TISSUE INHIBITOR OF METALLOPROTEINASE-3 IS UP-REGULATED BY TRANSFORMING GROWTH FACTOR-β1 IN VITRO AND EXPRESSED IN FIBROBLASTIC FOCI IN VIVO IN IDIOPATHIC PULMONARY FIBROSIS

2006 ◽  
Vol 32 (5) ◽  
pp. 201-214 ◽  
Author(s):  
Jorge García-Alvarez ◽  
Remedios Ramirez ◽  
Marco Checa ◽  
Robert K. Nuttall ◽  
Clara L. Sampieri ◽  
...  
Keyword(s):  
Growth Factor ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor

scholarly journals Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis

2015 ◽  
Vol 45 (5) ◽  
pp. 1434-1445 ◽  
Author(s):  
Lutz Wollin ◽  
Eva Wex ◽  
Alexander Pautsch ◽  
Gisela Schnapp ◽  
Katrin E. Hostettler ◽  
...  
Keyword(s):  
Growth Factor ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Tyrosine Kinases ◽  
Cell Injury ◽  
Transforming Growth Factor ◽  
Alveolar Epithelial Cell ◽  
Phase Iii ◽  
Lung Fibroblasts

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease characterised by fibrosis of the lung parenchyma and loss of lung function. Although the pathogenic pathways involved in IPF have not been fully elucidated, IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix (ECM) proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and transforming growth factor-β are believed to play important roles in the pathogenesis of IPF. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with IPF, which has recently been demonstrated in phase III clinical trials.

scholarly journals Increased serum and bone matrix levels of transforming growth factor β1 in patients with GH deficiency in response to GH treatment

2011 ◽  
Vol 165 (3) ◽  
pp. 393-400 ◽  
Author(s):  
Thor Ueland ◽  
Tove Lekva ◽  
Kari Otterdal ◽  
Tuva B Dahl ◽  
Nicoleta Cristina Olarescu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cortical Bone ◽  
Transforming Growth Factor ◽  
Bone Cells ◽  
Gh Deficiency ◽  
Bone Matrix ◽  
Transforming Growth Factor Β1 ◽  
Gh Treatment

ObjectivePatients with adult onset GH deficiency (aoGHD) have secondary osteoporosis, which is reversed by long-term GH substitution. Transforming growth factor β1 (TGFβ1 or TGFB1) is abundant in bone tissue and could mediate some effects of GH/IGFs on bone. We investigated its regulation by GH/IGF1in vivoandin vitro.Design and methodsThe effects of GH substitution (9–12 months, placebo controlled) on circulating and cortical bone matrix contents of TGFβ1 were investigated in patients with aoGHD. The effects of GH/IGF1 on TGFβ1 secretion in osteoblasts (hFOB), adipocytes, and THP-1 macrophages as well as the effects on release from platelets were investigatedin vitro.ResultsIn vivoGH substitution increased TGFβ1 protein levels in cortical bone and serum.In vitro, GH/IGF1 stimulation induced a significant increase in TGFβ1 secretion in hFOB. In contrast, no major effect of GH/IGF1 on TGFβ1 was found in adipocytes and THP-1 macrophages. Finally, a minor modifying effect on SFLLRN-stimulated platelet release of TGFβ1 was observed in the presence of IGF1.ConclusionGH substitution increases TGFβ1in vivoandin vitro, and this effect could contribute to improved bone metabolism during such therapy, potentially reflecting direct effect of GH/IGF1 on bone cells.

Comparison of Release Profiles of Various Growth Factors from Biodegradable Carriers

1998 ◽  
Vol 530 ◽  
Author(s):  
Y. Tabata ◽  
M. Yamamoto ◽  
Y. Ikada
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
The Body ◽  
Bone Morphogenetic Protein 2 ◽  
Biodegradable Hydrogel ◽  
Tgf Β1

