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PubMed2005

Ellagic acid blocks activation of pancreatic stellate cells.

Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic fibrosis and inflammation. Ellagic acid is a plant-derived polyphenol found in fruits and nuts, and has anti-oxidant and anti-inflammatory properties. But, little is known about the effects of ellagic acid on PSCs as well as on the activation of signal transduction pathways. We here evaluated the effects of ellagic acid on the activation and cell functions of PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype unless otherwise stated. Ellagic acid inhibited platelet-derived growth factor (PDGF)-BB-induced proliferation and migration, interleukin (IL)-1beta- and tumor necrosis factor (TNF)-alpha-induced monocyte chemoattractant protein-1 production, and expression of alpha-smooth muscle actin and collagen genes. Ellagic acid inhibited PDGF-BB-induced tyrosine phosphorylation of PDGF beta-receptor and the downstream activation of extracellular signal-regulated kinase and Akt. Ellagic acid inhibited IL-1beta- and TNF-alpha-induced activation of activator protein-1 and mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase), but not of nuclear factor-kappaB. In addition, ellagic acid inhibited transformation of freshly isolated cells to an activated, myofibroblast-like phenotype. In conclusion, ellagic acid inhibited key cell functions and activation of PSCs.

Animals↗
PubMed2006

Chondroitin sulfate A chains enhance platelet derived growth factor-mediated signalling in fibrosarcoma cells.

Platelet derived growth factor is involved in the autocrine growth stimulation of malignant cells, the stimulation of angiogenesis and the recruitment and regulation of tumor fibroblasts. PDGF has been shown to physically interact with glycosaminoglycans which are abundant in the fibrosarcoma cell microenvironment. Aim of the present study was to examine the effects of glycosaminoglycans on the mitogenic function of platelet derived growth factor in two human fibrosarcoma cell lines (B6FS, HT1080). For this purpose exogenously added glycosaminoglycans, regulators of endogenous glycosaminoglycan synthesis (sodium chlorate as selective inhibitor and beta-D-xyloside as a stimulator) and specific glycosidases to cleave cell-associated glycosaminoglycans, were utilized. Platelet derived growth factor demonstrated a growth stimulating effect on B6FS, whereas no effect was evident on HT1080 fibrosarcoma cells. Beta-D-xyloside had no effect on the basal level or the platelet derived growth factor-induced cell proliferation, whereas sodium chlorate severely reduced the basal level of proliferation in both cell lines. Significant co-stimulatory effects of chondroitin sulfate A in combination with platelet derived growth factor BB on the growth of HT1080 and B6FS cells were found. The co-stimulatory effect of chondroitin sulfate A was not due to transcriptional up regulation of platelet derived growth factor receptors genes, but rather to more efficient signalling of tyrosine kinase receptors. In conclusion, this study shows that chondroitin sulfate A can enhance the mitogenic activity of platelet-derived growth factor in fibrosarcoma cells utilizing a pathway which involves tyrosine kinases. This result introduces a new modulating role for chondroitin sulfate in signalling pathways critical for cancer growth.

Becaplermin↗
PubMed2006

The effect of collagen-targeting platelet-derived growth factor on cellularization and vascularization of collagen scaffolds.

Platelet-derived growth factor BB (PDGF-BB) was an important inductive factor during wound healing, but the lack of efficient delivery system limited its clinical application. Here, a peptide of seven amino acids was firstly utilized to engineer PDGF-BB to construct a collagen-targeting system. This peptide functioned as collagen-binding domain (CBD) to specially target the PDGF-BB to the collagen and restrict its diffusion. In our study, in vitro activity assay showed that the CBD-fused PDGF (CBD-PDGF) and native PDGF (NAT-PDGF) possessed similar activity to stimulate the human fibroblast proliferation. As expected, this peptide promoted the binding of PDGF to collagen scaffolds, and CBD-PDGF caused more cells to proliferate on the collagen gel than NAT-PDGF when the same amounts of PDGF were added. In the in vivo experiment, CBD-PDGF-loaded collagen scaffolds were uniformly cellularized and vascularized compared to that of NAT-PDGF-loaded scaffolds. Our study demonstrated that the CBD targeted PDGF to the collagen scaffold to exert its functions, and it suggested this could be an effective system for targeting tissue regeneration and wound repair.

