Expression and matrix deposition of latent transforming growth factor β binding proteins in normal and fibrotic rat liver and transdifferentiating hepatic stellate cells in culture

Breitkopf, Katja; Lahme, Birgit; Tag, Carmen G.; Gressner, A. M.

doi:10.1053/jhep.2001.21996

Cited by 50 publications

(29 citation statements)

References 51 publications

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“…The value of serum TGF-β1 levels has certain limitations, including the potential contamination of samples by TGF-β1 from platelets, interference by plasmin activity in the plasma that increases the amount of TGF-β1, the binding of TGF-β1 to the ECM and vascular endothelium at sites of injury, sequestration by soluble proteins and the complicated clearance of TGF-β1. These factors explain why plasma levels of TGF-β1 are unlikely to be of diagnostic value (Breitkopf et al 2001). In agreement with these observations and in parallel with our study, serum TGF-β1 levels showed no statistically significant differences among fibrosis stages in paediatric patients.…”

Section: Discussionsupporting

confidence: 92%

“…In hepatic pathology, TGF-β1 is the most important stimulus for the production of ECM by HSCs (Sasaki et al 1992) and is also an inhibitor of hepatocyte growth and proliferation (Nakamura et al 1985). In liver biopsies from patients with chronic liver disease, TGF-β1 levels are correlated with type I collagen mRNA (Breitkopf et al 2001). The value of serum TGF-β1 levels has certain limitations, including the potential contamination of samples by TGF-β1 from platelets, interference by plasmin activity in the plasma that increases the amount of TGF-β1, the binding of TGF-β1 to the ECM and vascular endothelium at sites of injury, sequestration by soluble proteins and the complicated clearance of TGF-β1.…”

Section: Discussionmentioning

confidence: 99%

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Performance of diagnostic biomarkers in predicting liver fibrosis among hepatitis C virus-infected Egyptian children

Nassef

Shady

Galal

et al. 2013

Mem. Inst. Oswaldo Cruz

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Performance of diagnostic biomarkers in predicting liver fibrosis among hepatitis C virus-infected Egyptian children

Nassef

Shady

Galal

et al. 2013

Mem. Inst. Oswaldo Cruz

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“…ut-PA regulates matrix degradation (45) and is involved in inflammation and angiogenesis (14). Plasmin generated by ut-PA is required for the release of active TGF-␤ 1 from its latent form bound to the latency-associated peptide (9). Finally, downregulation of TIMP-1 in the subgroup of patients with improvement in liver fibrosis is in agreement with previous reports on the effects of AT1 receptor blockers in experimental models of liver injury (21,22).…”

