An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis

Cho, Jaejin; Hocher, Berthold; Herbst, Hermann; Jia, Jidong; Ruehl, Martin; Hahn, Eckhart G.; Riecken, E. O.; Schuppan, Detlef

doi:10.1016/s0016-5085(00)70370-2

Cited by 158 publications

(121 citation statements)

References 44 publications

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“…39,41 Further supporting the concept that endothelin is important in fibrogenesis are in vivo studies showing a reduction in the fibrogenic response with endothelin antagonism. 86,87 These data are even more compelling given data in experimental models of fibrogenesis demonstrating increases in ET A and ET B receptor density on stellate cells after injury. 19,40 In a variety of diseases leading to parenchymal wound healing, including the liver, angiotensin II appears to be important in fibrogenesis.…”

Section: Fibrogenesis and Cirrhosismentioning

confidence: 99%

Vascular mediators in the injured liver

2003

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Section: Fibrogenesis and Cirrhosismentioning

confidence: 99%

Vascular mediators in the injured liver

2003

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“…Hydroxyproline content of the liver was quantified colorimetrically using 100 mg frozen liver tissue samples according to the method of Jamall et al 19 and the modification of Cho et al, 20 as described previously. 21 Histological Evaluation of the Tissues Sections of paraffin-embedded liver tissue were prepared and stained with hematoxylin and eosin, Gomori methenamine silver, Sirius red and chloracetate esterase to allow histological evaluation of liver fibrosis (staging) and the inflammatory activity in the liver (grading).…”

Section: Determination Of Hydroxyproline Contentmentioning

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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“…For this reason, its regulation is an active area of investigation. Competitive antagonists of endothelins and endothelin receptors have been shown to block contraction of stellate cells in culture (Rockey and Chung, 1996;Cho et al, 2000) but are as yet untested in humans. An open question concerns the effect of contraction on hepatic blood flow in the setting of acute and chronic injury, respectively.…”

Section: Contractionmentioning

confidence: 99%

“…This may reflect the other immunological functions of this cytokine: animals that overexpress interferon-γ in the liver exhibit a diffuse inflammatory infiltrate (Toyonaga et al, 1994). Other compounds that block stellate cell activation include endothelin antagonists (Rockey and Chung, 1996;Cho et al, 2000), pentoxifylline Preaux et al, 1997), halofuginone (Pines et al, 1997;Bruck et al, 2001), fumagillin (Wang et al, 2000) and inhibitors of angiotensin II (Yoshiji et al, 2001). Natural products also have yielded candidate compounds, based on studies in culture and in experimental models of fibrosis.…”

Section: Inhibition Of Stellate Cell Activationmentioning

confidence: 99%

Chronic liver injury, TGF-β, and cancer

Bissell

2001

Exp Mol Med

154

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Cells termed myofibroblasts are prominent in the injury response of all epithelial tissues. They exhibit proliferation, migration, production of collagen and other extracellular matrix (ECM) molecules, and contraction, all for containing the injury and closing the wound. When the injury is limited in time, the final stage of the repair involves a dismantling of the cellular apparatus and restoration of normal tissue structure. With multiple cycles of repair, however, there is net accumulation of ECM, to the detriment of tissue structure and function. Repair-related ECM coalesces into fibrous bundles and, over time, undergoes changes that render it resistant to degradation. The result is a scar. In the skin, a scar may have cosmetic importance only. In the liver, however, extensive scarring is the setting for unregulated growth and neoplasia; also, fibrous bands disrupt normal blood flow, leading to portal hypertension and its complications. With regard to therapy for fibrosis, the first consideration is elimination of the injury factor. However, given that many liver diseases do not have effective therapies at present, strategies targeting fibrogenesis per se are under development. The main source of myofibroblast-like cells and ECM production in the liver is the perisinusoidal stellate cell, which responds to injury with a pleiotypic change termed activation. Activation is orchestrated by cytokines and the ECM itself. Among the cytokines involved in this process, transforming growth factor-beta (TGF-β) is particularly prominent. The early changes in ECM include de novo production of a specific "fetal" isoform of fibronectin, which arises from sinusoidal endothelial cells. It is stimulated by TGF-β and acts directly on stellate cells to promote their activation. Based on these and other advances in understanding the fundamentals of the injury response, several strategies now exist for altering fibrogenesis, ranging from agents that block TGF-β to traditional Chinese herbal extracts. Arrest of fibrogenesis, even with underlying cirrhosis, is likely to extend life or prolong the time to transplant. Whether it reduces the risk of hepatocellular carcinoma remains to be proven. Although TGF-β antagonists are effective anti-fibrogenic agents, they will require detailed safety testing because of the finding that several forms of epithelial neoplasia are associated with altered regulation of TGF-β.

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An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis

Cited by 158 publications

References 44 publications

Vascular mediators in the injured liver

Vascular mediators in the injured liver

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

Chronic liver injury, TGF-β, and cancer

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