An update on primary sclerosing cholangitis

Maggs, James; Chapman, Roger W.

doi:10.1097/mog.0b013e3282f9e239

Cited by 103 publications

(57 citation statements)

References 40 publications

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“…Therefore, development of causative treatment is challenging and no specific medical therapy is currently available (216). UDCA is the only medication to date showing some efficacy in PSC patients, primarily on liver biochemistry (117). Other drugs such as immunosuppressive, antifibrotic, or antibiotic agents were suggested but have not been assessed in large clinical trials (38,216).…”

Section: Animal Models Of Pscmentioning

confidence: 99%

Animal models of chronic liver diseases

Liu

Meyer

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

201

154

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Chronic liver diseases are frequent and potentially life threatening for humans. The underlying etiologies are diverse, ranging from viral infections, autoimmune disorders, and intoxications (including alcohol abuse) to imbalanced diets. Although at early stages of disease the liver regenerates in the absence of the insult, advanced stages cannot be healed and may require organ transplantation. A better understanding of underlying mechanisms is mandatory for the design of new drugs to be used in clinic. Therefore, rodent models are being developed to mimic human liver disease. However, no model to date can completely recapitulate the “corresponding” human disorder. Limiting factors are the time frame required in humans to establish a certain liver disease and the fact that rodents possess a distinct immune system compared with humans and have different metabolic rates affecting liver homeostasis. These features account for the difficulties in developing adequate rodent models for studying disease progression and for testing new pharmaceuticals to be translated into the clinic. Nevertheless, traditional and new promising animal models that mimic certain attributes of chronic liver diseases are established and being used to deepen our understanding in the underlying mechanisms of distinct liver diseases. This review aims at providing a comprehensive overview of recent advances in animal models recapitulating different features and etiologies of human liver diseases.

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Section: Animal Models Of Pscmentioning

confidence: 99%

Animal models of chronic liver diseases

Liu

Meyer

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

201

154

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“…In two-thirds of patients, primary sclerosing cholangitis is associated with IBD mainly ulcerative colitis (UC). 12 The etiology is still poorly understood and there are no mechanistic explanations for the strong association between primary sclerosing cholangitis and IBD to date.…”

mentioning

confidence: 99%

Alterations in Enterohepatic Fgf15 Signaling and Changes in Bile Acid Composition Depend on Localization of Murine Intestinal Inflammation

Rau

Stieger²,

Monte

et al. 2016

Inflammatory Bowel Diseases

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BACKGROUND: Fibroblast growth factor (FGF) 15/19 is part of the gut-liver crosstalk accounting for bile acid (BA) metabolism regulation. Dysregulation of fibroblast growth factor 15/19 signaling is observed in different pathological conditions, for example, in gastrointestinal diseases such as inflammatory bowel disease (IBD). To understand the molecular bases, we analyzed the enterohepatic regulation of Fgf15-mediated pathway in 2 different inflammatory bowel disease mouse models. METHODS: Target genes of the BA-farnesoid-X-receptor (Fxr)-Ffg15 axis were quantified by RT-PCR or western blotting in gut and liver of dextran sulfate sodium (DSS)-treated and IL10 mice. Serum Fgf15 levels were analyzed by ELISA. Biliary and fecal BA composition was differentiated by HPLC-MS/MS. RESULTS: Dextran sulfate sodium-treated mice with ileum-sparing colitis showed higher Fgf15 serum levels. In contrast, IL10 mice with ileitis had a trend toward decreased Fgf15 serum levels compared with controls and increased expression of Asbt as a negative Fxr-target gene. In hepatic tissue of both models, no histological changes, but higher interleukin 6 (IL-6) mRNA expression and down-regulation of Fxr and Cytochrom P450 7a1 mRNA expression were observed. Fibroblast growth factor receptor 4 up-regulation was in line with higher Fgf15 serum levels in dextran sulfate sodium-treated mice. A distinct fecal BA profile was observed in both models with significantly higher levels of taurine-conjugated BA in particular tauro--muricholic acid in IL10 mice. CONCLUSIONS: Ileum-sparing colitis is characterized by activation of Fxr-Fgf15 signaling with higher expression of Fxr-target gene Fgf15, whereas ileal inflammation showed no signs of Fxr-Fgf15 activation. Abundance of BA such as T--MCA may be important for intestinal Fxr activation in mice.

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“…The most promising drug so far has been UDCA, showing beneficial effects primarily on liver biochemistry. 9 Thus, there is currently no proven pharmacological therapy for PSC. 3 The most definitive treatment of PSC is still liver transplantation.…”

mentioning

confidence: 99%

β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis

Strack

Schulte

Varnholt

et al. 2011

Laboratory Investigation

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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 b-adrenoceptors, we used the Mdr2 À/À mouse model, which develops periportal fibrosis similar to human PSC. Liver tissues of Mdr2 À/À mice untreated or treated with the b-adrenoceptor antagonist propranolol were analyzed for inflammation and fibrosis progression at different time points by histological scoring and immunostaining for a-smooth muscle actin (a-SMA), CD45 and S100A4. Transaminases and hydroxyproline contents were determined. Expression of angiotensinogen, endothelin-1, TGF-b, TNF-a, 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 À/À mice, but immunostaining revealed no sinusoidal and only minor periportal contribution of myofibroblasts with prominent fibroblasts. Propranolol treatment of Mdr2 À/À mice improved liver architecture. Additionally, inflammation and fibrosis were significantly reduced. After 3 months of treatment, the antifibrotic effect of the b-blockade was most obvious. The transcript levels of procollagen 1A1, TNF-a, TGF-b, 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 b-adrenoceptors is a promising option to support future therapeutic strategies in the treatment of human PSC.

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An update on primary sclerosing cholangitis

Cited by 103 publications

References 40 publications

Animal models of chronic liver diseases

Animal models of chronic liver diseases

Alterations in Enterohepatic Fgf15 Signaling and Changes in Bile Acid Composition Depend on Localization of Murine Intestinal Inflammation

β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis

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