Role of αvβ6 integrin in acute biliary fibrosis

Wang, Bruce; Dolinski, Brian; Kikuchi, N; Leone, Diane R.; Peters, Marion G.; Weinreb, Paul H.; Violette, Shelia M.; Bissell, D. Montgomery

doi:10.1002/hep.21849

Cited by 149 publications

(149 citation statements)

References 45 publications

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“…For example, the integrin αvβ6 is up-regulated only on biliary epithelium during experimental cholestatic liver fibrosis, 59 implying that antagonists to this integrin might be more rational in biliary than in parenchymal liver diseases.…”

Section: Cellular Sources Of Ecm In Hepatic Fibrosis: An Evolving Parmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, posttranscriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.The field of hepatic fibrosis is flourishing thanks to continued experimental advances complemented by exciting progress in the treatment of chronic liver disease. 1 Control of chronic hepatitis B and C by antiviral therapies has established that advanced fibrosis can regress in association with improved clinical outcomes, 2-4 thereby intensifying enthusiasm to uncover the mechanistic basis for hepatic fibrogenesis and its attenuation. At the same time, simple paradigms defining the cellular sources of extracellular matrix (ECM), and the roles of cytokines and paracrine interactions among resident liver cells and inflammatory cells have yielded a more nuanced understanding of how the liver responds to injury. These advances have had a collateral benefit towards understanding fibrosis in other organs, particularly the pancreas. 5 Thus, a review of the mechanisms underlying hepatic fibrosis is not only timely, but is more clinically relevant than ever. This article focuses on recent advances in the field, building on established principles from earlier reviews 6,7 while weaving in their clinical relevance, but also emphasizing the molecular subtleties that have emerged through continued progress in the field. General PrinciplesFibrosis, or scarring of the liver, is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although even acute injury will activate mechanisms of fibrogenesis, the sustained signals associated with chronic liver disease caused by infection, Cirrhosis, the most advanced stage ...

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Section: Cellular Sources Of Ecm In Hepatic Fibrosis: An Evolving Parmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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“…50 In the liver, ␣v␤6 is exclusively expressed on activated cholangiocytes that are potent promoters of liver fibrogenesis. 17,26,51 Its successful targeting by a blocking antibody 51 or a small molecule inhibitor specifically blocked proliferation of profibrogenic cholangiocytes and concomitant TGF␤1 activation at the site of fibrogenesis. 17,26 Promising targeted approaches are summarized in Table 3.…”

Section: Antifibrotic Drug Developmentmentioning

confidence: 99%

Targeting Liver Fibrosis

2009

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We have made striking progress in our understanding of the biochemistry and cell biology that underlies liver fibrosis and cirrhosis, including the development of strategies and agents to prevent and reverse fibrosis. However, translation of this knowledge into clinical practice has been hampered by (1) the limitation of many in vitro and in vivo models to confirm mechanisms and to test antifibrotic agents, and (2) the lack of sensitive methodologies to quantify the degree of liver fibrosis and the dynamics of fibrosis progression or reversal in patients. Furthermore, whereas cirrhosis and subsequent decompensation are accepted hard clinical endpoints, fibrosis and fibrosis progression alone are merely plausible surrogates for future clinical deterioration. In this review we focus on an optimized strategy for preclinical antifibrotic drug development and highlight the current and future techniques that permit noninvasive assessment and quantification of liver fibrosis and fibrogenesis. The availability of such noninvasive methodologies will serve as the pacemaker for the clinical development and validation of potent antifibrotic agents. (HEPATOLOGY 2009;50:1294-1306

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“…by a V b 6 integrin contributes to peribiliary fibrosis in models of cholestatic liver injury (Wang et al, 2007a;Patsenker et al, 2008;Sullivan et al, 2010). Peribiliary collagen deposits probably represent early activation of portal fibroblasts by TGFb1 (Dranoff and Wells, 2010;Lee and Friedman, 2011).…”

Section: Antifibrinolytic Therapy Reduces Liver Injury and Fibrosismentioning

confidence: 99%

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

Joshi

Kopec

Towery

et al. 2014

J Pharmacol Exp Ther

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Hepatic fibrin deposition has been shown to inhibit hepatocellular injury in mice exposed to the bile duct toxicant a-naphthylisothiocyanate (ANIT). Degradation of fibrin clots by fibrinolysis controls the duration and extent of tissue fibrin deposition. Thus, we sought to determine the effect of treatment with the antifibrinolytic drug tranexamic acid (TA) and plasminogen activator inhibitor-1 (PAI-1) deficiency on ANIT-induced liver injury and fibrosis in mice. Plasmin-dependent lysis of fibrin clots was impaired in plasma from mice treated with TA (1200 mg/kg i.p., administered twice daily). Prophylactic TA administration reduced hepatic inflammation and hepatocellular necrosis in mice fed a diet containing 0.025% ANIT for 2 weeks. Hepatic type 1 collagen mRNA expression and deposition increased markedly in livers of mice fed ANIT diet for 4 weeks. To determine whether TA treatment could inhibit this progression of liver fibrosis, mice were fed ANIT diet for 4 weeks and treated with TA for the last 2 weeks. Interestingly, TA treatment largely prevented increased deposition of type 1 collagen in livers of mice fed ANIT diet for 4 weeks. In contrast, biliary hyperplasia/inflammation and liver fibrosis were significantly increased in PAI-1 2/2 mice fed ANIT diet for 4 weeks. Overall, the results indicate that fibrinolytic activity contributes to ANIT diet-induced liver injury and fibrosis in mice. In addition, these proof-of-principle studies suggest the possibility that therapeutic intervention with an antifibrinolytic drug could form a novel strategy to prevent or reduce liver injury and fibrosis in patients with liver disease.

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Role of αvβ6 integrin in acute biliary fibrosis

Cited by 149 publications

References 45 publications

Mechanisms of Hepatic Fibrogenesis

Mechanisms of Hepatic Fibrogenesis

Targeting Liver Fibrosis

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

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