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At least 739 records · Page 41Linked to original sources
PubMed2001

Effect on the healing of periapical perforations in dogs of the addition of growth factors to calcium hydroxide.

The purpose of this study was to investigate the effect of the addition of platelet-derived growth factor-BB and insulin-like growth factor-I to calcium hydroxide in the repair of apical perforations in dogs. Fifty-one premolar teeth of four beagle dogs were used. After developing periapical lesions root apices were artificially perforated. The teeth were divided into the three groups: group 1, the apical perforations were not sealed; group 2, the perforated areas were obturated with calcium hydroxide; and group 3, calcium hydroxide plus growth factors was applied to the sites of perforation. All canals were filled by a lateral condensation technique. Animals were killed 12 wk later, and sections were hematoxylin & eosin-stained and immunostained for osteonectin. The amount of inflammation was evaluated histomorphologically. The one-way ANOVA test demonstrated that the three groups were significantly different from one another. In group 3 there was no inflammatory reaction of apical tissue, and the connective tissue adjacent to the newly formed hard tissue was strongly immunostained for osteonectin. Most sections in group 1 showed no apical healing. Moderate healing was found in group 2. In conclusion the combination of platelet-derived growth factor-BB and insulin-like growth factor-I with calcium hydroxide improved healing of apical perforation in dogs.

Alveolar Bone Loss↗
PubMed1997

Effects of growth factors on acid-induced damage to rat gastric epithelial cells.

We previously established a model of cell damage induced by an acidified medium in the rat gastric epithelial cell line RGM1. Treatment of the cells with epidermal growth factor (EGF, 1-10 ng/ml) for 4 h prevented acid-induced cell damage in a concentration-dependent manner. In contrast, basic fibroblast growth factor (1-10 ng/ml) and platelet-derived growth factor BB (1-10 ng/ml) had no effect on cell damage. EGF did not affect DNA synthesis by the cells for 4 h. Pretreatment of the cells with cycloheximide (10 micrograms/ml) for 1.5 h before EGF treatment significantly attenuated the cytoprotective effect of EGF by > 50%. Replacement of Na+ with K+ in the acidified medium totally abolished the effect of EGF. Co-incubation with amiloride (1 mM) had no influence on the protective effect of EGF. These results indicate that the cytoprotective effect of EGF appears to involve both the activation of amiloride-resistant Na+/H+ exchangers and the synthesis of a new protein related to Na+/H+ exchangers.

Amiloride↗
PubMed1997

The role of platelet-derived growth factor-BB-induced increase in cytosolic free Ca2+ in activation of mitogen-activated protein kinase and DNA synthesis in vascular smooth muscle cells.

BACKGROUND: Platelet derived growth factor (PDGF)-BB is an important vascular smooth muscle cell (VSMC) mitogen. PDGF-BB induces an increase in intracellular free calcium concentration ([Ca2+]i), an activation of mitogen-activated protein (MAP) kinase and an increase in DNA synthesis. The increase in [Ca2+]i is thought to be an important second messenger in the intracellular signalling cascade, leading to growth of VSMC. OBJECTIVE: The aim of the present study was to elucidate the role of the PDGF-BB-induced increase in [Ca2+]i in the activation of MAP kinase and increase in DNA synthesis. Binding of [Ca2+]i was performed by the intracellular chelator bis-(2-amino-5-methylphenoxy) ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (MAPTAM). METHODS: Ca2+ levels were measured by the Fura-2 method. MAP kinase activation was determined by Western blotting. DNA synthesis was determined by measurement of incorporation of [3H]-thymidine into the cell DNA. RESULTS: Administration of 50 ng/ml PDGF-BB induced an increase in [Ca2+]i, an activation of MAP kinase and an increase in DNA synthesis. In bis-(2-amino-5-methylphenoxy) ethane-N,N,N'N'-tetraacetic acid tetraacetoxymethyl ester (MAPTAM)-treated cells the PDGF-BB-induced effect on [Ca2+]i was totally blunted, whereas no effect on MAP kinase activation and DNA synthesis could be observed. CONCLUSIONS: These findings show that the effect of PDGF-BB on MAP kinase activation is independent of calcium level. [Ca2+]i might be implicated in the PDGF-BB-induced mitogenic process only in conjugation with other signalling components.