Animals↗
PubMed2004

Differential growth factor control of bone formation through osteoprogenitor differentiation.

The osteogenic factors bone morphogenetic protein (BMP-7), platelet-derived growth factor (PDGF)-BB, and fibroblast growth factor (FGF-2) regulate the recruitment of osteoprogenitor cells and their proliferation and differentiation into mature osteoblasts. However, their mechanisms of action on osteoprogenitor cell growth, differentiation, and bone mineralization remain unclear. Here, we tested the hypothesis that these osteogenic agents were capable of regulating osteoblast differentiation and bone formation in vitro. Normal human bone marrow stromal (HBMS) cells were treated with BMP-7 (40 ng ml(-1)), PDGF-BB (20 ng ml(-1)), FGF-2 (20 ng ml(-1)), or FGF-2 plus BMP-7 for 28 days in a serum-containing medium with 10 mM beta-glycerophosphate and 50 microg ml(-1) ascorbic acid. BMP-7 stimulated a morphological change to cuboidal-shaped cells, increased alkaline phosphatase (ALKP) activity, bone sialoprotein (BSP) gene expression, and alizarin red S positive nodule formation. Hydroxyapatite (HA) crystal deposition in the nodules was demonstrated by Fourier transform infrared (FTIR) spectroscopy only in BMP-7- and dexamethasone (DEX)-treated cells. DEX-treated cells appeared elongated and fibroblast-like compared to BMP-7-treated cells. FGF-2 did not stimulate ALKP, and cell morphology was dystrophic. PDGF-BB had little or no effect on ALKP activity and biomineralization. Alizarin Red S staining of cells and calcium assay indicated that BMP-7, DEX, and FGF-2 enhanced calcium mineral deposition, but FTIR spectroscopic analysis demonstrated no formation of HA similar to human bone in control, PDGF-BB-, and FGF-2-treated samples. Thus, FGF-2 stimulated amorphous octacalcium phosphate mineral deposition that failed to mature into HA. Interestingly, FGF-2 abrogated BMP-7-induced ALKP activity and HA formation. Results demonstrate that BMP-7 was competent as a sole factor in the differentiation of human bone marrow stromal cells to bone-forming osteoblasts confirmed by FTIR examination of mineralized matrix. Other growth factors, PDGF, and FGF-2 were incompetent as sole factors, and FGF-2 inhibited BMP-7-stimulated osteoblast differentiation.

Becaplermin↗
PubMed2006

Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation.

OBJECTIVE: Reactive oxygen species (ROS) produced by NAD(P)H oxidases (Nox) play a significant role in the pathophysiology of cardiovascular diseases. Expression and activity of NAD(P)H oxidases are regulated by growth factors such as angiotensin II and platelet-derived growth factor (PDGF). We characterized the effects of the novel Nox inhibitor VAS2870 on PDGF-dependent ROS liberation and cellular events in vascular smooth muscle cells (VSMC). METHODS AND RESULTS: PDGF-BB increased NAD(P)H oxidase activity (lucigenin-enhanced chemiluminescence) and intracellular ROS levels (detected by confocal laserscanning microscopy using 2,7-DCF) to 229+/-9% and 362+/-54% at 1 and 2 h, respectively. Preincubation with VAS2870 (10 and 20 microM) completely abolished PDGF-mediated NAD(P)H oxidase activation and ROS production. Since ROS are involved in various growth factor-induced cellular functions, the influence of VAS2870 on PDGF-induced DNA synthesis and chemotaxis was determined. PDGF promoted a 4.2+/-0.2-fold increase of VSMC migration (modified Boyden chamber, p<0.01) and increased DNA synthesis by maximally 3.2+/-0.4-fold (BrdU incorporation, p<0.01) in a concentration-dependent manner. Preincubation with VAS2870 (0.1-20 microM) did not affect PDGF-induced cell cycle progression. However, it abolished PDGF-dependent chemotaxis of VSMC in a concentration-dependent manner (100% inhibition at 10 microM). These findings were related to PDGF-dependent signaling events. Western blot analyses using phospho-specific antibodies revealed that the downstream signaling molecules Akt, Erk, and Src were activated by PDGF. However, VAS2870 blocked PDGF-dependent activation of Src, but not of Akt and Erk, in a concentration-dependent manner. CONCLUSIONS: VAS2870 effectively suppresses growth factor-mediated ROS liberation in VSMC. Furthermore, it completely inhibits PDGF-dependent VSMC migration, whereas it does not affect DNA synthesis. These divergent effects reflect the critical role of Src activity, which-in contrast to Akt and Erk-appears to be redox-sensitive and is absolutely required for PDGF-induced chemotaxis, but not cell cycle progression.

