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Simvastatin Attenuates Liver Injury in Rodents with Biliary Cirrhosis Submitted to Hemorrhage/Resuscitation

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Abstract

Liver function deterioration is a major cause of death in variceal bleeding. The effects of bleeding on intrahepatic microvascular dysfunction, which contributes to liver injury in cirrhosis, are largely unknown. The aims of this study were to evaluate the impact of hemorrhage/resuscitation (H/R) on cirrhotic microcirculation, and whether simvastatin, a drug that improves liver microcirculation, has hepatoprotective effects. The study was performed in three groups of rats: controls, rats with biliary cirrhosis (CBDL), and CBDL rats pretreated with three doses (5 mg × kg−1 × day−1) of simvastatin. Rats were submitted to H/R or sham procedure. Subsequently, livers were isolated and perfused for functional assessment of liver microcirculation. Liver transcriptome was assessed with microarrays. H/R significantly impaired endothelial-dependent vasorelaxation in cirrhotic (P = 0.035) but not control livers. H/R induced a similar increase in ALT in control and cirrhotic rats, whereas the increase in AST was 10 times higher in cirrhotic than in control rats (P = 0.007). Simvastatin prevented the impairment in endothelial-dependent vasorelaxation induced by H/R, and reduced by half the increase in ALT and AST (P < 0.05). Transcriptomics showed a marked upregulation of genes related to inflammatory response after H/R in cirrhotic livers, but not in controls, and this was blunted by simvastatin. In conclusion, H/R aggravates liver microvascular dysfunction in cirrhosis, and upregulates liver inflammatory pathways. This does not occur in control livers. Simvastatin prevented H/R-induced liver endothelial dysfunction, and attenuated liver injury and liver inflammatory response, suggesting that it might have potential for protecting the cirrhotic liver during bleeding complications.
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Keywords: 3-hydroxy-3-methylglutaryl-coenzyme; ALT; AST; AVB; Ach; AoCLF; CBDL; CPD; Endothelial dysfunction; GAPDH; GSEA; Gene Set Enrichment Analysis; H&E; H/R; HMG-CoA; IL1B; IL6; LPS; Limma; MAP; MELD; Mtx; PCR; RNA; TLR4; acetylcholine; acute on chronic liver failure; acute variceal bleeding; alanine transferase; aspartate transferase; citrate phosphate dextrose; common biliar duct ligation; glyceraldehyde 3-phosphate dehydrogenase; hematoxylin and eosin; hemorrhage/resuscitation; interleukin 1b; interleukin 6; linear models for microarray data; liposaccharide; liver injury; liver transcriptome; mean arterial pressure; methoxamine; microarrays; model end liver disease; portal hypertension; real-time polymerase chain reaction; ribonucleic acid; statins; toll-like receptor 4

Document Type: Research Article

Affiliations: 1: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), University of Barcelona, Barcelona, Spain, Division of Gastroenterology, Department of Medicine, University of Santa Catarina, Florianópolis, Brazil 2: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), University of Barcelona, Barcelona, Spain 3: CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Madrid, Spain 4: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), University of Barcelona, Barcelona, Spain, CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Madrid, Spain 5: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), University of Barcelona, Barcelona, Spain, CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Madrid, Spain 6: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), University of Barcelona, Barcelona, Spain, CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Madrid, Spain, Swiss Liver Center, Inselspital, Bern University, Bern, Switzerland 7: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), University of Barcelona, Barcelona, Spain, CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Madrid, Spain, