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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interstitial fibrosis is a marker of progression of renal impairment in diabetic nephropathy. Transforming growth factor (TGF)-beta 1 is one of a group of pro-fibrotic cytokines and growth factors that have been associated with the development of interstitial fibrosis. We have examined the modulating influence of glucose on the production of TGF-beta 1 by cultured human proximal tubular cells. Incubation of growth-arrested human proximal tubular cells (HPTC) (72 hours in serum free medium) in 25 mmol/L D-glucose resulted in increased expression of TGF-beta 1 mRNA (as assessed by reverse transcription polymerase chain reaction). This was apparent after 6 hours and increased up to 120 hours exposure. TGF-beta 1 secretion, however, as measured by specific enzyme-linked immunoassay, was unaffected by exposure to 25 mmol/L D-glucose. Sequential stimulation of HPTC, first with 25 mmol/L D-glucose for 48 hours and then with platelet-derived growth factor (PDGF) isoforms, resulted in a dose-dependent secretion of TGF-beta 1. Pre-exposure to 5 mmol/L D-glucose or 25 mmol/L L-glucose did not prime for TGF-beta 1 release. At 50 ng/ml PDGF this effect was greatest for the AA isoform (AA 31.4 +/- 7.1, AB 20.98 +/- 8.9, BB 7.8 +/- 2.2, P < 0.05 for all versus control, n = 3, mean +/- SEM ng/10(6) cells/24 hours). These effects were blocked by the addition of antibody to the PDGF alpha-receptor. TGF-beta 1 secretion was inhibited in a dose-dependent manner by pretreatment with cyclohexamide, but was not affected by pretreatment with actinomycin D. Stimulation of HPTC with a single dose of PDGF induced TGF-beta 1 mRNA; however, only after application of a second dose of PDGF (after TGF-beta 1 mRNA induction) did TGF-beta 1 protein secretion occur. We also demonstrated that PDGF stimulation of HPTC induced an inherently more stable TGF-beta 1 mRNA transcript. These findings demonstrate that elevated D-glucose concentration alone is insufficient to lead to increased TGF-beta 1 secretion by HPTC despite increased mRNA expression. However, application of a second stimulus such as PDGF, when TGF-beta 1 mRNA expression is increased, leads to increased protein synthesis and secretion of TGF-beta 1. This implies that elevated glucose concentrations might prime proximal tubular cells for TGF-beta 1 synthesis and thus contribute to the development of interstitial fibrosis.
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PMID:Elevated D-glucose concentrations modulate TGF-beta 1 synthesis by human cultured renal proximal tubular cells. The permissive role of platelet-derived growth factor. 763 30

The platelet content of platelet-derived growth factor (PDGF), a mitogen stored in the alpha-granules, was studied during preparation and storage of platelet concentrates (PC) and compared to the growth-promoting activity of platelets, beta-thromboglobulin (beta-TG) and lactate dehydrogenase (LD). We compared PC prepared from platelet-rich plasma (PRP-PC; n = 10) and from buffy coat. Two different pre-preparation storage periods of the buffy coat were used: 4 h (BC-PC:4h; n = 10) and 24 h (BC-PC:24h; n = 5). The platelet content of PDGF and beta-TG was measured by a RIA technique and the growth-promoting activity by incorporation of 3H-thymidine in stimulated fibroblasts. The platelet content of PDGF, beta-TG and the growth-promoting activity of the platelets decreased in a similar way during preparation and storage of PRP-PC (31 +/- 2, 35 +/- 2 and 33 +/- 7%, respectively, at day 5 of storage; mean +/- SEM). The release of LD was minor (3.9 +/- 0.5% at day 5). At day 1 of storage the platelet content of PDGF was significantly better preserved in BC-PC:4h than in BD-PC:24h (88 +/- 2 and 81 +/- 3%, respectively; p = 0.03). Comparing BC-PC:4h and PRP-PC we found a significantly better preservation of PDGF in BC-PC:4h until day 3 of storage (80 +/- 2 and 75 +/- 1%, respectively at day 3; p = 0.046). In conclusion the preparation of PC according to the PRP method initially induces a higher loss of PDGF, and hence of the growth-promoting activity, than the BC method.
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PMID:Growth factor release during preparation and storage of platelet concentrates. 766 Jun 37