Animals↗
PubMed2004

PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis.

Cancer metastases are commonly found in the lymphatic system. Like tumor blood angiogenesis, stimulation of tumor lymphangiogenesis may require the interplay of several tumor-derived growth factors. Here we report that members of the PDGF family act as lymphangiogenic factors. In vitro, PDGF-BB stimulated MAP kinase activity and cell motility of isolated lymphatic endothelial cells. In vivo, PDGF-BB potently induced growth of lymphatic vessels. Expression of PDGF-BB in murine fibrosarcoma cells induced tumor lymphangiogenesis, leading to enhanced metastasis in lymph nodes. These data demonstrate that PDGF-BB is an important growth factor contributing to lymphatic metastasis. Thus, blockage of PDGF-induced lymphangiogenesis may provide a novel approach for prevention and treatment of lymphatic metastasis.

Animals↗
PubMed2005

Galectin-1 is an inductor of pancreatic stellate cell activation.

Pancreatic stellate cells (PSCs) play a key role in the development of pancreatic fibrosis, a pathological feature of chronic pancreatitis and pancreatic cancer. Here, we show that activation of rat PSCs in vitro is associated with increased expression of galectin-1 (gal-1) and that gal-1 modulates PSC function. Expression of the lectin was stimulated by fetal calf serum and platelet-derived growth factor. PSCs exposed to exogenous gal-1 proliferated at a higher rate and synthesised more collagen than controls. Gal-1-dependent collagen synthesis was blocked by lactose but not by cellobiose, suggesting that gal-1 acts on PSCs through targeting beta-galactoside-containing glycoconjugates. Analysis of gal-1 signalling in PSCs revealed an activation of the extracellular signal-regulated kinases 1 and 2 and enhanced DNA binding of AP-1 transcription factors. Together, our data implicate gal-1 in PSC activation and suggest further studies to analyse the role of endogenous lectins in the development of pancreatic fibrosis in vivo.

Actins↗
PubMed2005

Effects of separate application of three growth factors (TGF-beta1, EGF, and PDGF-BB) on mechanical properties of the in situ frozen-thawed anterior cruciate ligament.

OBJECTIVE: To clarify effects of a separate application of TGF-beta1, EGF, and PDGF-BB on the material properties of the in situ frozen-thawed anterior cruciate ligament. DESIGN: Twenty-eight rabbits were divided into four groups after undergoing the in situ freeze-thaw treatment in the right anterior cruciate ligament. In 3 of the 4 groups, 4 ng TGF-beta1, 20 ng EGF, and 4 microg PDGF-BB was applied to the frozen anterior cruciate ligament, respectively. In the remaining sham treatment group, only fibrin sealant as a vehicle was applied. Each animal was sacrificed at 12 weeks after surgery. BACKGROUND: If the role of growth factors in ligament healing and remodeling is understood, better therapies can be designed for ligament trauma. METHODS: The freeze-thaw treatment was performed three times using the originally developed cryo-probe. The cross-sectional area of the anterior cruciate ligament was measured by the optical non-contact method. After preconditioning, each specimen was stretched to failure. The ligament strain was determined with a video dimension analyzer. RESULTS: The tensile strength and the tangent modulus of the anterior cruciate ligament in the TGF-beta1 group was significantly higher than in the sham group, but significantly lower than in the normal control group. There were no significant differences in the strength and the modulus between the EGF group, the PDGF-BB group, and the sham group. CONCLUSIONS: In this model, an application of 4 ng TGF-beta1 significantly inhibited some of the material deterioration that occurs in the in situ frozen-thawed anterior cruciate ligament, while an application of 20 ng EGF or 4 microg PDGF-BB did not significantly affect the deterioration. RELEVANCE: This information will be useful in the future to develop a new biological therapy for ligament reconstruction to prevent the graft deterioration after transplantation.