Section: Discussionsupporting

confidence: 88%

Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C

Colmenero

Bataller

Sancho‐Bru

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

113

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Colmenero J, Bataller R, Sancho-Bru P, Domínguez M, Moreno M, Forns X, Bruguera M, Arroyo V, Brenner DA, Ginès P. Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am J Physiol Gastrointest Liver Physiol 297: G726 -G734, 2009. First published July 23, 2009 doi:10.1152/ajpgi.00162.2009.-Angiotensin II promotes liver fibrogenesis by stimulating nonphagocytic NADPH oxidase (NOX)-induced oxidative stress. Angiotensin II type 1 (AT1) receptor blockers attenuate experimental liver fibrosis, yet their effects in human liver fibrosis are unknown. We investigated the effects of losartan on hepatic expression of fibrogenic, inflammatory, and NOX genes in patients with chronic hepatitis C (CHC). Fourteen patients with CHC and liver fibrosis received oral losartan (50 mg/ day) for 18 mo. Liver biopsies were performed at baseline and after treatment. The degree of inflammation and fibrosis was evaluated by histological analysis (METAVIR). Collagen content was measured by morphometric quantification of Sirius red staining. Overall collagen content and fibrosis stage remained stable in the whole series, yet the fibrosis stage decreased in seven patients. Inflammatory activity improved in seven patients. The effect of losartan on hepatic expression of 31 profibrogenic and inflammatory genes and components of the NOX complex was assessed by quantitative PCR. Losartan treatment was associated with a significant decrease in the expression of several profibrogenic and NOX genes including procollagen ␣1(I) and ␣1(IV), urokinase-type plasminogen activator, metalloproteinase type 2, NOX activator 1 (NOXA-1) and organizer 1 (NOXO-1), and Rac-1. Losartan was well tolerated in all patients and was effective in attenuating the activity of the systemic renin-angiotensin system. No effects on serum liver tests or viral load were observed. We conclude that prolonged administration of losartan, an oral AT1 receptor blocker, is associated with downregulation of NOX components and fibrogenic genes in patients with CHC. Controlled studies are warranted to assess the effect of AT1 receptor blockers in chronic liver injury.angiotensin; liver fibrosis; antifibrogenic ACCUMULATING EVIDENCE INDICATES that the renin-angiotensin system (RAS) is a major mediator in liver fibrogenesis. Key components of the RAS are locally expressed in chronically injured livers and activated hepatic stellate cells de novo generate angiotensin II (5), the main effector peptide of this system. Angiotensin II induces an array of fibrogenic actions in hepatic stellate cells (HSC) including cell proliferation, migration, secretion of proinflammatory cytokines, and collagen synthesis (34). The fibrogenic and inflammatory actions of angiotensin II in the liver are largely mediated by angiotensin type 1 (AT1) receptors (5). The production of intracellular reactive oxygen species generated by the nonphagocytic NADPH oxidase (NOX) complex is a key event in the angiotensin II-mediated fibrogenesis (...

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“…In contrast activated HSCs (7 days in culture) are not equally responsive to TGF-β [15]. Furthermore, increased expression of TGF-β and constitutively phosphorylated Smad3 in activated HSCs indicate autocrine stimulation [16][17][18][19]. Since TGF-β also induces Smad7 expression in quiescent HSCs, a tightly controlled TGF-β signaling is anticipated, whereas lack of Smad7 expression in autocrine activated MFBs could be relevant for the pathogenesis of progressive liver fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling

Seyhan¹,

Hamzavi

Wiercinska

et al. 2006

Journal of Cellular and Molecular Medicine

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Background/Aims: Profibrogenic TGF-β signaling in hepatic stellate cells is modulated during transdifferentiation. Strategies to abrogate TGF-β effects provide promising antifibrotic results, however, in vivo data regarding Smad activation during fibrogenesis are scarce. Methods: Here, liver fibrosis was assessed subsequent to bile duct ligation by determining liver enzymes in serum and collagen deposition in liver tissue. Activated hepatic stellate cells were identified by immunohistochemistry and immunoblots for alpha smooth muscle actin. Cellular localization of Smad3 and Smad7 proteins was demonstrated by immunohistochemistry. RTPCR for Smad4 and Smad7 was conducted with total RNA and Northern blot analysis for Smad7 with mRNA. Whole liver lysates were prepared to detect Smad2/3/4 and phospho- Smad2/3 by Western blotting. Results: Cholestasis induces TGF-β signaling via Smad3 in vivo , whereas Smad2 phosphorylation was only marginally increased. Smad4 expression levels were unchanged. Smad7 expression was continuously increasing with duration of cholestasis. Hepatocytes of fibrotic lesions exhibited nuclear staining Smad3. In contrast to this, Smad7 expression was localized to activated hepatic stellate cells. Conclusions: Hepatocytes of damaged liver tissue display increased TGF-β signaling via Smad3. Further, negative feedback regulation of TGF-β signaling by increased Smad7 expression in activated hepatic stellate cells occurs, however does not interfere with fibrogenesis.

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Expression and matrix deposition of latent transforming growth factor β binding proteins in normal and fibrotic rat liver and transdifferentiating hepatic stellate cells in culture

Cited by 50 publications

References 51 publications

Performance of diagnostic biomarkers in predicting liver fibrosis among hepatitis C virus-infected Egyptian children

Performance of diagnostic biomarkers in predicting liver fibrosis among hepatitis C virus-infected Egyptian children

Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C

Liver fibrogenesis due to cholestasis is associated with increased Smad7 expression and Smad3 signaling

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