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Collagen Deposition (collagen + deposition)
Selected AbstractsAMINOGUANIDINE AMELIORATES OVEREXPRESSION OF PROSCLEROTIC GROWTH FACTORS AND TYPE IV COLLAGEN DEPOSITION IN EXPERIMENTAL DIABETIC NEPHROPATHYNEPHROLOGY, Issue 3 2000Gilbert Re [source] Tumor necrosis factor,like weak inducer of apoptosis is a mitogen for liver progenitor cells,,HEPATOLOGY, Issue 1 2010Janina E. E. Tirnitz-Parker Liver progenitor cells (LPCs) represent the cell compartment facilitating hepatic regeneration during chronic injury while hepatocyte-mediated repair mechanisms are compromised. LPC proliferation is frequently observed in human chronic liver diseases such as hereditary hemochromatosis, fatty liver disease, and chronic hepatitis. In vivo studies have suggested that a tumor necrosis factor family member, tumor necrosis factor,like weak inducer of apoptosis (TWEAK), is promitotic for LPCs; whether it acts directly is not known. In our murine choline-deficient, ethionine-supplemented (CDE) model of chronic liver injury, TWEAK receptor [fibroblast growth factor-inducible 14 (Fn14)] expression in the whole liver is massively upregulated. We therefore set out to investigate whether TWEAK/Fn14 signaling promotes the regenerative response in CDE-induced chronic liver injury by mitotic stimulation of LPCs. Fn14 knockout (KO) mice showed significantly reduced LPC numbers and attenuated inflammation and cytokine production after 2 weeks of CDE feeding. The close association between LPC proliferation and activation of hepatic stellate cells in chronic liver injury prompted us to investigate whether fibrogenesis was also modulated in Fn14 KO animals. Collagen deposition and expression of key fibrogenesis mediators were reduced after 2 weeks of injury, and this correlated with LPC numbers. Furthermore, the injection of 2-week-CDE-treated wildtype animals with TWEAK led to increased proliferation of nonparenchymal pan cytokeratin,positive cells. Stimulation of an Fn14-positive LPC line with TWEAK led to nuclear factor kappa light chain enhancer of activated B cells (NF,B) activation and dose-dependent proliferation, which was diminished after targeting of the p50 NF,B subunit by RNA interference. Conclusion: TWEAK acts directly and stimulates LPC mitosis in an Fn14-dependent and NF,B-dependent fashion, and signaling via this pathway mediates the LPC response to CDE-induced injury and regeneration. (HEPATOLOGY 2010) [source] Deficiency of tenascin-C attenuates liver fibrosis in immune-mediated chronic hepatitis in mice,THE JOURNAL OF PATHOLOGY, Issue 1 2007A El-Karef Abstract Tenascin-C (TNC), an extracellular matrix glycoprotein, is upregulated in chronic liver disease. Here, we investigated the contribution of TNC to liver fibrogenesis by comparing immune-mediated hepatitis in wild-type (WT) and TNC-null (TNKO) mice. Eight-week-old BALB/c mice received weekly intravenous injections of concanavalin A to induce hepatitis, and were sacrificed one week after the 3rd, 6th, 9th, and 12th injections. In WT livers, immunohistochemical staining revealed a gradual increase in TNC deposition. TNC mRNA levels also increased sequentially and peaked after the 9th injection. Collagen deposition, stained with picrosirius red, was significantly less intense in TNKO mice than in WT mice, and procollagen I and III transcripts were significantly upregulated in WT mice compared with TNKO mice. Inflammatory infiltrates were most prominent after the 3rd-6th injections in both groups and were less intense in TNKO mice than in WT mice. Interferon- ,, tumour necrosis factor- ,, and interleukin-4 mRNA levels were significantly higher in WT mice than in TNKO mice, while activated hepatic stellate cells (HSCs) and myofibroblasts, a cellular source of TNC and procollagens, were more common in WT livers. Transforming growth factor (TGF)- ,1 mRNA expression was significantly upregulated in WT mice, but not in TNKO mice. In conclusion, TNC can promote liver fibrogenesis through enhancement of inflammatory response with cytokine upregulation, HSC recruitment, and TGF-, expression during progression of hepatitis to fibrosis. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Microplasmin improves surgical outcome in a rabbit model for trabeculectomyACTA OPHTHALMOLOGICA, Issue 2009E VANDEWALLE Purpose This study was designed to study the efficacy and safety of Microplasmin as an anti-scarring agent after trabeculectomy in a rabbit model. Methods The effect of Microplasmin was investigated in vivo in a rabbit model for glaucoma surgery. Clinical outcome measures were intra-ocular pressure, bleb area and survival, side effects on slit lamp examination. Moreover, (immuno-) histochemical analysis of the eyes was performed, with quantification of inflammation (CD 45) and collagen deposition (Trichrome and Sirius Red). In the first experiment (n=10), Microplasmin anterior chamber injection was compared to placebo injection. In the second experiment (n=3), topical Microplasmin drops were compared to placebo drops. In the third experiment (n=5) the combination of Microplasmin anterior chamber injection and topical drops was compared to placebo injection and drops. All experiments were conducted in a masked observator way. Results Microplasmin significantly augmented the bleb area and survival in a rabbit model of trabeculectomy after a single anterior chamber injection or combination therapy (injection combined with drops) compared to control. Collagen deposition was borderline reduced after Microplasmin administration compared to control. No significant changes in inflammation were noticed in the anterior chamber or in the conjunctiva. Conclusion Microplasmin single injection or combination with postoperative drops improved the outcome after trabeculectomy. In a rabbit model, larger blebs were produced for a longer period compared to control, and collagen deposition tended to decrease in this small series. [source] Comparison of a Long-Pulse Nd:YAG Laser and a Combined 585/1,064-nm Laser for the Treatment of Acne Scars: A Randomized Split-Face Clinical StudyDERMATOLOGIC SURGERY, Issue 11 2009SEONG UK MIN MD BACKGROUND Nonablative laser is gaining popularity because of the low risk of complications, especially in patients with darker skin. OBJECTIVE To compare the efficacy and safety of a long-pulse neodymium-doped yttrium aluminium garnet (Nd:YAG) laser and a combined 585/1,064-nm laser for the treatment of acne scars. MATERIALS AND METHODS Nineteen patients with mild to moderate atrophic acne scars received four long-pulse Nd:YAG laser or combined 585/1,064-nm laser treatment sessions at fortnightly intervals. Treatments were administered randomly in a split-face manner. RESULTS Acne scars showed mild to moderate improvement, with significant Echelle d'évaluation clinique des cicatrices d'acné (ECCA) score reductions, after both treatments. Although intermodality differences were not significant, combined 585/1,064-nm laser was more effective for deep boxcar scars. In patients with combined 585/1,064-nm laser-treated sides that improved more than long-pulse Nd:YAG laser-treated sides, ECCA scores were significantly lower for combined 585/1,064-nm laser treatment. Histologic evaluations revealed significantly greater collagen deposition, although there was no significant difference between the two modalities. Patient satisfaction scores concurred with physicians' evaluations. CONCLUSION Both lasers ameliorated acne scarring with minimal downtime. In light of this finding, optimal outcomes might be achieved when laser treatment types are chosen after considering individual scar type and response. [source] Histometric and Histochemical Analysis of the Effect of Trichloroacetic Acid Concentration in the Chemical Reconstruction of Skin Scars MethodDERMATOLOGIC SURGERY, Issue 10 2006SUNG BIN CHO MD BACKGROUND Atrophic scars can be induced by various causes, including severely inflamed acne, chicken pox, and trauma. Many treatment modalities are used for reconstructing and improving the appearance of scars with various treatment results. OBJECTIVE A recent report shows the clinical efficacy of the chemical reconstruction of skin scars (CROSS) method, which consists of the focal application of trichloroacetic acid (TCA) in a higher concentration. Histometric analysis of the CROSS method, however, has not yet been established. METHODS In this study, five hairless mice were used to evaluate the effect of the CROSS method and to analyze the difference between the CROSS method and simple TCA application. RESULTS Similar histologic changes were observed in the two methods, including epidermal and dermal rejuvenation with new collagen deposition. These changes, however, were more prominent in the CROSS method,treated areas, particularly when 100% TCA was used. CONCLUSION The results of this study suggest that treatment of atrophic scars using the CROSS method is more effective than simple application of TCA in activating fibroblasts in the dermis and increasing the amount of collagen. [source] Glycolic Acid Treatment Increases Type I Collagen mRNA and Hyaluronic Acid Content of Human SkinDERMATOLOGIC SURGERY, Issue 5 2001Eric F. Bernstein MD Background. Chronic solar irradiation results in both morphologic and functional changes in affected skin. ,-hydroxy acids, such as glycolic acid, have been shown to improve photodamaged skin. Objective. To investigate alterations in collagen gene induction and epidermal and dermal hyaluronic acid production as a result of administered glycolic acid. Methods. In this study we compared collagen gene expression from skin biopsy specimens, and epidermal and dermal hyaluronic acid immunohistochemical staining between glycolic acid-treated and vehicle-treated skin. Forearm skin was treated with 20% glycolic acid lotion or a lotion vehicle control twice a day for 3 months. Results. Epidermal and dermal hyaluronic acid and collagen gene expression were all increased in glycolic acid-treated skin as compared to vehicle-treated controls. Conclusion. Our data suggest that epidermal and dermal remodeling of the extracellular matrix results from glycolic acid treatment. Longer treatment intervals may result in collagen deposition as suggested by the measured increase in mRNA. [source] Augmentation of all- trans -retinoic acid concentration in plasma by preventing inflammation responses induced by atRA-loaded microspheres with concurrent treatment of dexamethasoneDRUG DEVELOPMENT RESEARCH, Issue 4 2004Kyeongsoon Park Abstract All- trans retinoic acid (atRA)-loaded microspheres severely induce inflammatory responses after microsphere implantation. Fibroblasts and a thick band of fibrous capsule resulting from the inflammatory responses could hamper drug permeation to the bloodstream because fibroblasts actively metabolize atRA into polar metabolites and the thick fibrous capsule acts as a diffusion barrier. In the present study, we investigated whether the fibroblast proliferation and collagen deposition induced by atRA released from microspheres might affect the atRA concentration in plasma and atRA metabolism with or without treatment of dexamethasone as an anti-inflammatory drug. After subcutaneous injection of atRA-loaded microspheres in rats, it was observed that atRA-loaded microspheres induced severe inflammatory responses and stimulated fibroblast proliferation and collagen deposition in fibrous capsules. On the other hand, the orally treated dexamethasone effectively prevented inflammatory responses in a dose-dependent manner and suppressed about 49% of the number of fibroblasts and collagen deposition in fibrous capsules at 14 days. In addition, after the treatment of dexamethasone, the atRA concentration in plasma was increased, and its metabolism was decreased approximately by 40% at 7 days, compared to the group treated alone with atRA-loaded microspheres. In conclusion, the concurrent treatment of dexmethasone with atRA-loaded microspheres could prevent inflammatory responses and metabolism of atRA, thereby maintaining the atRA concentration in plasma for longer periods in the therapeutic range. Drug Dev. Res. 61:197,206, 2004. © 2004 Wiley-Liss, Inc. [source] Assessment of Carotid Compliance Using Real Time Vascular Ultrasound Image Analysis in Marfan SyndromeECHOCARDIOGRAPHY, Issue 4 2009Anatoli Kiotsekoglou M.D. Background: Fibrillin-1 deficiency, dysregulated cytokine transforming growth factor-,, and increased collagen deposition related to fibrillin-1 gene