Animals↗
PubMed2004

Interleukin-4 inhibits platelet-derived growth factor-induced preadipocyte proliferation.

Interleukin-4 (IL-4) activates STAT6 in 3T3-L1 preadipocytes but its functional role is not known. In this report, we first assessed interleukin-4 receptor alpha (IL-4Ralpha) expression during adipogenesis. IL-4Ralpha was highly expressed in proliferating 3T3-L1 preadipocytes. Receptor expression was down-regulated in post-confluent growth arrested preadipocytes. Induction of differentiation led to a transient 36-h increase in expression, but then levels decreased to undetectable amounts 3-8 days after induction of differentiation. Depending on the cell type, IL-4 either increases or decreases cell proliferation. In growth arrested preconfluent 3T3-L1 preadipocytes, IL-4 alone had no effect on preadipocyte proliferation. In contrast, IL-4 inhibited platelet-derived growth factor (PDGF-BB) induced preadipocyte proliferation. PDGF-BB, but not IL-4, induced STAT3 tyrosine and AKT serine phosphorylation. Both PDGF-BB and IL-4 induced STAT6 tyrosine phosphorylation, but the bands showed distinct electrophoretic migration patterns. IL-4 alone and IL-4 added to the differentiation cocktail had no effect on adipocyte formation or PPARgamma expression. Collectively, these studies demonstrate that IL-4 inhibits PDGF-BB-induced preadipocyte proliferation, possibly through STAT6 activation. The pattern of IL-4 receptor expression suggests that the effects of IL-4 are targeted primarily towards preadipocytes.

3T3-L1 Cells↗
PubMed2005

Astrapterocarpan isolated from Astragalus membranaceus inhibits proliferation of vascular smooth muscle cells.

The inhibitory effects of astrapterocarpan, formononetin, and calycosin isolated from Astragalus membraneceus on platelet-derived growth factor (PDGF)-BB-induced proliferative response in rat vascular smooth muscle cells (A10 cells) were investigated. Astrapterocarpan significantly inhibited PDGF-BB-induced cell proliferation and DNA synthesis in a concentration-dependent manner. This inhibition was not attributed to toxicity. In contrast, formononetin and calycosin had no effect. We next examined the effect of astrapterocarpan on PDGF-BB signal transduction. Astrapterocarpan inhibited PDGF-BB-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERIC1/2) mitogen-activated protein (MAP) kinase. However, this compound had no effect on phosphorylation of PDGF-beta-receptor, Akt kinase and p38 MAP kinase. These results indicated that astrapterocarpan inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and that this effect may be mediated, at least in part, by inhibition of the ERK1/2 MAP kinase cascade.

Animals↗
PubMed2005

Differential immunoexpressions of cytoskeletons in renal epithelial and interstitial cells in rat and canine fibrotic kidneys, and in kidney-related cell lines under fibrogenic stimuli.

Myofibroblasts play an important role in chronic renal interstitial fibrosis. However, the origin and developmental mechanisms remain to be elucidated. The myofibroblasts may express various cytoskeletons during the development. Immunoexpressions of vimentin, desmin and alpha-smooth muscle actin (alpha-SMA) were analyzed using experimentally (cisplatin and unilateral ureteral obstruction) induced rat and spontaneous canine fibrotic kidneys or kidney-related cell lines incubated with transforming growth factor-beta1 (TGF-beta1), platelet-derived growth factor-BB (PDGF-BB) or their combination at various concentrations. In rat fibrotic kidneys, both renal epithelia and interstitial cells showed positive reactions to alpha-SMA and vimentin, supporting epithelial-mesenchymal transition (EMT) theory; however, renal epithelia did not react to desmin, though interstitial cells were reactive. Renal epithelia in canine fibrotic kidneys did not show a positive reaction to alpha-SMA, whereas interstitial cells reacted strongly to alpha-SMA; conversely, renal epithelia reacted strongly to desmin, but interstitial cells did not; vimentin expression was infrequently seen in renal epithelia and interstitial cells of canine kidneys. Exposure of TGF-beta1 to porcine renal epithelial cells (LLC-PK1), rat renal interstitial cells (NRK-49F), and rat immature mesenchymal cells (MT-9) dose-dependently increased selectively alpha-SMA-positive cell numbers. Moreover, PDGF-BB exhibited an additive effect on TGF-beta1-induced alpha-SMA expression in these cell lines when simultaneously added. alpha-SMA was the most plastic cytoskeleton under fibrogenic stimuli. This study shows that there are interspecies differences in cytoskeletal immunoexpressions of renal epithelia or interstitial cells between rat and canine fibrotic kidneys, and that the derivation of renal myofibroblasts may be heterogeneous, such as renal epithelia, interstitial cells or immature mesenchymal cells.