AbstractA biodegradable hydrogel was prepared by glutaraldehyde crosslinking of acidic gelatin with an isoelectric point (IEP) of 5.0 as a carrier to release basic growth factors on the basis of polyion complexation. Basic fibroblast growth factor (bFGF), transforming growth factor β1 (TGF-β1), and bone morphogenetic protein-2 (BMP-2) were sorbed from their aqueous solution into the dried gelatin hydrogels to prepare respective growth factor-incorporating hydrogels. Under an in vitro non-degradation condition, approximately 20 % of incorporated bFGF and TGF-β1 was released from the hydrogels within initial 40 min, followed by no further release, whereas a large initial release of BMP-2 was observed. After subcutaneous implantation of the gelatin hydrogels incorporating 125I-labeled growth factor in the mouse back, the remaining radioactivity was measured to estimate the in vivo release profile of growth factors. Incorporation into gelatin hydrogels enabled bFGF and TGF-β1 to retain in the body for about 15 days and the retention period well correlated with that of the gelatin hydrogel. Taken together, it is likely that the growth factors ionically complexed with acidic gelatin were released in vivo as a result of hydrogel biodegradation. On the contrary, basic BMP-2 did not ionically interact with acidic gelatin, resulting in no sustained released by the present biodegradable carrier system.

scholarly journals Platelet-induced cell signaling during liver regeneration

2021 ◽  
Vol 108 (Supplement_4) ◽  
Author(s):  
A Balaphas ◽  
J Meyer ◽  
R Perozzo ◽  
M Zeisser Labouebe ◽  
S Berndt ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Transforming Growth Factor ◽  
Fold Increase ◽  
Transforming Growth Factor Β1 ◽  
Remnant Liver ◽  
Liver Sinusoidal Endothelial Cells

Abstract Objective To investigate the mechanisms driving the interaction of platelets with liver sinusoidal endothelial cells (LSEC) during liver regeneration. Methods Platelets were tracked in vivo in mice by intravital confocal microscopy after partial hepatectomy. In vitro, we isolated highly pure mouse LSEC and analyzed their interactions with platelets, hepatic stellate cells (HSC), Kupffer cells and hepatocytes. Results Recruited platelets adhered to LSEC in vivo within the remnant liver segments following partial hepatectomy and were necessary for the interleukin 6 (IL-6) burst that occurred afterwards. In vitro, platelets were activated after incubation with LSEC and released transforming growth factor β1 (TGF-β1), which stimulated LSEC to secrete IL-6 (fold increase of 9.8±0.73 relative to baseline). Antibody-mediated neutralization of TGF-B1 or its downstream SMAD signalling pathway prevented the effects of activated platelets on LSEC. We also demonstrated that IL-6 released by LSEC stimulates HSC to produce hepatocyte growth factor (HGF) a main mitogen for hepatocytes. Conclusion Our results suggest that after hepatectomy, platelets initiate liver regeneration by interacting with LSEC and stimulate IL-6 release, which in turn stimulates HSC to produce HGF.

scholarly journals Requirement of Cyclin D1 in Mesangial Cell Mitogenesis

2000 ◽  
Vol 11 (8) ◽  
pp. 1398-1408
Author(s):  
STEFAN LANG ◽  
ANDREA HARTNER ◽  
R. BERND STERZEL ◽  
HARALD O. SCHÖCKLMANN
Keyword(s):  
Growth Factor ◽  
Protein Expression ◽  
Cyclin D1 ◽  
Transforming Growth Factor ◽  
D1 Protein ◽  
Transforming Growth Factor Β1 ◽  
Protein Levels ◽  
Cyclin D1 Protein

Abstract. Hyperplasia of mesangial cells (MC) is a frequent finding in glomerulonephritis. The control and function of cyclin D1, a regulator of cell cycle progression, in MC proliferation in vivo and in vitro were investigated. In a rat model of mesangioproliferative glomerulonephritis, increases in the number of cyclin D1-positive MC nuclei were prominent on day 5 of the disease, preceding the peak of MC hyperplasia. In growth-arrested rat MC in culture, mitogenic stimulation with serum or platelet-derived growth factor (PDGF) led to rapid increases in cyclin D1 protein expression. Transforming growth factor-β1 inhibited PDGF induction of cyclin D1 protein at 12 h. In an examination of the subcellular distribution of cyclin D1, it was observed that stimulation of MC with PDGF for 6 h caused translocation of cyclin D1 from the cytoplasm into the nucleus. Coincubation with PDGF and transforming growth factor-β1 completely inhibited this effect, without altering the cellular cyclin D1 protein abundance at that time point. To test whether reduction of cyclin D1 protein levels was sufficient to inhibit mitogenesis, MC were transfected with antisense oligonucleotides (ODN) complementary to rat cyclin D1 mRNA. Antisense ODN against cyclin D1 reduced the serum- or PDGF-induced protein expression of cyclin D1 to 27 or 10% of control levels, respectively. These inhibitory effects were correlated with diminished cyclin-dependent kinase 4 activity. Antisense ODN against cyclin D1 also decreased the PDGF-induced increase in p21Waf-1 protein levels. The MC proliferation caused by serum or PDGF was markedly inhibited by antisense ODN against cyclin D1, as measured by [3H]thymidine uptake and cell counts. It is concluded that increased cyclin D1 protein expression of MC is required for MC proliferation. Targeting cyclin D1 expression may represent an effective means to inhibit MC proliferation in vitro and in vivo.