mutations could predispose to impaired carotid compliance (CC) in Marfan syndrome (MFS). We sought to detect any alterations in CC using the vascular image analysis system (VIA). Methods and Results: Thirty-two MFS patients, 20 men and 12 women (mean age 34.2 ± 12.05 years), and 29 controls matched for age, sex, and body surface area (BSA) were recruited. The entire length of each carotid system was initially scanned longitudinally using a 14 MHz linear transducer. Then, a stereotactic clamp held the transducer in contact with the carotid artery. Arterial diameter changes during the cardiac cycle were recorded for 1 minute from both right (RCCA) and left common carotid arteries (LCCA) separately using the VIA system. RCCA and LCCA compliance and distensibility measurements were significantly reduced in MFS patients when compared to controls, P < 0.05. RCCA and LCCA intima-media thickness did not differ between patients and controls, P > 0.05. MFS diagnosis and age were associated with reduced CC in both carotid arteries after adjusting for variables such as, sex, BSA, heart rate, beta-blockade, intima-media thickness, and aortic root size. Conclusions: Our findings showed a reduction in CC in adult patients with MFS. This could be attributed to fibrillin-1 deficiency resulting in structural abnormalities in the carotid arterial wall. [source] First-line treatment with bortezomib rapidly stimulates both osteoblast activity and bone matrix deposition in patients with multiple myeloma, and stimulates osteoblast proliferation and differentiation in vitroEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2010Thomas Lund Abstract Objectives:, The aim of the study was to investigate the effect of bortezomib on osteoblast proliferation and differentiation, as well as on bone matrix deposition for the first time in bisphosphonate-naïve, previously untreated patients with myeloma. Methods:, Twenty newly diagnosed patients received four cycles of bortezomib treatment, initially as monotherapy and then combined with a glucocorticoid from cycle two to four. Bone remodeling markers were monitored closely during treatment. Furthermore, the effects of bortezomib and a glucocorticoid on immature and mature osteoblasts were also studied in vitro. Results:, Treatment with bortezomib caused a significant increase in bone-specific alkaline phosphatase and pro-collagen type I N-terminal propeptide, a novel bone formation marker. The addition of a glucocorticoid resulted in a transient decrease in collagen deposition. In vitro bortezomib induced osteoblast proliferation and differentiation. Differentiation but not proliferation was inhibited by glucocorticoid treatment. Conclusions:, Bortezomib used as first-line treatment significantly increased collagen deposition in patients with multiple myeloma and osteolytic lesions, but the addition of a glucocorticoid to the treatment transiently inhibited the positive effect of bortezomib, suggesting that bortezomib may result in better healing of osteolytic lesions when used without glucocorticoids in patients that have obtained remission with a previous therapy. The potential bone-healing properties of single-agent bortezomib are currently being explored in a clinical study in patients who have undergone high-dose therapy and autologous stem cell transplantation. [source] TLR3 modulates immunopathology during a Schistosoma mansoni egg-driven Th2 response in the lungEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2008Amrita D. Joshi Abstract We examined the role of TLR3 in Th2-driven pulmonary granulomatous disease, using wildtype (TLR3+/+) and TLR3 gene-deficient (TLR3,/,) mice in a well-established model of Schistosoma mansoni egg-induced pulmonary granuloma. The intravenous bolus injection of S. mansoni eggs into S. mansoni -sensitized TLR3+/+ mice was associated with an increase in TLR3 transcript expression in alveolar macrophages and ex vivo spleen and lung cultures at day 8 after egg injection. Lungs from TLR3,/, mice showed an increase in granuloma size, greater collagen deposition around the granuloma, and increased Th2 cytokine and chemokine levels compared with similarly sensitized and challenged TLR3+/+ mice. Macrophages from TLR3,/, mice exhibited an M2 phenotype characterized by increased arginase and CCL2 expression. Significantly greater numbers of CD4+CD25+ T cells were present in the lungs of TLR3,/, mice compared with TLR3+/+ mice at day 8 after egg embolization. Cells derived from granulomatous lung and lung draining lymph nodes of TLR3,/, mice released significantly higher levels of IL-17 levels relative to TLR3+/+ cells. Thus, our data suggest that TLR3 has a major regulatory role during a Th2-driven granulomatous response as its absence enhanced immunopathology. [source] Cardiac L-type calcium current is increased in a model of hyperaldosteronism in the ratEXPERIMENTAL PHYSIOLOGY, Issue 6 2009Beatriz Martin-Fernandez Accumulating evidence supports the importance of aldosterone as an independent risk factor in the pathophysiology of cardiovascular disease. It has been postulated that aldosterone could contribute to ventricular arrhythmogeneity by modulation of cardiac ionic channels. The aim of this study was to analyse ex vivo the electrophysiological characteristics of the L-type cardiac calcium current (ICaL) in a model of hyperaldosteronism in the rat. Aldosterone was administered for 3 weeks, and cardiac collagen deposition and haemodynamic parameters were analysed. In addition, RT-PCR and patch-clamp techniques were applied to study cardiac L-type Ca2+ channels in isolated cardiomyocytes. Administration of aldosterone induced maladaptive cardiac remodelling that was related to increased collagen deposition, diastolic dysfunction and cardiac hypertrophy. In addition, ventricular myocytes isolated from the aldosterone-treated group showed increased ICaL density and conductance and prolongation of the action potential duration. No changes in kinetics or in voltage dependence of activation and inactivation of ICaL were observed, but relative expression of CaV1.2 mRNA levels was higher in cardiomyocytes isolated from the aldosterone-treated group. The present study demonstrates that aldosterone treatment induces myocardial