Animals↗
PubMed1997

Tyrosine kinase inhibitor markedly suppresses the development of coronary lesions induced by long-term treatment with platelet-derived growth factor in pigs in vivo.

Platelet-derived growth factor (PDGF) plays an important role in the development of coronary atherosclerosis. However, it remains to be examined what morphologic and functional changes are induced in vivo by the long-term treatment with PDGF itself or what pharmacologic interventions could suppress those changes in vivo. Our study was designed to address these points. We examined the effects of long-term treatment with PDGF on the porcine coronary artery in vivo. Under aseptic conditions, the proximal segments of the left porcine coronary artery were gently wrapped with cotton mesh absorbing sepharose beads either with or without recombinant human PDGF-AA or -BB. Two weeks after the operation, coronary hyperconstrictions to intracoronary serotonin or histamine were noted at the sites treated with PDGF-AA or -BB. Histologically, neointimal formation and geometric remodeling (reduction of the total vessel area) were noted at the PDGF-treated sites. These functional and histologic changes of the coronary artery induced by PDGF were markedly inhibited by cotreatment with ST 638, a specific inhibitor of tyrosine kinases. A Western blot analysis showed that ST 638 markedly suppressed the PDGF-induced tyrosine phosphorylations in the coronary segment. These results indicate that long-term treatment with PDGF induces neointimal formation, geometric remodeling, and vasospastic responses in vivo, for all of which, activation of tyrosine kinases is substantially involved.

Absorption↗
PubMed2003

Promoting healing with recombinant human platelet-derived growth factor--BB in a previously irradiated problem wound.

OBJECTIVES/HYPOTHESIS: Persistent, poorly healing wounds are a significant clinical problem in patients who have had previous irradiation. Despite current treatments, refractory nonhealing soft tissue wounds persist. The study described one of the earliest reported uses of recombinant human platelet-derived growth factor-BB (rhPDGF) gel to improve the healing of a previously irradiated refractory dermal wound to the neck that had been present for 12 years. STUDY DESIGN: Case report and literature review. METHODS: Review of local healing management of previously irradiated wounds and review of patients chart one year after follow-up treatment. RESULTS: A 47-year-old man had a 12-year history of a persistent, painful, nonhealing full-thickness dermal wound on the left side of his neck after radiation therapy and chemotherapy for a T2N2bM0 nasopharyngeal carcinoma. He had been tumor free for 12 years. Despite multiple modalities of therapy over a 1-year period (including moist hydrogel dressings, topical and oral antibiotics, serial debridement, and hyperbaric oxygen), the wound did not heal. After 6 months of topical rhPDGF gel treatment, sufficient granulation tissue developed within the dermal wound that a split-thickness skin graft was successfully performed. Symptomatically, the patient's continuous pain at the neck resolved after rhPDGF treatment. Serial histological biopsy specimens before and after rhPDGF treatment confirmed the wound transformation from a chronic state to a short-term healing state. CONCLUSION: In previously irradiated tissue, rhPDGF can be useful in helping refractory wounds to heal by inducing further granulation formation. If such treatment is planned, the patient should be informed of the possible theoretical risks of its use when it is in proximity to a previously treated neoplastic site.

Administration, Topical↗
PubMed1997

Differential effects of platelet-derived growth factor BB in accelerating wound healing in aged versus young animals: the impact of tissue hypoxia.