Actins↗
PubMed2006

Canine retinal angioblasts are multipotent.

The purpose of this study was to culture and characterize endothelial cells and angioblasts, vascular precursors, from adult and neonatal dog retina and determine if angioblasts are committed to endothelial cell lineage or have the potential to be multipotent, i.e. express phenotypic characteristics of other vascular cell types. Endothelial cells were established from adult dog retina (ADREC) by the technique of Gitlin and D'Amore. For angioblasts, pieces of neonatal day 2 (P2) avascular peripheral retina were placed under coverslips until sufficient cells had explanted. All cells were maintained initially on hyaluronic acid (HA)/fibronectin (FN) substratum. Neonatal canine retinal angioblasts (NCRA) were maintained initially on retinal-derived growth factor with alpha-amino adipic acid to inhibit growth of Muller cells. Cell lines were characterized by enzyme histochemistry [menadione-dependent alpha glycerophosphate dehydrogenase (alphaGPDH), marker for angioblasts] and immunocytochemistry. Once characterized, cells were grown on FN, or collagens I or IV substrata and fed platelet-derived growth factor-BB (PDGF-BB) or fibroblast growth factor-2 (FGF-2). The phenotypic expression of a marker for endothelial cells [acetylated LDL (acLDL) uptake] or a marker for pericytes and smooth muscle cells, production of alpha smooth muscle actin (alphaSMA), was evaluated under those conditions. The canine retinal cell lines that were established had the following characteristics when maintained on serum and a retinal extract. Angioblasts had low expression of vWf and VEGF-R2 (two markers for canine endothelial cells), and very low uptake of acLDL but high expression of alphaGPDH and adenosine A2a receptors (A2aR) (two markers for canine angioblasts in vivo). ADREC had high expression of endothelial cell markers (vWf, VEGF-R2, and acLDL uptake) but minimal expression of alphaGPDH and A2aR. Both angioblasts and endothelial cells expressed CXCR4, a marker for hemangioblasts. Angioblasts grown on any of the substrata in the presence of FGF-2 had high uptake of acLDL and low expression of alphaSMA, while those grown in the presence of PDGF-BB had high expression of alphaSMA and low uptake of acLDL. In conclusion, angioblasts cultured from peripheral vascular retina have low expression of endothelial cell markers and high alphaGPDH and A2aR, markers for canine angioblasts in vivo. Angioblasts will internalize acLDL when maintained on FGF-2 and express alphaSMA when maintained on PDGF-BB, suggesting that they have the potential to become endothelial cells or pericytes, i.e. are multipotent.

Actins↗
PubMed2006

CRSBP-1/LYVE-l-null mice exhibit identifiable morphological and functional alterations of lymphatic capillary vessels.

CRSBP-1, a membrane glycoprotein, can mediate cell-surface retention of secreted growth factors containing CRS motifs such as PDGF-BB. CRSBP-1 has recently been found to be identical to LYVE-1, a specific marker for lymphatic capillary endothelial cells. The in vivo role of CRSBP-1/LYVE-1 is unknown. CRSBP-1-null mice are overtly normal and fertile but exhibit identifiable morphological and functional alterations of lymphatic capillary vessels in certain tissues, marked by the constitutively increased interstitial-lymphatic flow and lack of typical irregularly-shaped lumens. The CRSBP-1 ligands PDGF-BB and HA enhance interstitial-lymphatic flow in wild-type mice but not in CRSBP-1-null animals.