fibrosis, cardiac hypertrophy, increase of ICaL density, upregulation of L-type Ca2+ channels and prolongation of action potential duration. It could be proposed that aldosterone, through these mechanisms, might exert pro-arrhythmic effects in the pathological heart. [source] CCR2 promotes hepatic fibrosis in mice,HEPATOLOGY, Issue 1 2009Ekihiro Seki Chemokines and chemokine receptors contribute to the migration of hepatic stellate cells (HSCs) and Kupffer cells, two key cell types in fibrogenesis. Here, we investigate the role of CCR2, the receptor for monocyte chemoattractant protein (MCP)-1, MCP-2, and MCP-3, in hepatic fibrosis. Hepatic CCR2, MCP-1, MCP-2, and MCP-3 messenger RNA expression was increased after bile duct ligation (BDL). Both Kupffer cells and HSCs, but not hepatocytes, expressed CCR2. BDL- and CCl4 -induced fibrosis was markedly reduced in CCR2,/, mice as assessed through collagen deposition, ,-smooth muscle actin expression, and hepatic hydroxyproline content. We generated CCR2 chimeric mice by the combination of clodronate, irradiation, and bone marrow (BM) transplantation allowing full reconstitution of Kupffer cells, but not HSCs, with BM cells. Chimeric mice containing wild-type BM displayed increased macrophage recruitment, whereas chimeric mice containing CCR2,/, BM showed less macrophage recruitment at 5 days after BDL. Although CCR2 expressed in the BM enhanced macrophage recruitment in early phases of injury, CCR2 expression on resident liver cells including HSCs, but not on the BM, was required for fibrogenic responses in chronic fibrosis models. In vitro experiments demonstrated that HSCs deficient in CCR2,/, or its downstream mediator p47phox,/, did not display extracellular signal-regulated kinase and AKT phosphorylation, chemotaxis, or reactive oxygen species production in response to MCP-1, MCP-2, and MCP-3. Conclusion: Our results indicate that CCR2 promotes HSC chemotaxis and the development of hepatic fibrosis. (HEPATOLOGY 2009.) [source] Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct,ligated rats,HEPATOLOGY, Issue 5 2005Ramón Bataller Recent evidence indicates that the renin,angiotensin system (RAS) plays a major role in liver fibrosis. Here, we investigate whether the circulatory RAS, which is frequently activated in patients with chronic liver disease, contributes to fibrosis progression. To test this hypothesis, we increased circulatory angiotensin II (Ang II) levels in rats undergoing biliary fibrosis. Saline or Ang II (25 ng/kg/h) were infused into bile duct,ligated rats for 2 weeks through a subcutaneous pump. Ang II infusion increased serum levels of Ang II and augmented bile duct ligation,induced liver injury, as assessed by elevated liver serum enzymes. Moreover, it increased the hepatic concentration of inflammatory proteins (tumor necrosis factor , and interleukin 1,) and the infiltration of CD43-positive inflammatory cells. Ang II infusion also favored the development of vascular thrombosis and increased the procoagulant activity of tissue factor in the liver. Livers from bile duct,ligated rats infused with Ang II showed increased transforming growth factor ,1 content, collagen deposition, accumulation of smooth muscle ,-actin,positive cells, and lipid peroxidation products. Moreover, Ang II infusion stimulated phosphorylation of c-Jun and p42/44 mitogen-activated protein kinase and increased proliferation of bile duct cells. In cultured rat hepatic stellate cells (HSCs), Ang II (10,8 mol/L) increased intracellular calcium and stimulated reactive oxygen species formation, cellular proliferation and secretion of proinflammatory cytokines. Moreover, Ang II stimulated the procoagulant activity of HSCs, a newly described biological function for these cells. In conclusion, increased systemic Ang II augments hepatic fibrosis and promotes inflammation, oxidative stress, and thrombogenic events. (HEPATOLOGY 2005;41:1046,1055.) [source] Targeting TGF-,1 by employing a vaccine ameliorates fibrosis in a mouse model of chronic colitisINFLAMMATORY BOWEL DISEASES, Issue 6 2010Yanbing Ma MSc Abstract Background: Intestinal fibrosis and stricture formation are major complications of inflammatory bowel disease (IBD), for which there are currently few effective treatments. We sought to investigate whether targeting transforming growth factor-beta1 (TGF-,1), a key profibrotic mediator, with a peptide-based virus-like particle vaccine would be effective in suppressing intestinal fibrosis by using a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis. Methods: The vaccine was prepared by inserting a peptide derived from mouse TGF-,1 into a carrier hepatitis B core antigen using gene recombination methods. Chronic colitis was induced in BALB/c mice by 8 weekly TNBS administrations. Mice were subcutaneously injected with vaccine, carrier, or phosphate-buffered saline (PBS) in 2 separate studies: either before or after acute inflammatory responses commenced. Results: Sera from vaccinated mice exhibited significantly elevated levels of TGF-,1-specific immunoglobulin G (IgG), which inhibited TGF-,1-induced luciferase production in mink lung epithelial cells. In the chronic colitis model, mice receiving vaccine showed improved body weight gain and significantly reduced colonic collagen deposition. Hematoxylin and eosin staining and semiquantitative scoring indicated that vaccination even ameliorated colonic inflammation. Cytokine profile analysis revealed that levels of TGF-,1, interleukin (IL)-17, and IL-23 in vaccinated mouse colon tissues were decreased, and that percentages of IL-17-expressing CD4+ lymphocytes in mesenteric lymph node cells were reduced. Furthermore, Smad3 phosphorylation, a key event in TGF-, signaling, was decreased in colonic tissue in vaccinated mice. Conclusions: This TGF-,1 peptide-based vaccine, which suppressed excessive TGF-,1 bioactivity, may prevent the development of intestinal fibrosis and associated complications, presenting a novel approach in the treatment of IBD. (Inflamm Bowel Dis 2010) [source] Molecular mechanisms of calorie restriction's protection against age-related sclerosisIUBMB LIFE, Issue 12 2006Elena Chiarpotto Abstract The current knowledge on the molecular mechanisms of the protective effect of calorie restriction (CR) against age-related fibrosclerosis is tentatively reviewed with specific reference to the role of oxidative stress in aging. The effects of oxidative stress are often mediated by its own final products. Of these, 4-hydroxy-2,3-nonenal (HNE) induces the expression and synthesis of transforming growth factor ,1 (TGF,1) and activates nuclear binding of transcription factor activator protein 1 (AP-1) thus stimulating fibrogenesis. Several studies have shown that, as well as extending mean and maximum life span in a variety of species, CR delays the onset and slows the progression of a variety of age-associated diseases, including diabetes, cardiovascular diseases and neoplasia. However, the anti-aging mechanisms of CR are still not clearly understood. Of the numerous hypotheses put forward, one that still remains popular is protection against the age-associated increase of oxidative stress and consequent cell damage. CR protects the rat aorta from the age-related increase of both oxidative damage and fibrosis; as regards the possible mechanism/s of CR's protection against fibrosclerosis, it is conceivable that, by decreasing oxidative stress, CR reduces HNE levels and consequently TGF,1 expression and collagen deposition, likely by down-regulating the activation of Jun-N terminal kinase and of AP-1. Through the modulation of reactive oxygen species and oxidative stress CR may also attenuate the age-associated increase in the inflammatory milieu, thus preserving vascular functional integrity by suppressing the age-associated increase in inflammatory enzyme activities and prostanoids. iubmb Life, 58: 695-702, 2006 [source] CCN2, connective tissue growth factor, stimulates collagen deposition by gingival fibroblasts via module 3 and ,6- and ,1 integrinsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2006Edwin C.K. Heng Abstract CCN2, (connective tissue growth factor, CTGF) is a matricellular factor associated with fibrosis that plays an important role in the production and maintenance of fibrotic lesions. Increased collagen deposition and accumulation is a common feature of fibrotic tissues. The mechanisms by which CCN2/CTGF contributes to fibrosis are not well understood. Previous studies suggest that CTGF exerts some of its biological effects at least in part by integrin binding, though this mechanism has not been previously shown to contribute to fibrosis. Utilizing full length CCN2/CTGF, CCN2/CTGF fragments, and integrin neutralizing antibodies, we provide evidence that the effects of CCN2/CTGF to stimulate extracellular matrix deposition by gingival fibroblasts are mediated by the C-terminal half of CCN2/CTGF, and by ,6 and ,1 integrins. In addition, a synthetic peptide corresponding to a region of CCN2/CTGF domain 3 that binds ,6,1 inhibits the collagen-deposition assay. These studies employed a new and relatively rapid assay for CCN2/CTGF-stimulated collagen deposition based on Sirius Red staining of cell layers. Data obtained support a pathway in which CCN2/CTGF could bind to ,6,1 integrin and stimulate collagen deposition. These findings provide new experimental methodologies applicable to uncovering the mechanism and signal transduction pathways of CCN2/CTGF-mediated collagen deposition, and may provide insights into potential therapeutic strategies to treat gingival fibrosis and other fibrotic conditions. J. Cell. Biochem. 98: 409,420, 2006. © 2006 Wiley-Liss, Inc. [source] Oversulfated chondroitin sulfate-E binds to BMP-4 and enhances osteoblast differentiationJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2008Tatsuya Miyazaki Small leucine-rich proteoglycans, such as biglycan, and their side chain sulfated glycosaminoglycans (GAGs), have been suggested to be involved in bone formation and mineralization processes. The present study was designed to investigate whether chondroitin sulfate (CS), one of the GAG, and its oversulfated structures coupled with bone morphogenetic protein-4 (BMP-4) alter the differentiation and subsequent mineralization of MC3T3-E1 osteoblastic cells. CS-E, one of the oversulfated CS structure, enhanced cell growth, alkaline phosphatase (ALP) activity, collagen deposition, and mineralization whereas heparin enhanced only ALP activity and mineralization. As well as CS-E, CS-H, and CPS also enhanced the mineralization of the cells. CS-E enhanced the mineralization of the cells by interacting with protein in the conditioned medium. CS-E induced mineralization was significantly inhibited by an antibody against BMP-4. The addition of exogenous BMP-4 further increased the capacity of CS-E to enhance mineralization. Fluorescence correlation spectroscopy method using fluoresceinamine-labeled GAG revealed that the oversulfated GAGs have a high affinity for BMP-4. The disaccharide analysis of the cells indicated that MC3T3-E1 cells are capable of producing oversulfated structures of CS by themselves. The lack of CS from the cells after chondroitinase treatment resulted in the inhibition of mineralization. These results in the present study indicate that oversulfated CS, which possesses 4,6-disulfates in N -acetyl-galactosamine, binds to BMP-4 and promotes osteoblast differentiation and subsequent mineralization. J. Cell. Physiol. 217: 769,777, 2008. © 2008 Wiley-Liss, Inc. [source] Bone morphogenetic protein-mediated type II collagen expression in pilomatricoma and cutaneous mixed tumorJOURNAL OF CUTANEOUS PATHOLOGY, Issue 3 2005Hideki Mieno Background:, We have previously reported that type II collagen deposition in overlying dermo,epidermal junction (DEJ) of pilomatricoma is mediated by bone morphogenetic protein 2/4 (BMP 2/4) expressed by shadow cells (SCs) of pilomatricoma. Objective:, This time, we studied the expression of type II collagen and BMP in a large number of cases of pilomatricoma and extended our study to cutaneous mixed tumor (CMT). Results:, We found type II collagen deposition in the overlying DEJ (16 of 50 cases) and in the SCs (19/50) of pilomatricoma. The number of case of type II collagen deposition in DEJ (DEJ+) and in SCs (SC+) of pilomatricoma correlated to the chronological stage of pilomatricoma. We also found type II collagen deposition in overlying DEJ (two of 11) and in the stromal chondroid tissue (four of 11) of