Cirrhosis and its clinical consequences can be aggravated by bacterial infections, ultimately leading to the development of acute on chronic liver failure (ACLF), characterized by acute decompensation, organ failure, and high mortality within 28 days. Little is known about cellular and molecular mechanisms of ACLF in patients with cirrhosis, so no therapeutic options are available. We developed a sepsis-associated preclinical model of ACLF to facilitate studies of pathogenesis and evaluate the protective effects of simvastatin. Male Wistar rats inhaled CCl4 until they developed cirrhosis (at 10 weeks) or cirrhosis with ascites (at 15-16 weeks). Male Sprague-Dawley rats received bile-duct ligation for 28 days or intraperitoneal thioacetamide for 10 weeks to induce cirrhosis. After induction of cirrhosis, some rats received a single injection of lipopolysaccharide (LPS) to induce ACLF; some were given simvastatin or vehicle (control) 4 hours or 24 hours before induction of ACLF. We collected data on changes in hepatic and systemic hemodynamics, hepatic microvascular phenotype and function, and survival times. Liver tissues and plasma were collected and analyzed by immunoblots, quantitative polymerase chain reaction, immuno(fluoro)histochemistry and immunoassays. Administration of LPS aggravated portal hypertension in rats with cirrhosis by increasing the severity of intrahepatic microvascular dysfunction, exacerbating hepatic inflammation, increasing oxidative stress, and recruiting hepatic stellate cells and neutrophils. Rats with cirrhosis given LPS had significantly shorter survival times than rats with cirrhosis given the control. Simvastatin prevented most of ACLF-derived complications and increased survival times. Simvastatin appeared to increase hepatic sinusoidal function and reduce portal hypertension and markers of inflammation and oxidation. The drug significantly reduced levels of transaminases, total bilirubin, and ammonia, as well as LPS-mediated activation of hepatic stellate cells in liver tissues of rats with cirrhosis. In studies of rats with cirrhosis, we found administration of LPS to promote development of ACLF, aggravating the complications of chronic liver disease and decreasing survival times. Simvastatin reduced LPS-induced inflammation and liver damage in rats with ACLF, supporting its use in treatment of patients with advanced chronic liver disease.

Beta-Cell mass reduction is a central aspect in the development of type 1 and type 2 diabetes, and substitution or regeneration of the lost beta-cells is a potentially curative treatment of diabetes. To study the effects of gastrin on beta-cell mass in rats with 95% pancreatectomy (95%-Px), a model of pancreatic regeneration, rats underwent 95% Px or sham Px and were treated with [15 leu] gastrin-17 (Px + G and S + G) or vehicle (Px + V and S + V) for 15 d. In 95% Px rats, gastrin treatment reduced hyperglycemia (280 +/- 52 mg vs. 436 +/- 51 mg/dl, P < 0.05), and increased beta-cell mass (1.15 +/- 0.15 mg)) compared with vehicle-treated rats (0.67 +/- 0.15 mg, P < 0.05). Gastrin treatment induced beta-cell regeneration by enhancing beta-cell neogenesis (increased number of extraislet beta-cells in Px + G: 0.42 +/- 0.05 cells/mm(2) vs. Px + V: 0.27 +/- 0.07 cells/mm2, P < 0.05, and pancreatic and duodenal homeobox 1 expression in ductal cells of Px + G: 1.21 +/- 0.38% vs. Px + V: 0.23 +/- 0.10%, P < 0.05) and replication (Px + G: 1.65 +/- 0.26% vs. S + V: 0.64 +/- 0.14%; P < 0.05). In addition, reduced beta-cell apoptosis contributed to the increased beta-cell mass in gastrin-treated rats (Px + G: 0.07 +/- 0.02%, Px + V: 0.23 +/- 0.05%; P < 0.05). Gastrin action on beta-cell regeneration and survival increased beta-cell mass and improved glucose tolerance in 95% Px rats, supporting a potential role of gastrin in the treatment of diabetes. (Endocrinology 152: 2580-2588, 2011)