Animals↗
PubMed2004

Growth factor production in human endothelial cells after Chlamydia pneumoniae infection.

Seroepidemiological and histopathological studies have suggested a link of atherosclerosis with chronic Chlamydia pneumoniae infection. The present study was designed to examine the effect of C. pneumoniae on expression of basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) in human endothelial cells. Using reverse transcription-polymerase chain reaction, immunoblotting and enzyme-linked immunosorbent assay we found stimulation of bFGF expression depending on the number of infecting bacteria and the time of infection as well. This stimulatory effect was diminished by heat and UV light treatment of the chlamydial inoculum, suggesting that viable bacteria but not bacterial LPS may be essential for eliciting this growth factor. In contrast, the expression of both PDGF-A and PDGF-B was not increased following C. pneumoniae infection. This study demonstrates that C. pneumoniae activates endothelial cells to produce bFGF, a growth factor which is linked to the development of atherosclerotic plaques.

Arteriosclerosis↗
PubMed2005

Zedoariae rhizoma and curcumin inhibits platelet-derived growth factor-induced proliferation of human hepatic myofibroblasts.

During the course of liver fibrogenesis, hepatic myofibroblast cells (hMF), mostly derived from hepatic stellate cells (HSC), proliferate and synthesize excessive amounts of extracellular matrix (ECM) components. To evaluate the antiproliferative effect of a traditional herbal medicine, Zedoariae rhizoma water extracts (ZR) was examined on the growth inhibition of human hMF since proliferation of hMF is known to be central for the development of fibrosis during liver injury, and factors that may limit their growth are potential antifibrotic agents. The aim of this study was to test the effects of ZR on the proliferation and to clarify the molecular mechanisms of ZR inhibition of HSC proliferation in cultured human hMF. The cells were stimulated by platelet-derived growth factor (PDGF)-BB in the presence or absence of ZR. Proliferation was determined by bromodeoxy-uridine (BrdU) incorporation. The mRNA expressions of collagen alpha1(I) and (IV) were evaluated by a quantitative reverse transcription-polymerase chain reaction (RT-PCR). PDGF-receptor tyrosine phosphorylation was detected using anti-phosphotyrosine antibody. PDGF-receptor radioligand binding assay was performed by [125I]PDGF-BB. ZR inhibited the PDGF-BB-induced cell-proliferation and collagen alpha1(I) and (IV) mRNA expressions. ZR reduced the autophosphorylation of the PDGF-receptor. ZR blocked PDGF-BB binding to its receptor in a non-competitive manner. Furthermore, the 80% aqueous acetone extract of ZR was also found to show a decreasing effect against the proportion of S phase cells after PDGF stimulation. To clarify the active compounds, the principal constituents of seven sesquiterpenes (curdione, dehydrocurdione, germacrone, curcumenol, isocurcumenol, zedoarondiol and curcumenone) and a diarylheptanoid (curcumin) were examined. Among them, curcumin was found to decrease the proportion of S phase cells after PDGF stimulation at a dose of 30-50 microM. Potent antiproliferative and antifibrogenic effects of ZR toward hMF indicated that ZR might have therapeutic implications in chronic liver disease, indicating a novel role for ZR as a growth inhibitory mediator and pointing out its potential involvement in the negative regulation of liver fibrogenesis. In conclusion, ZR has an inhibitory effect on PDGF-induced proliferation of hMF and the blocking of PDGF-BB binding to its receptor may be the mechanism behind this effect.

Actins↗
PubMed2005

Airway fibroblasts exhibit a synthetic phenotype in severe asthma.

