prepare an autologous platelet concentrate suspended in plasma, also known as platelet-rich plasma, that contains growth factors and administer it to wound sites. The purpose of this study was to quantitate platelet number and growth factors released from a prepared platelet concentrate. Whole blood was drawn from 10 healthy patients undergoing cosmetic surgery and concentrated into platelet-rich plasma. Platelet counts on whole blood and platelet-rich plasma were determined using a Cell-Dyn 3200. Platelet-derived growth factor-BB, transforming growth factor-beta1, vascular endothelial growth factor, endothelial growth factor, and insulin-like growth factor-1 were measured in the platelet-rich plasma using the enzyme-linked immunosorbent assay method. In addition, platelet activation during the concentration procedure was analyzed by measuring P selectin values in blood serum. An 8-fold increase in platelet concentration was found in the platelet-rich plasma compared with that of whole blood (baseline whole blood, 197 +/- 42 x 10 platelets/microl; platelet concentrate, 1600 +/- 330 x 10 platelets/microl). The concentration of growth factors also increased with increasing platelet number. However, growth factor concentration varied from patient to patient. On average for the whole blood as compared with platelet-rich plasma, the platelet-derived growth factor-BB concentration increased from 3.3 +/- 0.9 ng/ml to 17 +/- 8 ng/ml, transforming growth factor-beta1 concentration increased from 35 +/- 8 ng/ml to 120 +/- 42 ng/ml, vascular endothelial growth factor concentration increased from 155 +/- 110 pg/ml to 955 +/- 1030 pg/ml, and endothelial growth factor concentration increased from 129 +/- 61 pg/ml to 470 +/- 320 pg/ml. No increase was found for insulin-like growth factor-1. In addition, no increase in platelet activation occurred during the concentration procedure as determined by the platelet surface receptor P selectin (45 +/- 16 pg/ml to 52 +/- 11 pg/ml, p = 0.65). In conclusion, a variety of potentially therapeutic growth factors were detected and released from the platelets in significant levels in platelet-rich plasma preparations. Sufficient concentrates and release of these growth factors through autologous platelet gels may be capable of expediting wound healing in a variety of as yet undetermined specific wound applications.

Adult↗
PubMed2006

Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity ulcers.

BACKGROUND: Diabetic foot ulcer is a major health care problem that leads to amputation. METHODS: Patients with full-thickness diabetic neurotrophic foot ulcers present for longer than 8 weeks without healing were entered into one of five randomized, prospective, blinded clinical trials comparing treatment with platelet-derived growth factor (PDGF) or placebo gel for up to 20 weeks. The purpose of these trials was to assess the safety and efficacy of PDGF used with good wound care. Each patient had an adequate arterial blood supply, was free of infection, was off-loaded, and was extensively débrided. The ulcers had been present for at least 8 weeks. RESULTS: A total of 922 patients were entered into the study. Analysis of ulcers with a baseline area of less than 10 cm (95 percent of patients) showed that patients treated with PDGF at 100 mug/g had a significant increase in complete healing compared with patients given placebo (50 percent versus 36 percent, p < 0.007). PDGF also decreased the time to complete healing by 30 percent (14 weeks versus 20 weeks, p = 0.01). Adverse events were similar in both treatment groups, as were recurrent ulcer rates. CONCLUSION: PDGF applied once daily was effective in healing chronic diabetic neurotrophic foot ulcers when used in conjunction with good wound care.

Administration, Topical↗
PubMed2005

Endovascular treatment of aneurysms: gene expression of neointimal cells recruited on the embolic agent and evolution with recurrence in an experimental model.