Platelet-derived growth factor BB (PDGF-BB) plays a central role in wound healing. Platelet-derived growth factor has been shown to accelerate healing in preclinical and clinical studies, but its wound-healing effects in older animals have not been examined. An ischemic incisional model in young female (5 months) and aged male (60 months) rabbits was used to determine the influence of platelet-derived growth factor on day 14 postwounding with reduced blood supply. Wounds in aged ischemic animals were severely impaired in breaking strength compared with their nonischemic control wounds and wounds in young animals (p < 0.001). Topical platelet-derived growth factor (10 microg per wound) partially reversed the reduction in breaking strength in aged ischemic animals but was ineffective in young animals. Histologic studies showed that new granulation tissue deposition and mononuclear cell infiltration was dramatically lower in ischemic wounds of aged animals compared with their control wounds as well as wounds from young animals under both nonischemic and ischemic conditions. Platelet-derived growth factor partially reversed this deficit in old ischemic wounds but not in young ischemic wounds. Epithelial growth was reduced in wounds from aged animals compared with wounds from young animals after 14 days of healing. Platelet-derived growth factor treatment increased ischemic wound epithelial growth in aged ischemic animals about threefold compared with paired controls. In conclusion, wound healing in aged rabbits was severely impaired by ischemia, and a single topical platelet-derived growth factor treatment partially reversed this deficit.

Aging↗
PubMed1998

Augmentation of skeletal muscle flap survival using platelet derived growth factor.

Distal muscle flap ischemia and necrosis is a recognized complication of acute elevation of large skeletal muscle flaps. The aim of this study was to investigate whether the angiogenic properties of platelet derived growth factor (PDGF) could be used to augment skeletal muscle flap survival through the induction of new blood vessel formation before flap elevation. We compared this form of flap augmentation with that achieved by subjecting the muscle to a bipedicled vascular delay procedure. The animal model used was the latissimus dorsi muscle of the male homozygous (hr/hr) hairless mouse. Four groups of animals were investigated in this study (n = 10 per group). Group 1 was the control group in which the entire muscle was elevated as a thoracodorsally based island flap. In group 2, the muscle was subjected to a bipedicled vascular delay procedure. In group 3, the muscle was treated with 500 microg of recombinant human platelet derived growth factor BB. In group 4, the muscle was treated with placebo. Ten days later the entire latissimus dorsi muscle was elevated as a thoracodorsally based island flap in groups 2, 3, and 4. Percentage muscle flap survival was quantitated in all groups 5 days after elevation of the entire muscle. Angiogenesis was then quantitated by analyzing capillary to muscle fiber ratios after alkaline phosphatase staining of representative latissimus dorsi muscle samples from the proximal, middle, and distal flap segments. Percentage muscle flap survival was significantly better in PDGF treated muscles when compared with the vascularly delayed muscles (p < 0.001). Histologic analysis of latissimus dorsi muscle flaps demonstrated a significantly greater number of capillaries in the middle (p < 0.001) and distal (p < 0.001) flap segments of PDGF-treated flaps when compared with the vascularly delayed flaps. Treatment of skeletal muscle with PDGF before flap creation resulted in survival of the entire muscle flap. Our results suggest that this survival may be secondary to PDGF-induced angiogenesis.

Animals↗
PubMed2002

Factors in the fracture microenvironment induce primary osteoblast angiogenic cytokine production.