scholarly journals Elevated expression of NEU1 sialidase in idiopathic pulmonary fibrosis provokes pulmonary collagen deposition, lymphocytosis, and fibrosis

2016 ◽  
Vol 310 (10) ◽  
pp. L940-L954 ◽  
Author(s):  
Irina G. Luzina ◽  
Virginia Lockatell ◽  
Sang W. Hyun ◽  
Pavel Kopach ◽  
Phillip H. Kang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Recombinant Adenovirus ◽  
Global Gene Expression

Idiopathic pulmonary fibrosis (IPF) poses challenges to understanding its underlying cellular and molecular mechanisms and the development of better therapies. Previous studies suggest a pathophysiological role for neuraminidase 1 (NEU1), an enzyme that removes terminal sialic acid from glycoproteins. We observed increased NEU1 expression in epithelial and endothelial cells, as well as fibroblasts, in the lungs of patients with IPF compared with healthy control lungs. Recombinant adenovirus-mediated gene delivery of NEU1 to cultured primary human cells elicited profound changes in cellular phenotypes. Small airway epithelial cell migration was impaired in wounding assays, whereas, in pulmonary microvascular endothelial cells, NEU1 overexpression strongly impacted global gene expression, increased T cell adhesion to endothelial monolayers, and disrupted endothelial capillary-like tube formation. NEU1 overexpression in fibroblasts provoked increased levels of collagen types I and III, substantial changes in global gene expression, and accelerated degradation of matrix metalloproteinase-14. Intratracheal instillation of NEU1 encoding, but not control adenovirus, induced lymphocyte accumulation in bronchoalveolar lavage samples and lung tissues and elevations of pulmonary transforming growth factor-β and collagen. The lymphocytes were predominantly T cells, with CD8+ cells exceeding CD4+ cells by nearly twofold. These combined data indicate that elevated NEU1 expression alters functional activities of distinct lung cell types in vitro and recapitulates lymphocytic infiltration and collagen accumulation in vivo, consistent with mechanisms implicated in lung fibrosis.

The Effect of Relaxin Treatment on Skeletal Muscle Injuries

2005 ◽  
Vol 33 (12) ◽  
pp. 1816-1824 ◽  
Author(s):  
Shinichi Negishi ◽  
Yong Li ◽  
Arvydas Usas ◽  
Freddie H. Fu ◽  
Johnny Huard
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Functional Recovery ◽  
Muscle Regeneration ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
C2c12 Cells ◽  
Muscle Injuries

Background Injured skeletal muscle can repair itself via spontaneous regeneration; however, the overproduction of extracellular matrix and excessive collagen deposition lead to fibrosis. Neutralization of the effect of transforming growth factor-β1, a key fibrotic cytokine, on myogenic cell differentiation after muscle injury can prevent fibrosis, enhance muscle regeneration, and thereby improve the functional recovery of injured muscle. Hypothesis The hormone relaxin, a member of the family of insulin-like growth factors, can act as an antifibrosis agent and improve the healing of injured muscle. Study Design Controlled laboratory study. Methods In vitro: Myoblasts (C2C12 cells) and myofibroblasts (transforming growth factor-β1-transfected myoblasts) were incubated with relaxin, and cell growth and differentiation were examined. Myogenic and fibrotic protein expression was determined by Western blot analysis. In vivo: Relaxin was injected intramuscularly at different time points after laceration injury. Skeletal muscle healing was evaluated via histologic, immunohistochemical, and physiologic tests. Results Relaxin treatment resulted in a dose-dependent decrease in myofibroblast proliferation, down-regulated expression of the fibrotic protein α-smooth muscle actin, and promoted the proliferation and differentiation of myoblasts in vitro. Relaxin therapy enhanced muscle regeneration, reduced fibrosis, and improved injured muscle strength in vivo. Conclusion Administration of relaxin can significantly improve skeletal muscle healing. Clinical Relevance These findings may facilitate the development of techniques to eliminate fibrosis, enhance muscle regeneration, and improve functional recovery after muscle injuries.

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