PURPOSE: The authors attempted to identify genes associated with healing or recurrence after embolization in an aneurysm model in which neointima formation at the neck varies according to flow zones. A better understanding of the relationship between blood flow, molecular events, and healing or recurrence may provide future avenues to improve results of endovascular treatment of aneurysms. METHODS: Bilateral carotid venous pouch aneurysms were constructed in 36 dogs and embolized with gelatin sponges. Angiography and pathological studies were performed at T0 and/or 3 weeks (n=22). Angiographic results and neointima formation were scored using a qualitative index applied to the distal (inflow) and proximal (outflow) zones of the neck. In 14 animals, mRNA expression 1 to 14 days after embolization at the proximal or distal segment of the sponge was analyzed by RT-PCR, attempting to correlate flow zones, gene expression, and neointima formation. RESULTS: Aneurysms recurred at 3 weeks, as shown by significantly worse angiographic scores as compared to T0 (P<.01). Neointimal scores differed at pathology, with a more complete neointima at the proximal as compared to the distal aspect of the sponge at 3 weeks (P=.027). Embolization was followed by migration of CD31+, CD14+, smooth muscle alpha-actin+ (SMA+) cells that progressively expressed metalloproteinases (MMP-9,-12,-14), but stable or lesser, retarded expression of inhibitors (TIMP1-4). Growth factors (PDGF-BB, TGF-beta1, TNF-alpha, MCP-1 and Ang-1) were expressed at increasing levels, maximal at 7 to 14 days. Differences between distal and proximal zones were limited to increased expression of MMP-2 proximally (P<.035). CONCLUSION: Gene expression after embolization is compatible with patterns associated with neointima formation. The authors have not identified key factors involved in recurrence.

Actins↗
PubMed2001

PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo.

We present evidence that some low-grade oligodendrogliomas may be comprised of proliferating glial progenitor cells that are blocked in their ability to differentiate, whereas malignant gliomas have additionally acquired other mutations such as disruption of cell cycle arrest pathways by loss of Ink4a-Arf. We have modeled these effects in cell culture and in mice by generating autocrine stimulation of glia through the platelet-derived growth factor receptor (PDGFR). In cell culture, PDGF signaling induces proliferation of glial precursors and blocks their differentiation into oligodendrocytes and astrocytes. In addition, coexpression of PDGF and PDGF receptors has been demonstrated in human gliomas, implying that autocrine stimulation may be involved in glioma formation. In this study, using somatic cell type-specific gene transfer we investigated the functions of PDGF autocrine signaling in gliomagenesis by transferring the overexpression of PDGF-B into either nestin-expressing neural progenitors or glial fibrillary acidic protein (GFAP)-expressing astrocytes both in cell culture and in vivo. In cultured astrocytes, overexpression of PDGF-B caused significant increase in proliferation rate of both astrocytes and neural progenitors. Furthermore, PDGF gene transfer converted cultured astrocytes into cells with morphologic and gene expression characteristics of glial precursors. In vivo, gene transfer of PDGF to neural progenitors induced the formation of oligodendrogliomas in about 60% of mice by 12 wk of age; PDGF transfer to astrocytes induced the formation of either oligodendrogliomas or mixed oligoastrocytomas in about 40% of mice in the same time period. Loss of Ink4a-Arf, a mutation frequently found in high-grade human gliomas, resulted in shortened latency and enhanced malignancy of gliomas. The highest percentage of PDGF-induced malignant gliomas arose from of Ink4a-Arf null progenitor cells. These data suggest that chronic autocrine PDGF signaling can promote a proliferating population of glial precursors and is potentially sufficient to induce gliomagenesis. Loss of Ink4a-Arf is not required for PDGF-induced glioma formation but promotes tumor progression toward a more malignant phenotype.

Animals↗
PubMed2000

A 16-amino acid peptide from human alpha2-macroglobulin binds transforming growth factor-beta and platelet-derived growth factor-BB.