The mechanism by which phenytoin (PHT) induces gingival overgrowth remains unclear. We hypothesized that PHT increases macrophage production of platelet-derived growth factor (PDGF), an important cytokine in connective tissue growth and repair, and that excessive production PDGF in gingiva could lead to redundant growth. To test the hypothesis, rat peritoneal macrophages and human blood monocytes were cultured in the presence of PHT (5 to 20 micrograms/ml medium) or an equal volume of its solvent for 3 days and tested for expression of PDGF-B mRNA by in situ hybridization. Approximately 300 cells/culture well were examined (3 wells/drug level) for positive indication of PDGF-B mRNA. Data were compared by chi square test. All levels of PHT in both cell types induced a 2- to 8-fold increase in PDGF-B mRNA positive cells, significant in all cases at P < 0.001. Northern blot analysis of RNA from similarly cultured rat macrophages confirmed these findings. Cells treated with 10 micrograms PHT/ml medium or solvent revealed 2.2 +/- 0.3 and 1.0 +/- 0.2 (mean +/- SEM) arbitrary units PDGF mRNA respectively (t tests, P < 0.05). Additionally, rat macrophages were cultured in presence of 5 micrograms PHT/medium or its solvent and medium was analyzed for PDGF secretion by radioimmunoassay. Mean values (+/- SEM) were 1.28 +/- 0.49 and 0.78 +/- 0.07 ng/mg protein respectively (t test, P < 0.05). These data showed that PHT augmented the expression of c-sis, the gene for PDGF-B, and offered a possible explanation for PHT-induced gingival overgrowth.
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PMID:Phenytoin increases gene expression for platelet-derived growth factor B chain in macrophages and monocytes. 846 38

Fibrosing alveolitis (FA) is a major and often fatal complication of systemic sclerosis (SSC). The critical role of fibroblasts in the pathogenesis of FA has long been recognized. Characterization of fibroblast activation in the lungs may improve our understanding and the management of this disease. We analyzed bronchoalveolar lavage (BAL) fluid samples from 9 healthy controls and 43 patients with FA caused by lung involvement form SSC. The chemoattractant activity (CAA) of cultured human fibroblasts elicited by native BAL fluid was measured in Boyden chambers. In addition, procollagen III peptide was measured in BAL fluid as a marker of collagen synthesis. CAA (expressed as percentage of the chemoattractant effect of 0.25 ng/ml platelet-derived growth factor; PDGF) was elevated in the SSC patients compared with that of the controls (control: 12.6 +/- 4.0%; SSC: 68.8 +/- 15.2%; p < 0.01). A positive correlation was found between BAL total cell count and CAA (r = 0.60, p < 0.01). An inverse correlation existed between CAA and total lung capacity (r = -0.55, p < 0.05). The patients were followed up for 13.3 +/- 1.4 months (mean +/- SEM). Twenty-seven patients received immunosuppressive therapy, whereas 16 refused therapy. The patients were assigned to two groups according to their CAA being lower or higher than 36% of the PDGF response (= mean value of the controls + 2 SD).
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PMID:Pathogenetic and clinical significance of fibroblast activation in scleroderma lung disease. 857 17

It has been proposed that healthy gingiva is in a continuous state of wound repair. Thus, one might expect to find cells in normal gingiva producing growth factors associated with wound healing such as platelet-derived growth factor B chain (PDGF-B). One might also expect to find increased numbers of these cells or increased amounts of these growth factors in conditions which involve increased tissue volume such as drug-induced gingival overgrowth (DGO). The purpose of this study was to quantify PDGF-B gene expression and identify cells producing PDGF-B in normal gingiva and DGO. Cyclosporine A (CSA) was selected as a prototype of the overgrowth condition. Twelve patients with clinical CSA DGO and 12 patients with no DGO or history of drugs known to cause DGO were selected for study. Frozen sections of gingival specimens from these patients were subjected to in situ hybridization for PDGF-B mRNA. Positive cells were counted and expressed as mean +/- SEM cells/mm2 of lamina propria. Morphometric analysis revealed 6.2 +/- 1.9 cells/mm2 for control gingiva and 10.3 +/- 3.4 cells/mm2 for CSA DGO samples. There was no statistically significant difference between groups. PDGF-B gene expression was measured in these cells and expressed as mean +/- SEM silver grains/cells. There was a significant upregulation of PDGF-B gene expression in cells from the CSA DGO group (39.5 +/- 14.7 silver grains/cell for normal gingiva vs. 255.3 +/- 77.1 silver grains/cell for CSA DGO samples; P < 0.001). The presence of PDGF-B in these cells was confirmed in all cases by immunocytochemical localization. Additionally, PDGF-B producing cells were identified as macrophages in sections taken from an additional patient with CSA DGO by double immunofluorescence labeling of the CD51 membrane marker for macrophages and intracellular PDGF-B. These findings are consistent with the concept that healthy gingiva is in a continuous state of wound repair and support the hypothesis that CSA DGO is associated with enhanced macrophage PDGF-B gene expression rather than an increase in the number of PDGF-B producing macrophages.
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PMID:PDGF-B producing cells and PDGF-B gene expression in normal gingival and cyclosporine A-induced gingival overgrowth. 870 59