BACKGROUND: Platelet-derived growth factor (PDGF) may have a significant role in airway remodeling in asthma, because it is a powerful inductor of many airway fibroblast activities such as collagen synthesis. OBJECTIVE: To determine whether PDGF is a significant contributor to airway remodeling in patients with asthma by enhancing airway fibroblast procollagen I expression. METHODS: Six normal controls without asthma, 10 subjects with mild to moderate asthma, and 5 subjects with severe asthma underwent bronchoscopy with endobronchial biopsy. Biopsies were placed in Dulbecco modified Eagle medium and fibroblasts cultured in the presence and absence of PDGF isoforms -AA, -BB, and -AB (1, 5, 10, 100 ng/mL) and insulin-like growth factor 1 (100 ng/mL). Fibroblast procollagen I and PDGF receptors (PDGFRs) alpha and beta expression were determined by ELISA. RESULTS: Platelet-derived growth factor BB significantly enhanced fibroblast procollagen I expression in patients with severe asthma compared with patients with mild/moderate asthma and normal controls. Furthermore, the baseline fibroblast expression of PDGFR-beta was significantly greater in patients with severe asthma compared with the other groups. CONCLUSION: This pilot study suggests that airway fibroblasts from patients with severe asthma exhibit a synthetic phenotype, which may be driven by the overexpression of PDGFR-beta.

Adult↗
PubMed2004

Distribution of galanin and galanin transcript in the brain of a galanin-overexpressing transgenic mouse.

The distribution of galanin mRNA-expressing cells and galanin-immunoreactive (IR) cell bodies and processes was studied in the brain of mice overexpressing galanin under the PDGF-B promoter (GalOE mice) and of wild type (WT) mice, both in colchicine-treated and non-treated animals. In this abstract, we only describe the results in GalOE mouse. A widespread ectopic expression of galanin (both mRNA and peptide) was found, that is a situation when neither transcript nor peptide could be seen in WT mice, not even after colchicine treatment. However, in some regions, such as claustrum, basolateral amygdala, thalamus, CA1 pyramidal cells, and Purkinje cells only galanin mRNA could be detected. In the forebrain galanin was seen in the mitral cells of the olfactory bulb, throughout the cortex, in the basolateral amygdaloid nucleus, claustrum, granular and pyramidal cell layers of the hippocampus, subiculum and presubiculum. In the thalamus, the anterodorsal, mediodorsal, intermediodorsal and mediodorsal lateral nuclei, the reuniens and reticular nuclei showed ectopic expression of galanin. Within the hypothalamus, neurons of the suprachiasmatic nucleus contained galanin. In the mesencephalon, the geniculate nucleus, nucleus ruber, the mesencephalic trigeminal and reticulotegmental nuclei ectopically expressed galanin. In the cerebellum, galanin was observed in the Purkinje cells and in the lateral and interposed cerebellar nuclei. In the pons, sensory and motor nuclei of the trigeminal nerve, the laterodorsal and dorsal tegmental nuclei, the pontine, reticulotegmental and gigantocellular reticular nuclei expressed galanin. Within the medulla oblongata, labeled cells were detected in the facial, ambiguus, prepositus, lateral paragigantocellular and lateral reticular nuclei, and spinal trigeminal nucleus. High densities of galanin-IR fibers were found in the axonal terminals of the lateral olfactory tract, the hippocampal and presumably the cerebellar mossy fibers system, in several thalamic and hypothalamic regions and the lower brain stem. Possible functional consequences of galanin overexpression are discussed.

Animals↗
PubMed2005

Controlled release from fibers of polyelectrolyte complexes.

Controlled release systems for delicate compounds, such as proteins, often suffer the drawbacks of decreased bioactivity and low encapsulation efficiency. This study introduces the concept of producing drug-loaded fibers from interfacial polyelectrolyte complexation. Chitosan-alginate fibers were produced by pulling from the interface between two polyelectrolyte solutions at room temperature. Depending on the component properties, the release time of encapsulated components from these fibers can range from hours to weeks. Dexamethasone was completely released within 2 h, whereas charged compounds such as BSA, PDGF-bb, and avidin showed sustained release for 3 weeks. The fibers were able to release PDGF-bb in a steady fashion for over 3 weeks without an initial burst. Furthermore, the bioactivity of PDGF-bb was retained over this period. Release kinetics could be controlled by the inclusion of heparin, which contains specific binding sites for various growth factors. By varying the alginate/heparin ratios in the anionic polyelectrolyte solution, the release of PDGF-bb could be significantly altered. In this study, interfacial polyelectrolyte complexation has been demonstrated to be a promising technique for producing drug-loaded fibers with high encapsulation efficiency, sustained release kinetics, and capacity to retain the bioactivity of the encapsulants.

Alginates↗