CMT. BMP 2 was expressed in most cases of pilomatricoma (37/50) and CMT (seven of 11). Conclusions:, The expression of type II collagen in pilomatricoma is dependent upon the chronological stage of pilomatricoma. Type II collagen expression in the overlying DEJ and chondroid matrix in CMT may be induced by BMP via the same mechanism as in pilomatricoma. [source] Essential pathogenic and metabolic differences in steatosis induced by choline or methione-choline deficient diets in a rat modelJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2007Reeta Veteläinen Abstract Background and Aim:, Choline deficient (CD) and methione-choline deficient (MCD) diets are rodent models for steatosis, with potentially dissimilar biochemical backgrounds. The aim of this study was to assess the metabolic and pathological derangements in rats fed CD and MCD diets. Methods:, Male Wistar rats received CD or MCD diet up to 7 weeks. Nutritional status, liver histopathology, Kupffer cell-mediated inflammation and injury, oxidative stress via thiobarbituric reactive species (TBARS), hepatic and plasma glutathione (GSH) and insulin homeostasis were assessed. Results:, In CD-fed rats, mainly microvesicular steatosis developed with occasional inflammatory cells. In MCD-fed rats, macrovesicular steatosis progressed to steatohepatitis (collagen deposition, activated stellate cells). Hepatic TBARS was increased and GSH decreased in the MCD-fed rats compared to no changes in the CD-fed rats. The CD-fed rats developed obesity, dyslipidemia and insulin resistance, in contrast to undetectable plasma lipids, unaffected insulin homeostasis and loss of body weight in the MCD-fed rats. Conclusions:, The CD diet induced uncomplicated steatosis as compared to progressive inflammation and fibrinogenesis in the MCD diet. CD and MCD diets represent two pathogenically different models of steatosis. Although equivalence for the outcome of both diets can be found in clinical steatosis, the results of models using these diets should be compared with caution. [source] Antifibrotic effects of tetrandrine on hepatic stellate cells and rats with liver fibrosisJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 1 2007Yi-Chao Hsu Abstract Background:, Anti-inflammation strategies are one of the proposed therapeutic approaches to hepatic fibrosis. Tetrandrine (C38H42O8N2, molecular weight: 622; Tet), an alkaloid isolated from the Chinese medicinal herb Stephania tetrandra, has been shown to exert anti-inflammatory activity in pulmonary diseases. The purpose of the present study was to investigate the in vitro and in vivo effects of Tet on hepatic fibrosis. Methods:, A cell line of rat hepatic stellate cells (HSC-T6) was stimulated with transforming growth factor-,1 (TGF-,1) or tumor necrosis factor-, (TNF-,). The inhibitory effects of Tet on the nuclear factor ,B (NF,B) signaling cascade and molecular markers including intercellular adhesion molecule-1 (ICAM-1) and ,-smooth muscle actin (,-SMA) secretion were assessed. Fibrosis was induced by dimethylnitrosamine (DMN) administration in rats for 4 weeks. Fibrotic rats were randomly assigned to one of the four groups: vehicle (0.7% carboxyl methyl cellulose, CMC), Tet (1 mg/kg), Tet (5 mg/kg), or silymarin (50 mg/kg), each given by gavage twice daily for 3 weeks starting after 1 week of DMN administration. At the end of the study, liver tissues were scored for fibrosis and analyzed for molecular markers of fibrosis. Results:, Tetrandrine (0.5,5.0 µmol/L) concentration-dependently inhibited NF,B transcriptional activity induced by TNF-,, including I,B, phosphorylation and mRNA expressions of ICAM-1 in HSC-T6 cells. In addition, Tet also inhibited TGF-,1-induced ,-SMA secretion and collagen deposition in HSC-T6 cells. Fibrosis scores of livers from DMN-treated rats with high-dose Tet (1.3 ± 0.3) were significantly reduced in comparison with DMN-treated rats receiving saline (2.0 ± 0.2). Hepatic collagen content of DMN rats was significantly reduced by either Tet or silymarin treatment. Double-staining results showed that ,-SMA- and NF,B-positive cells were decreased in the fibrotic livers by Tet and silymarin treatment. In addition, mRNA expression of ICAM-1, ,-SMA, and TGF-,1 was attenuated by Tet treatment. Moreover, levels of plasma aspartate aminotransferase and alanine aminotransferase activities were reduced by Tet and silymarin treatment. Conclusion:, Tetrandrine exerts antifibrotic effects in both HSC-T6 cells and in rats with DMN-induced fibrosis. [source] Effect of pro-inflammatory and immunoregulatory cytokines on human tenocytesJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 8 2010Thilo John Abstract Tendon injury induces a local inflammatory response, characterized by the induction of pro-inflammatory cytokines. The aim of the present study was to analyze the effects of TNF,, IL-6 and IL-10 on key parameters of tendon homeostasis. Cultured primary human tenocytes were treated with the recombinant cytokines IL-6, IL-10, TNF,, or combinations of TNF, with IL-6 and IL-10 (10 ng/mL, 6, 24 h). Expression of type I collagen, elastin, MMP-1, TNF,, IL-1,, IL-6, IL-10, and suppressors of cytokine signaling (SOCS1, 3) was analyzed with the use of RTD-PCR, immunocytochemistry, and Western blot analysis. In response to TNF,, tenocytes reduced their type I collagen deposition but increased their elastin gene expression and highly upregulated their expression for MMP-1, pro-inflammatory (TNF,, IL-1,) and immunoregulatory (IL-6, IL-10) cytokines. TNF, stimulation augmented SOCS1, whereas SOCS3 expression in tenocytes was also induced by IL-6. The treatment of tenocytes with IL-6 and IL-10 had no effect on cytokine expression. Neither IL-6 nor IL-10 modulated the observed effects of TNF, significantly. These results indicate that TNF, strongly activates the tenocytes to amplify their own TNF, expression and, subsequently, that of other regulatory cytokines and matrix degrading enzymes. However, the impact of IL-6 and IL-10 on tenocytes remains unclear. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1071,1077, 2010 [source] Salutary effects of Corydalis yanhusuo extract on cardiac hypertrophy due to pressure overload in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2007Chengping Wen We have evaluated the effects of an alcohol extract from the rhizome of Corydalis yanhusuo W.T. (CY), a well-known traditional Chinese medicinal herb, on pressure-overloaded cardiac hypertrophy induced by transverse abdominal aorta constriction (TAAC) in rats. Rats were given vehicle or CY extract (200 or 50 mg kg,1 per day) from the second week after induction of pressure overload, for a period of 7 weeks. Haemodynamic parameters, relative heart weight and myocyte cross-sectional area were measured in each group. We also estimated left ventricular (LV) collagen volume fraction (CVF) using Masson trichrome staining, and type I collagen expression by Western blot assay. Chronic TAAC caused notable cardiac hypertrophy and heart dysfunction. Significant collagen deposition and greater type I collagen expression were found in model control rats. These changes were not significantly reversed after treatment with 50 mgkg,1 CY, whereas 200 mgkg,1 significantly improved heart function and prevented cardiac hypertrophy, with parallel reductions in myocardial fibrosis, as evidenced by reduced LV CVF and reduced levels of type I collagen. In conclusion, chronic treatment of rats with CY extract attenuated development of cardiac hypertrophy. [source] Protective effects of the Alisma orientalis extract on the experimental nonalcoholic fatty liver diseaseJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2006Xuezhi Hong The aim of this investigation was to evaluate the efficacy of Alisma orientalis methanolic extract (AOME) on the experimental nonalcoholic fatty liver disease (NAFLD) induced by high-fat diet. Rats were fed with high-fat diet for six weeks and then gavaged the AOME for another six weeks. Typical pathological symptoms of NAFLD occurred in the high-fat diet rats. Administration with the AOME (150,300 and 600 mg kg,1) markedly decreased the serum and liver lipids; the high level of fasting serum glucose was reduced and insulin resistance was improved. The AOME treatment was also helpful in preventing the oxidative stress by lessening lipid peroxidation and activating antioxidant enzymes. Markers of the liver injury, aminotransferase abnormalities and hepatomegaly were improved and morphological changes, such as liver steatosis, mixed inflammation and collagen deposition, were lessened in rats treated with the AOME. These results suggested that the AOME showed hepatoprotective effects on NAFLD and may be a potential clinical application for treatment of this chronic liver disease. [source] Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachloride-induced hepatic fibrosis in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2003Tzung-Yan Lee ABSTRACT Carbon tetrachloride (CCl4) is metabolized by cytochrome P450 to form a reactive trichloromethyl radical that triggers a chain of lipid peroxidation. These changes lead to cell injury, and chronic liver injury leads to excessive deposition of collagen in liver, resulting in liver fibrosis. The aim of this study was to evaluate the effects of long-term Salvia miltiorrhiza administration in CCl4 -induced hepatic injury in rats. Salvia miltiorrhiza (10, 25 or 50 mg kg,1 twice a day) was given for 9 weeks, beginning at the same time as the injections of CCl4. Rats receiving CCl4 alone showed a decreased hepatic glutathione level and an increased glutathione-S-transferase content. The hepatic thiobarbituratic acid-reactive substance levels were increased. CCl4 also caused a prominent collagen deposition in liver histology that was further supported by the increased hepatic mRNA expression of transforming growth factor-,1, tissue inhibitor of metallproteinase-1 and procollagen I. Salvia miltiorrhiza administration led to a dose-dependent increase in hepatic glutathione levels and a decrease in peroxidation products. Additionally, it reduced the mRNA expression of markers for hepatic fibrogenesis. In conclusion, long-term administration of Salvia miltiorrhiza in rats ameliorated the CCl4 -induced hepatic injury that probably related to a reduced oxidant stress and degree of hepatic fibrosis. [source] Curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitroJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2002Hee-Chul Kang We previously demonstrated that curcumin, a well-known antioxidant, inhibits collagen deposition in carbon tetrachloride-induced liver injury in rats. The major effector cells responsible for collagen synthesis in the liver are activated hepatic stellate cells. In this study, we investigated the inhibitory effects of curcumin on the collagen synthesis and activation of rat hepatic stellate cells in-vitro, and on hepatic stellate cell activation in-vivo. The effects of curcumin on the production of collagen and smooth muscle ,-actin proteins and of ,1(I) collagen mRNA were studied in-vivo and in-vitro. The effect of curcumin on DNA synthesis was also determined in-vitro. In-vivo, treatment with curcumin reduced collagen deposition and smooth muscle ,-actin-positive areas and lowered mRNA levels of type I collagen in the liver. In-vitro, curcumin at a concentration of 5 ,g mL,1 reduced DNA synthesis, and downregulated smooth muscle ,-actin and type I collagen expression, and ,1(I) collagen mRNA expression. We concluded that curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitro, and thus may prove a valuable anti-fibrogenic agent. [source] Histological changes occurring after endoluminal ablation with two diode lasers (940 and 1319 nm) from acute changes to 4 monthsLASERS IN SURGERY AND MEDICINE, Issue 10 2008FACS, Ronald G. Bush MD Abstract Background Endovenous laser ablation of the saphenous vein was studied from a histologic analysis to establish changes that occur from time of injury to 4 months when the vein is difficult to visualize by ultrasound. Methods Twenty-four patients were examined after treatment with either a 1319 nm diode laser (Sciton, Palo Alto, CA) or a 940 nm diode (Dornier, Kennasaw, GA) 12 patients were randomly assigned to the 940 nm group and 12 patients to the 1319 nm group. Histologic evaluations were only done once per patient. All patients had symptomatic saphenous insufficiency with varicosities. All were in CEAP class 3 or 4. Sections of treated veins were submitted for