Neoangiogenesis is essential for successful wound repair. Platelets are among the earliest cells recruited to a site of skeletal injury and are thought to provide numerous factors critical to successful repair. The release of platelet-derived growth factor (PDGF) after skeletal injury increases osteoblast proliferation, chemotaxis, and collagen synthesis; however, its angiogenic effect on osteoblast biology remains unknown. The purpose of this study was to investigate the effect of recombinant human (rh)PDGF-BB on the synthesis of vascular endothelial growth factor (VEGF) by primary neonatal rat calvarial osteoblasts. Furthermore, the authors investigated whether PDGF works in concert with hypoxia, another component of the fracture microenvironment, to additively or synergistically induce VEGF production. Osteoblast cultures were stimulated with varying concentrations of rhPDGF-BB (1, 10, 50, and 100 ng/ml) in normoxic and hypoxic (<1% oxygen) conditions for 0, 3, 6, 12, and 24 hours, and VEGF gene expression was analyzed by Northern blot analysis. To determine whether rhPDGF-BB-induced VEGF messenger RNA (mRNA) expression was transcriptionally mediated or required de novo protein synthesis, transcription, and translation, studies were performed using actinomycin D and cycloheximide, respectively. Treatment with 50 ng/ml rhPDGF-BB resulted in a 2.4-fold increase in VEGF mRNA expression after 3 hours. Interestingly, rhPDGF-BB and hypoxia seemed to have an additive effect, resulting in a 3.7-fold increase in VEGF mRNA expression after 6 hours in primary neonatal rat calvarial osteoblasts. Furthermore, by using actinomycin D and cycloheximide, the authors demonstrated that the rhPDGF-BB-induced VEGF mRNA expression was transcriptionally mediate and not dependent on de novo protein synthesis. These data demonstrate that rhPDGF-BB transcriptionally increases osteoblasts VEGF mRNA expression in vitro. Furthermore, the semiquantitative results suggest that rhPDGF-BB and hypoxia act additively to increase VEGF mRNA expression. It is postulated that similar mechanisms may occur in vivo, at a site of skeletal injury, to induce neoangiogenesis and promote fracture repair.

Animals↗
PubMed1998

Exposure of vascular allografts to insulin-like growth factor-I (IGF-I) increases vascular expression of IGF-I ligand and receptor protein and accelerates arteriosclerosis in rats.

BACKGROUND: Accelerated arteriosclerosis limits the survival of transplanted hearts. We hypothesized that insulin-like growth factor-I (IGF-I) is crucial in accelerating transplant arteriosclerosis. Recently, we reported that exposure to IGF-I prior to transplantation accelerates transplant arteriosclerosis in the rat aorta allograft model. Here, we studied the mechanism whereby IGF-I exposure accelerates transplant arteriosclerosis. METHODS: The abdominal aorta was harvested from male Brown Norway rats and exposed to 0, 200, or 500 ng/ml of IGF-I at 37 degrees C for 30 min prior to transplantation to the abdominal position of male Lewis rats. The allografts were harvested 14 days later and processed for immunohistochemical staining for alpha-actin, growth factors (IGF-I, IGF-I receptor, platelet-derived growth factor-BB, and basic fibroblast growth factor), and immunological markers (major histocompatibility complex class II antigen, macrophage, and CD4- and CD8-positive T cells). RESULTS: By 14 days, the ex vivo IGF-I donor aorta treatment with IGF-I increased in a concentration-dependent manner the expression of IGF-I and IGF-I receptor in both the intima and the adventitia. In contrast, the expression of platelet-derived growth factor-BB was decreased in a concentration-dependent manner in the intima while basic fibroblast growth factor remained unchanged. The cell-mediated immune response was not affected by IGF-I at 14 days after transplantation, which suggests that the immune events associated with acceleration of transplant arteriosclerosis may occur at an earlier time. CONCLUSION: Acceleration of transplant arteriosclerosis by exposure to IGF-I is associated with increased IGF-I ligand and receptor expression in the allograft vascular wall. These data further suggest that IGF-I may be a major factor in mediating graft arteriosclerosis.

Actins↗
PubMed2001

Early induction of platelet-derived growth factor ligands and receptors in acute rat renal allograft rejection.