Alpha2-macroglobulin (alpha2M) is a major carrier of transforming growth factor-beta (TGF-beta) in vitro and in vivo. By screening glutathione S-transferase (GST) fusion proteins with overlapping sequences, we localized the TGFbeta-binding site to aa 700-738 of the mature human alpha2M subunit. In separate experiments, we screened overlapping synthetic peptides corresponding to aa 696-777 of alpha2M and identified a single 16-mer (718-733) that binds TGF-beta1. Platelet-derived growth factor-BB (PDGF-BB) bound to the same peptide, even though TGF-beta and PDGF-BB share almost no sequence identity. The sequence of the growth factor-binding peptide, WDLVVVNSAGVAEVGV, included a high proportion of hydrophobic amino acids. The analogous peptide from murinoglobulin, a human alpha2M homologue that does not bind growth factors, contained only three nonconservative amino acid substitutions; however, the MUG peptide failed to bind TGF-beta1 and PDGF-BB. These results demonstrate that a distinct and highly-restricted site in alpha2M, positioned near the C-terminal flank of the bait region, mediates growth factor binding. At least part of the growth factor-binding site is encoded by exon 18 of the alpha2M gene, which is notable for a 5' splice site polymorphism that has been implicated in Alzheimer's Disease.

Amino Acid Sequence↗
PubMed2004

Protease-activated receptor-2 (PAR-2) expression in human fibroblasts is regulated by growth factors and extracellular matrix.

Many cell types express a membrane receptor, activated by trypsin-like proteases, termed protease-activated receptor-2 (PAR-2). Previous studies describing PAR-2 expression on fibroblasts have been conflicting. In this report, we investigated in vitro PAR-2 expression on several fibroblast cell lines using flow cytometry, immunohistology, and immunoblots of cell lysates. Consistent PAR-2 expression was detected in cultured fibroblasts, although we observed heterogeneity of cellular expression among the cell lines. Some fibroblast lines expressed PAR-2 predominantly as an intracellular protein with differing cytoplasmic staining patterns, whereas other fibroblast lines displayed PAR-2 primarily as a cell surface receptor. Immunoblots of cell lysates with polyclonal anti-PAR-2 demonstrated a 44 kDa band, the predicted molecular weight for the PAR-2 core protein. Furthermore, we noted that expression of PAR-2 was subject to regulation. Fibroblasts grown within a collagen matrix downregulated receptor expression whereas increased PAR-2 expression was observed by the addition of fibroblast growth factors PDGF-BB and TGF-beta. This study may explain the previous inconsistencies in PAR-2 expression observed on tissue fibroblasts. Results indicate that the degree of fibroblast proliferation, attenuated by extracellular matrix and upregulated by growth factors, influences whether fibroblasts express PAR-2 and, thus, would be responsive to protease signaling.

Becaplermin↗
PubMed2003

Sample preparation technique and white cell content influence the detectable levels of growth factors in platelet concentrates.

BACKGROUND AND OBJECTIVES: Autologous platelet concentrate (PC) is applied locally to improve wound healing and tissue repair. Previous measurements of the growth factor content of platelets have given conflicting results. To date, there is no information on the influence of different preanalytical sample-preparation methods on the detectable amount of growth factors. MATERIALS AND METHODS: We measured the level of growth factors in PCs obtained by plateletpheresis and by leukapheresis. We subjected aliquots of these components to six different preparation methods: freezing/thawing once or twice; dissolution in 0.5% Triton-X-100; and clot formation by the addition of calcium and thrombin with subsequent incubation for 1 h, for 24 h, or for 1 h followed by freezing and thawing. RESULTS: In samples dissolved in Triton-X-100, higher levels of growth factors were detected than in the other specimens. In comparison to clot formation, freezing and thawing platelets twice was equivalent with respect to the release of platelet-derived growth factor (PDGF) but superior with respect to the release of transforming growth factor-beta1 (TGF-beta1). Overall, mean levels of 4.77 x 10(-16) g of PDGF-AB, 2.2 x 10(-17) g of PDGF-BB, and 2.41 x 10(-16) g of TGF-beta1 were found per single human platelet in white blood cell (WBC)-poor samples dissolved in Triton-X-100. CONCLUSIONS: Dissolving PC in Triton-X-100 releases maximum quantities of growth factors from platelets. The release of each growth factor by any sample preparation method should be investigated and interpreted separately. The preanalytical sample-preparation method, as well as the platelet and WBC content, influence the measurable levels of growth factors in PCs. The results implicate the need to correct, considerably upwards, previous estimations of the PDGF content of platelets.