Thiazolidinediones, insulin-sensitizing agents that lower insulin and lipid levels in insulin-resistant states, block agonist-induced Ca2+ entry into vascular smooth muscle (VSM) cells in vitro and lower blood pressure in animals and humans in vivo. In this study, we investigated the effects of ciglitazone and troglitazone on cell growth and DNA synthesis (as thymidine incorporation), and differentiation in cultured human aorta (haVSM) and human coronary artery (hcaVSM) VSM cells. Mitotically quiescent haVSM cells were stimulated with serum or platelet-derived growth factor (PDGF). Ciglitazone (40 micromol/L) inhibited haVSM cell proliferation by 84 +/- 16% (mean +/- SEM) (P < .05, n = 3), and serum and PDGF stimulated [3H]-thymidine incorporation by 91 +/- 18% (P < .03, n = 3) and 73 +/- 14% (P < .03, n = 4), respectively. Troglitazone (5 micromol/L) inhibited proliferation of haVSM cells by 78 +/- 14% (P < .05, n = 3) and hcaVSM cells by 91 +/- 18% (P < .05, n = 3). Proliferating VSM cells (synthetic phenotype) expressed small amounts of alpha-actin, whereas nonproliferating VSM cells (contractile phenotype) exhibited abundant alpha-actin. Exposure of proliferating haVSM cells to 40 micromol/L ciglitazone induced a marked increase in alpha-actin staining, consistent with transition to the well differentiated, contractile phenotype. To the extent that thiazolidinediones similarly affect growth factor-induced proliferation and differentiation of arterial myocytes in vivo, these agents may be useful in treating atherosclerosis and in preventing restenosis after angioplasty.
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PMID:Effects of thiazolidinediones on growth and differentiation of human aorta and coronary myocytes. 912 11

Periodontitis is a chronic inflammatory disease characterized by a progression that is very much dependent on host response. The gingiva can be considered to be in a constant state of wounding (pathologic wounding by bacterial plaque) and a constant state of maintenance/repair. In this context, any metabolic disturbance in the host which compromises tissue repair/wound healing will exacerbate the progression of periodontitis. Diabetes presents an interesting example because two major complications of diabetes are delayed wound healing and periodontitis. Our previous studies indicate that delayed wound healing and periodontitis may be manifestations of a general systemic deficit in diabetes involving alteration of macrophage cytokine gene expression. The present study was designed to determine whether: 1) diabetes-induced metabolic alterations affect gingival cytokine levels; and 2) diabetes-induced metabolic alterations modify the gingival cytokine profile in periodontitis. Sprague-Dawley rats (N=12/group) were injected with streptozotocin (65 mg/kg) into the tail vein to induce diabetes (defined by blood glucose levels > 250 mg/dl) or received the injection vehicle or no treatment as controls. Periodontitis was induced in additional groups of diabetic and control rats by gavage with Porphyromonas gingivalis A7436. After 90 days, serum glucose was analyzed to document diabetes; alveolar bone level was measured to document severity of periodontitis; gingiva was harvested circumferentially from the first and second molars; and cytokines in gingival homogenates were assayed by ELISA using commercial kits. Cytokine levels were expressed as mean+/-SEM pg/microg protein. Diabetes alone did not alter the gingival cytokine profile for platelet-derived growth factor B (PDGF-B), interleukin 1-beta (IL-1beta), transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha). Periodontitis alone demonstrated a significant increase (P < 0.05) in levels of PDGF-B and IL-1beta. Diabetes superimposed on periodontitis prevented these increases. Thus, diabetes-induced metabolic alterations do not affect gingival cytokine levels per se; however, they do alter the normal host response to periodontitis through blockage of periodontitis-induced increases in PDGF-B and IL-1beta.
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PMID:Diabetes prevents periodontitis-induced increases in gingival platelet derived growth factor-B and interleukin 1-beta in a rat model. 952 9

