transforming-growth-factor-beta and Cholangitis--Sclerosing

The pathogenesis of primary biliary cirrhosis (PBC) is unknown. The role of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), and the effect of ursodeoxycholic acid (UDCA) in modifying the cytokine environment in patients with PBC has remained largely unstudied. Our aims were to determine: (i) the relationship between serum levels of TNF-alpha and TGF-beta and the severity of PBC; and (ii) the effects of UDCA therapy on TNF-alpha and TGF-beta levels in patients with PBC.. We studied 90 patients who had been treated with UDCA (53 patients) or placebo (37 patients) for 2 years as part of a randomized, double-blind, controlled trial. Patients were divided into histological stage I/II or stage III/IV disease. Serum TNF-alpha and TGF-beta levels were quantified by enzyme-linked immunoabsorbent assay.. Baseline levels of TNF-alpha were significantly greater in patients with stage III/IV compared to stage I/II disease. After 2 years of treatment with UDCA, patients showed a significantly greater decrease in TNF-alpha levels and progression risk score compared to placebo-treated patients. TNF-alpha and TGF-beta levels were significantly reduced compared to baseline levels in the UDCA-treated group after 2 years, while there was no significant change in the levels of placebo-treated patients.. Serum TNF-alpha and TGF-beta levels may reflect severity of disease in patients with PBC. The beneficial effects of UDCA therapy may be explained by lowering serum levels of these two cytokines.

Topics: Adult; Biomarkers; Biopsy; Cholagogues and Choleretics; Cholangitis, Sclerosing; Double-Blind Method; Female; Hepatitis C; Humans; Liver; Liver Cirrhosis, Biliary; Liver Diseases, Alcoholic; Male; Middle Aged; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ursodeoxycholic Acid

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with high propensity to develop into cholangiocarcinoma. The hepatobiliary disorder of PSC is due to progressive fibrosis surrounding the intra- and extrahepatic bile ducts. Until now, no effective medical therapy exists. To study the progression of sclerosing cholangitis after inhibition of the sympathetic nervous system by blockade of the β-adrenoceptors, we used the Mdr2(-/-) mouse model, which develops periportal fibrosis similar to human PSC. Liver tissues of Mdr2(-/-) mice untreated or treated with the β-adrenoceptor antagonist propranolol were analyzed for inflammation and fibrosis progression at different time points by histological scoring and immunostaining for α-smooth muscle actin (α-SMA), CD45 and S100A4. Transaminases and hydroxyproline contents were determined. Expression of angiotensinogen, endothelin-1, TGF-β, TNF-α, CTGF and procollagen 1A1 was studied by real-time PCR on laser-microdissected areas of acinar zones I and II-III. After 3 months, periportal fibrosis had developed in Mdr2(-/-) mice, but immunostaining revealed no sinusoidal and only minor periportal contribution of myofibroblasts with prominent fibroblasts. Propranolol treatment of Mdr2(-/-) mice improved liver architecture. Additionally, inflammation and fibrosis were significantly reduced. After 3 months of treatment, the antifibrotic effect of the β-blockade was most obvious. The transcript levels of procollagen 1A1, TNF-α, TGF-β, CTGF and endothelin-1 were markedly repressed in the portal areas of treated mice. Taken together, these data show that propranolol efficiently delays progression of sclerosing cholangitis. Therefore, the blockade of β-adrenoceptors is a promising option to support future therapeutic strategies in the treatment of human PSC.

Topics: Actins; Adrenergic beta-Antagonists; Animals; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Sub-Family B Member 4; Bile Ducts; Blood Pressure; Cholangitis, Sclerosing; Collagen Type I; Collagen Type I, alpha 1 Chain; Connective Tissue Growth Factor; Endothelin-1; Histological Techniques; Immunohistochemistry; Lasers; Leukocyte Common Antigens; Liver Cirrhosis; Mice; Mice, Knockout; Microdissection; Propranolol; Reverse Transcriptase Polymerase Chain Reaction; S100 Calcium-Binding Protein A4; S100 Proteins; Sympathetic Nervous System; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder of unknown etiology characterized by progressive fibrosis and stricturing of the biliary tract. Transforming growth factor-beta (TGF-beta) is a family of cytokines produced by biliary tract epithelial cells that promote fibrinogenesis. Our objective was to determine whether TGF-beta levels are increased in the blood and/or bile of PSC patients compared to patients with other causes of obstructed biliary tracts (controls). Serum and bile TGF-beta levels were documented by enzyme-linked immunoassay in 10 adult PSC and 10 control patients obtained at the time of endoscopic retrograde cholangiography. Serum and bile TGF-beta levels were similar in the two groups (PSC versus control sera, 33.4 +/- 4.3 versus 27.5 +/- 7.7 ng/ml, and bile, 367 +/- 275 versus 457 +/- 247 ng/mg, respectively). Serum and bile TGF-beta levels are not increased in patients with PSC. Hence, the results of this pilot study do not support the hypotheses that PSC is caused by dysregulated TGF-beta expression.

Topics: Alkaline Phosphatase; Bile; Case-Control Studies; Cholangiography; Cholangitis, Sclerosing; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Pilot Projects; Severity of Illness Index; Transforming Growth Factor beta

To determine what changes are occurring in patients with primary sclerosing cholangitis (PSC) by examining perisinusoidal macrophages (Kupffer cells) in liver biopsies; 2-to measure transforming growth factor beta (TGFbeta) as a marker of fibrosis in these patients.. Transmission electron microscopy and immunohistochemistry of 15 PSC, 26 primary biliary cirrhosis (PBC), 30 alcoholic liver disease (ALD) and 51 with normal histology was used. Five PSC, 30 ALD and 120 normal volunteers were sampled for serum levels of TGFbeta.. There was a three-fold increase in relative numbers of Kupffer cells in PSC compared to PBC and to patients whose livers had normal histology. In PSC there was an accumulation of perisinusoidal macrophages, which was not associated with focal necrosis or with cholestasis. The levels of TGFbeta in PSC were 54 +/- 2 in cirrhotic versus 34 +/- 5 in non-cirrhotic patients (p < 0.005).. The persistent activation of these macrophages may lead to the chronic release of TGFbeta and contribute to chronic inflammation, fibrosis and cirrhosis.

Topics: Adolescent; Adult; Aged; Biopsy; Case-Control Studies; Cholangitis, Sclerosing; Female; Humans; Immunohistochemistry; Liver; Liver Cirrhosis, Biliary; Liver Diseases, Alcoholic; Macrophages; Male; Microscopy, Electron; Middle Aged; Transforming Growth Factor beta