BACKGROUND: Acute rejection is the single most important risk factor for the development of subsequent chronic rejection. Platelet-derived growth factor (PDGF) is a major mitogen that mediates mesenchymal cell proliferation in chronic rejection. Therefore, we investigated whether PDGF ligands and receptors are induced during acute renal allograft rejection in rat. METHODS: Kidney transplantations were performed from Dark Agouti (DA) to Wistar-Furth (WF) rats, and syngenic controls were performed from DA to DA rats. Allografts were immunosuppressed with cyclosporine (CsA) 1.5 mg/kg/d subcutaneously or left untreated. Grafts were harvested at 1, 3, 5, and 7 days for histology and immunohistochemistry. RESULTS: In syngenic grafts, no histological signs of acute rejection were seen and the expression of PDGF ligands and receptors remained almost nonexistent. In nontreated allografts, intense rejection resulted in graft necrosis in 7 days. Acute rejection was associated with the induction of all PDGF ligands and receptors (P<0.05 compared to syngenic controls). The expression of PDGF ligands and receptors was located mainly to graft-infiltrating macrophages but also to capillary endothelium and arteriolar smooth muscle cells. CsA significantly ameliorated acute rejection but failed to inhibit the induction of PDGF and its receptors in CsA-treated allografts. CONCLUSIONS: Our results demonstrate that PDGF ligands and receptors are induced during acute rejection. PDGF may be induced directly as a reparative response to graft injury in acute rejection or indirectly by various inflammatory mediators released by graft-infiltrating inflammatory cells. This study indicates that PDGF ligands and receptors are already induced in acute rejection, which suggests a link between acute rejection and the subsequent development of chronic rejection.

Acute Disease↗
PubMed2002

The effect of acute rejection and cyclosporin A-treatment on induction of platelet-derived growth factor and its receptors during the development of chronic rat renal allograft rejection.

BACKGROUND: In the development of chronic kidney allograft rejection acute rejection (AR) is the single most important risk factor. Although Cyclosporin A (CsA) medication has decreased the incidence of AR, chronic rejection (CR) is still the major reason for late allograft loss. Platelet-derived growth factor (PDGF) is a major mitogen mediating mesenchymal cell proliferation in CR. We have investigated the impact of AR and different doses of CsA on the expression of PDGF ligands and receptors in the development of CR. METHODS: Kidney transplantations were performed from DA to WF rats and syngenic controls were done from DA to DA rats. Two groups of allografts were treated daily with CsA either at low dose (1.5 mg/kg) or high dose (5 mg/kg). Third group of allografts was treated with CsA 5 mg/kg/day for 1 week and then left untreated until the development of AR. AR episodes were treated with CsA 5 mg/kg/day. Grafts were harvested 3 months after transplantation for histology and immunohistochemistry (PDGF-AA, -BB and PDGFR-alpha, -beta). RESULTS: In syngenic grafts no histological signs of CR were seen and the expression of PDGF ligands and receptors remained almost nonexistent. AR episodes increased the chronic rejection changes. High-dose CsA-treatment ameliorated inflammation compared to low-dose CsA-treatment, although it failed to inhibit the development of chronic changes. More fibrosis was even seen in high-dose than in low-dose CsA-treated grafts. CR in each allograft group was associated with induction of all PDGF ligands and receptors (P<0.05 compared with syngenic controls) in interstitial inflammatory cells, capillary endothelium, and arterial smooth muscle cells. In the group with AR episodes the expression was further increased. CONCLUSIONS: Our results demonstrate that CsA treatment cannot inhibit the expression of PDGF ligands and receptors in the development of chronic kidney allograft rejection and that AR episodes induce even more PDGF and its receptors in the graft indicating a link between AR and subsequent development of CR.

Animals↗
PubMed2005

Randomized clinical trial comparing OASIS Wound Matrix to Regranex Gel for diabetic ulcers.

OBJECTIVE: To compare healing rates at 12 weeks for full-thickness diabetic foot ulcers treated with OASIS Wound Matrix, an acellular wound care product, versus Regranex Gel. DESIGN: Randomized, prospective, controlled multicenter trial at 9 outpatient wound care clinics. SUBJECTS: A total of 73 patients with at least 1 diabetic foot ulcer were entered into the trial and completed the protocol. INTERVENTION: Patients were randomized to receive either OASIS Wound Matrix (n = 37) or Regranex Gel (n = 36) and a secondary dressing. Wounds were cleansed and debrided, if needed, at a weekly clinic visit. Dressings were changed as needed. The maximum treatment period for each patient was 12 weeks. PRIMARY OUTCOME MEASURE: Incidence of healing in each group at 12 weeks. RESULTS: After 12 weeks of treatment, 18 (49%) OASIS-treated patients had complete wound closure compared with 10 (28%) Regranex-treated patients. CONCLUSION: Although the sample size was not large enough to demonstrate that the incidence of healing in the OASIS group was statistically superior (P = .055), the study results showed that treatment with OASIS is as effective as Regranex in healing full-thickness diabetic foot ulcers by 12 weeks.