The expression of platelet-derived growth factor-A (PDGF-A) mRNA was examined in the cotyledons of normal human placentae and those from patients with pre-eclampsia. These patients exhibited pre-delivery blood pressure of 154+/-4/99+/-4 mmHg (mean+/-SEM) and met the criteria established for pre-eclampsia. During labour they received MgSO4 infusion for various time intervals (4-25 h). The PDGF-A message was quantitated to beta-actin by the solution hybridization nuclease protection assay. Since the two groups differed in two parameters (pre-eclampsia and MgSO4 treatment), the direct comparison was not feasible. An analysis of covariance revealed a significant difference in the message between the pre-eclamptic and control groups (P<0.01); the gestational age was not a significant covariate for either group but the time on MgSO4 in pre-eclampsia group was significant (P<0.002). A linear regression analysis of PDGF-A mRNA values for the pre-eclamptic group showed a time-dependent downregulation of the message by MgSO4 (P<0.01, r=- 0.796). These results show a uniform expression of PDGF-A mRNA in cotyledons of normal human placenta between 35 and 40 weeks of gestation. Furthermore, MgSO4 has an inhibitory effect on the expression of this message which may have aside from its anticonvulsive action beneficial effect on the function of pre-eclamptic placenta.
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PMID:Expression of platelet-derived growth factor-A mRNA in human placenta: effect of magnesium infusion in pre-eclampsia. 969 64

Sclerosing basal cell carcinoma (S-BCC) is characterized by an abundant stroma. There is evidence that some tumor cells secrete cytokines that are mitogenic for stromal fibroblasts (FBs). From this study we report increased glycosaminoglycan (GAG) production by cultures of S-BCC FBs in comparison to cultures of nodular BCC (N-BCC) FBs and normal skin FBs. GAG production was measured by cetylpyridinium chloride precipitation of incorporated [3H]-glucosamine. The sclerosing BCC FBs demonstrated a significant increase in production of GAG over control FBs (P <.001) and over N-BCC FBs (P<.001). Values reported as a mean percentage +/- SEM for GAG production by S-BCC over control normal skin FBs are 359+/-28 and over N-BCC FBs are 266+/-27. In additional experiments, cell extract dilutions from S-BCC tumor, normal dermis, and normal epidermis were incubated with cultures of normal skin FBs. S-BCC-conditioned media was also incubated with normal FBs and GAG production was measured. For both S-BCC extracts and conditioned media, a dose response curve was established showing increased GAG production by normal FBs in relation to increasing the concentration of S-BCC extract or conditioned media. When S-BCC extract was added to normal FBs there was increased GAG production in comparison to normal FBs incubated with dermal or epidermal extracts (P<.001) for both. Two growth factors, transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF), already known to be mitogenic for FBs, were incubated with N-BCC and normal FBs in an effort to elucidate the potential cytokine(s) released by S-BCC, causing increased GAG production by surrounding FBs. Neither of these cytokines proved to be effective in promoting a significant increase in GAG production. Our findings support the hypothesis that BCCs release factors that alter stromal FB production of GAG.
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PMID:Increased glycosaminoglycans production in sclerosing basal cell carcinoma-derived fibroblasts and stimulation of normal skin fibroblast glycosaminoglycans production by a cytokine-derived from sclerosing basal cell carcinoma. 1109 89

DNA-Hyaluronan (DNA-HA) matrix formulations intended for use as gene delivery systems have been developed and their potential for delivering DNA encoding a model therapeutic cytokine, platelet-derived growth factor (PDGF), has been evaluated. The results of enzyme-mediated release kinetics studies suggested that the rate of DNA release from the DNA-HA matrices could be modulated by changing the DNA loading or the degree of crosslinking. SEM imaging of the DNA-HA matrix showed that it was gradually eroded by enzymatic action. The results of gel electrophoresis suggested that there was some degree of interaction between DNA and native HA and that portions of the DNA released from the DNA-HA matrices were associated with crosslinked HA fragments. Only fractions of the DNA released from the DNA-HA matrices were free and the rest was entrapped by HA fragments, which could serve as a mechanism for DNA protection. The results from cell transfection studies using DNA samples collected during the course of release studies confirmed this hypothesis. The PDGF produced by transfection of the DNA released from DNA-HA matrices induced human dermal fibroblast cells to proliferate.
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PMID:Characterization of DNA-hyaluronan matrix for sustained gene transfer. 1276 9


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