Adult↗
PubMedDate not supplied

HB-107, a nonbacteriostatic fragment of the antimicrobial peptide cecropin B, accelerates murine wound repair.

Antimicrobial peptides are essential to innate host defense as effectors of pathogen clearance and can modify host cell behaviors to promote wound repair. While these two functions appear interrelated, it is unclear whether the ability to aid in wound repair requires inherent antimicrobial function. We hypothesized that the influence of antimicrobial peptides on wound repair is not dependent on antimicrobial function. To explore this, we analyzed the microbial killing activity of peptide fragments and correlated this with the ability to influence wound repair in mice. HB-107, a peptide lacking antimicrobial activity and originally derived from the antimicrobial cecropin B, showed up to 64 percent improvement in wound repair compared to scrambled peptide and vehicle controls, an effect comparable to treatment with recombinant human platelet-derived growth factor-BB (formulated as Regranex). Wounds treated with HB-107 showed keratinocyte hyperplasia and increased leukocyte infiltration. Furthermore, HB-107 stimulated interleukin-8 secretion from cultured endothelial cells, an effect that may explain the increase in leukocyte migration. These findings confirm that antimicrobial peptides can function as effectors of cutaneous wound repair. Moreover, this study furthers our understanding of antimicrobial peptides by showing that their wound repair properties can be independent of antimicrobial function.

Animals↗
PubMed2002

PDGF-BB induces MAP kinase phosphorylation and VEGF expression in neurofibroma-derived cultured cells from patients with neurofibromatosis 1.

Neurofibromas of neurofibromatosis 1 (NF1) are highly vascular. Because the number of PDGF beta receptors in neurofibroma-derived cultured cells (NF-derived cells) has been reported to be increased, we tested whether platelet-derived growth factor BB (PDGF-BB) could induce expression of vascular endothelial growth factor (VEGF) in NF-derived cells. When analysed by reverse transcription-polymerase chain reaction, VEGF mRNA expression was found to be stimulated by PDGF-BB and TGF-beta1. Those growth factors stimulated the secretion of VEGF from NF-derived cells. PDGF-BB furthermore induced the mitogen-activated protein kinase phosphorylation in NF-derived cells from patients with NF1. In conclusion, PDGF-BB stimulated VEGF secretion in NF-derived cells, and this stimulation is probably important in neurofibroma hypervascularization.

Aged↗
PubMed2005

Hypoxia-inducible factor-1alpha is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer.

AIMS: Hypoxia-inducible factor-1 (HIF-1) is the key transcription factor regulating the cellular response to hypoxia, including angiogenesis. Growth factors play an important role in tumour growth and angiogenesis and some have been shown to be induced by HIF-1 in vitro. This study investigated if angiogenesis or growth factors or their receptors are associated with HIF-1alpha in invasive breast cancer. METHODS AND RESULTS: High levels of HIF-1alpha, detected by immunohistochemistry in 45 breast cancers, were positively associated with increased microvessel density (as a measure of angiogenesis) (P = 0.023). Furthermore, high levels of HIF-1alpha were associated with epithelial expression (> or = 10%) of epidermal growth factor receptor (EGFR) (P = 0.011), platelet-derived growth factor (PDGF)-BB (P < 0.001), and basic fibroblast growth factor (bFGF) (P = 0.045). A positive, yet insignificant, trend for HIF-1alpha to be associated with epithelial expression of transforming growth factor (TGF)-alpha (P = 0.081) and vascular endothelial growth factor (VEGF) (P = 0.109) was noticed as well as an inverse association with stromal expression of TGF-beta-R1 (P = 0.070). CONCLUSIONS: In invasive breast cancer, HIF-1alpha is associated with angiogenesis, and expression of growth factors bFGF and PDGF-BB, and the receptor EGFR. Thus, agents targeting HIF-1 may combine different pathways of inhibiting breast cancer growth, including angiogenesis and growth factors.

Autocrine Communication↗