Administration, Cutaneous↗
PubMed2003

Differential contribution of three mitogen-activated protein kinases to PDGF-BB-induced mesangial cell proliferation and gene expression.

This study examined the role of mitogen-activated protein (MAP) kinase in PDGF-BB-induced proliferation and gene expression of human mesangial cells (MC). PDGF-BB stimulation of MC increased mRNA for transforming growth factor-beta1 (TGF-beta1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) and increased the cell numbers. To inhibit activation of extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38, MC were infected with recombinant adenovirus containing dominant-negative mutants of ERK, JNK, and p38 (Ad-DN-ERK, Ad-DN-JNK, Ad-DN-p38, respectively), respectively. Infection of MC with Ad-DN-ERK or Ad-DN-JNK inhibited PDGF-BB-induced increase in [(3)H]thymidine incorporation and cell numbers, whereas Ad-DN-p38 did not. Ad-DN-ERK inhibited MCP-1 and PAI-1 mRNA expression in MC, but not TGF-beta1. Ad-DN-JNK and Ad-DN-p38 inhibited TGF-beta1 and MCP-1 mRNA expression, but not PAI-1. The inhibition of activator protein-1 (AP-1) in MC, by adenovirus containing dominant-negative mutant of c-Jun (Ad-DN-c-Jun), inhibited PDGF-BB-induced cell proliferation and TGF-beta1, MCP-1, and PAI-1 expressions. Furthermore, Ad-DN-JNK or Ad-DN-p38, but not Ad-DN-ERK, attenuated PDGF-BB-induced AP-1 activation in MC, indicating the involvement of JNK and p38 in AP-1 activation. Our results indicated that ERK and JNK, but not p38, participated in PDGF-BB-induced MC proliferation. PDGF-BB-induced expression of TGF-beta1 was mediated by JNK and p38, MCP-1 expression was through ERK, JNK, and p38, whereas PAI-1 expression was due to only ERK. AP-1 activation, which was partially due to JNK and p38 activations, was involved in MC proliferation and these three gene expressions. Thus, three MAP kinases seem to contribute to progression of glomerular disease via different molecular mechanisms.

Adenoviridae↗
PubMed2003

Angiogenic protein Cyr61 is expressed by podocytes in anti-Thy-1 glomerulonephritis.

Dynamic recovery of glomerular structure occurs after severe glomerular damage in anti-Thy-1 glomerulonephritis (Thy-1 GN), but its mechanism remains to be investigated. To identify candidate genes possibly involved in glomerular reconstruction, screening was performed for genes that are specifically expressed by podocytes and are upregulated in glomeruli of Thy-1 GN. Among them, cysteine-rich protein 61 (Cyr61 or CCN1), a soluble angiogenic protein belonging to the CCN family, was identified. By Northern blot analysis, Cyr61 mRNA was markedly upregulated in glomeruli of Thy-1 GN from day 3 through day 7, when mesangial cell migration was most prominent. By in situ hybridization and immunohistochemistry, Cyr61 mRNA and protein were expressed by proximal straight tubules and afferent and efferent arterioles in normal rat kidneys and were intensely upregulated at podocytes in Thy-1 GN. Platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-beta1 (TGF-beta1), of which the gene expression in the glomeruli of Thy-1 GN was upregulated in similar time course as Cyr61, induced Cyr61 mRNA expression in cultured podocytes. Furthermore, supernatant of Cyr61-overexpressing cells inhibited PDGF-induced mesangial cell migration. In conclusion, it is shown that Cyr61 is strongly upregulated at podocytes in Thy-1 GN possibly by PDGF and TGF-beta. Cyr61 may be involved in glomerular remodeling as a factor secreted from podocytes to inhibit mesangial cell migration.

Angiogenesis Inducing Agents↗