evaluation after staining with hematoxylin,eosin. The evaluations were done acutely, at 1 and 4 months. Ultrasound findings were also evaluated and compared at the same intervals. Results Acutely, all examined veins revealed loss of intima. In the 1319 nm group numerous vacuoles were present in the subintimal layer. On gross exam at 1 month, both groups showed vein wall thickening, intraluminal thrombus and inflammatory changes. Histologic evaluation showed thrombus was present with many fibroblasts and inflammatory cells. At 4 months, collagen was the predominant histologic finding. However, the changes were less in regards to the injury response with the 1,319 nm group as manifested by less collagen deposition at 4 months. Conclusion This study demonstrates the cellular sequence that occurs after endovenous ablation. Fibroblast infiltration is a result of the injury response which leads to negative modeling of the thrombus and eventual collagen deposition. Replacement of the thrombus with collagen is necessary for eventual long-term success. Lasers Surg. Med. 40:676,679, 2008. © 2008 Wiley-Liss, Inc. [source] Extracellular signal-regulated kinase-dependent interstitial macrophage proliferation in the obstructed mouse kidneyNEPHROLOGY, Issue 5 2008YINGJIE HAN SUMMARY: Aim: A number of growth factors have been shown to induce proliferation of renal cell types in animal models of kidney disease. In vitro studies suggest that many such growth factors induce renal cell proliferation through the extracellular signal-regulated kinase (ERK) pathway. The aim of this study was to determine the functional role of ERK signalling in cell proliferation in the obstructed kidney. Methods: Unilateral ureteric obstruction was induced in C57BL/6J mice which then received an ERK inhibitor drug (U0126 100 mg/kg t.i.d.), vehicle (DMSO) or no treatment, starting at day 2 after unilateral ureteric obstruction surgery and continuing until animals were killed on day 5. Cell proliferation was assessed by uptake of bromodeoxyuridine (BrdU). Results: In normal mice, phosphorylation (activation) of ERK (p-ERK) was restricted to collecting ducts. Western blotting identified a marked increase in p-ERK in the obstructed kidney in the no-treatment and vehicle-treated groups. Immunostaining showed strong p-ERK staining in many tubules and in interstitial cells. U0126 treatment inhibited ERK phosphorylation as assessed by western blot and immunostaining. The number of BrdU+ cortical tubular cells was reduced by vehicle treatment but was not further changed by U0126 treatment. In contrast, interstitial cell proliferation in the obstructed kidney was unaltered by vehicle treatment, but this was significantly inhibited by U0126. This was associated with a reduction in interstitial macrophage accumulation, but no effect was seen upon interstitial accumulation of ,-SMA+ myofibroblasts. Renal fibrosis, as assessed by collagen deposition, was unaffected by U0126 or vehicle treatment. Conclusion: These studies show that accumulation of interstitial macrophages in the obstructed kidney is, in part, dependent upon the ERK signalling pathway. [source] Effect of Low Intensity Helium,Neon (HeNe) Laser Irradiation on Experimental Paracoccidioidomycotic Wound Healing DynamicsPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 1 2009Maria Carolina Ferreira The effect of HeNe laser on the extracellular matrix deposition, chemokine expression and angiogenesis in experimental paracoccidioidomycotic lesions was investigated. At days 7, 8 and 9 postinfection the wound of each animal was treated with a 632.8 nm HeNe laser at a dose of 3 J cm,2. At day 10 postinfection, the wounds were examined by using histologic and immunohistochemical methods. Results revealed that laser-treated lesions were lesser extensive than untreated ones, and composed mainly by macrophages and lymphocytes. High IL-1, expression was shown in the untreated group whereas in laser-treated animals the expression was scarce. On the other hand, the expression of CXCL-10 was found to be reduced in untreated animals and quite intensive and well distributed in the laser-treated ones. Also, untreated lesions presented vascular endothelial growth factor (VEGF) in a small area near the center of the lesion and high immunoreactivity for hypoxia-inducible factor-1 (HIF-1), whereas laser-treated lesions expressed VEGF surrounding blood vessels and little immunoreactivity for HIF-1. Laser-treated lesions presented much more reticular fibers and collagen deposition when compared with the untreated lesion. Our results show that laser was efficient in minimizing the local effects observed in paracoccidioidomycosis and can be an efficient tool in the treatment of this infection, accelerating the healing process. [source] Morphologic and morphometric analyses of acetic acid-induced colitis in rats after treatment with enemas from Myracrodruon urundeuva Fr. All. (Aroeira do Sertão)PHYTOTHERAPY RESEARCH, Issue 3 2002Lusmar Veras Rodrigues Abstract The present work showed the effects of Myracrodruon urundeuva Fr. All., popularly known as ,aroeira' (AE), in the form of enemas prepared from the stem bark, on several morphologic and morphometric parameters after acetic acid-induced colitis in rats. Enemas from 5-ASA were used as standard while the vehicle, carboxymethylcellulose, was used as a control. The results of the morphological evaluation showed that on day 1 acetic acid produced significantly more necrosis in the groups treated with AE (10% and 20%) or 5-ASA than the controls. However, on day 60, there were more caliciform and absorptive cells in the treated groups compared with the controls. A significantly higher number of eosinophil and mononuclear cells and also collagen deposition in the controls compared with the treated groups were observed on day 60. However, a higher number of polymorphonuclear cells was detected on day 60 only in the AE treated group but not in the 5-ASA group. These data indicate that animals treated with AE or 5-ASA showed complete epithelial tissue regeneration, while in the controls chronic inflammatory exudate persisted and tissue regeneration occurred through fibrosis. Copyright © 2002 John Wiley & Sons, Ltd. [source] | ||||||||||||||||||||||||||||