Common Bile Duct Ligation as Model for Secondary Biliary Cirrhosis
Cholestatic liver disease covers a range of biliary disorders marked by an impaired bile duct flow. Various conditions can result in bile obstruction including choledocholithiasis, surgical trauma, and autoimmune disorders. Cholestatic liver disease can b
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roduction Biliary, cholestatic liver diseases include a variety of disorders of bile duct flow obstruction or misformation and malfunction that can affect both sexes at every age and every geographical location [1]. Causes of bile flow obstruction can be choledocholithiasis, choledochal cysts, surgical trauma, constricting carcinomas, and autoimmune disorders [2, 3]. Two immune-mediated cholestatic diseases are primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, and primary sclerosing cholangitis (PSC) [1]. In PBC, small- to medium-sized intralobular bile ducts are affected, while in PSC primarily the medium-sized and large bile ducts are involved [1]. Consequently, ligation of the common bile duct might offer a better model for the investigation of PSC-related pathology rather than for PBC. Cholestatic liver disease can be mild, but generally progresses to more severe conditions with increased Mathieu Vinken (ed.), Experimental Cholestasis Research, Methods in Molecular Biology, vol. 1981, https://doi.org/10.1007/978-1-4939-9420-5_15, © Springer Science+Business Media, LLC, part of Springer Nature 2019
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hepatobiliary injury due to bile salt toxicity and mechanic stress, cholangitis, and ultimately liver fibrosis and cirrhosis [4, 5]. Bile flow obstruction induces various pathophysiological consequences, including liver dysfunction and portal hypertension, by hampering the hepatic blood flow and impairing the metabolic and synthetic capacities of the liver [6]. Furthermore, it might result in renal failure, ascites, compromised cardiac function, coagulation malfunctioning, pulmonary complications, and an increased endotoxin absorption due to intestinal mucosal barrier dysfunction, which may lead to impaired immune responses and sepsis [2, 6–8]. Common bile duct ligation (CBDL) in mice and rats offers a rewarding platform to investigate the pathophysiological processes and potentially intervening therapies in cholestatic liver disease and associated complications [9–13]. In mice, CBDL results in the gradual development of different stages of cholestatic-induced liver disease, which can be classified as the induction of cholestasis, subsequently accompanied by liver inflammation and finally the emergence of liver fibrosis and cirrhosis [9, 14, 15]. The timeframe in which these processes occur is greatly dependent on the mouse strains and their genetic background, but highly reproducible within one strain [9, 15, 16]. Induction of cholestasis by bile duct ligation is characterized by acute hepatocellular injury and biliary infarcts, which results in increased aminotransferase and aspartate transaminase levels and a rise in total and direct bilirubin levels [9, 14]. Cellular injury results in an inflammatory response which is mediated by immune cell infiltration and is characterized by the proliferation of bile ducts, dilatation of bile canaliculi, and portal tract enlargement [9, 14]. Bile duct proliferation in CBDL- operated mice is visualized in Fig
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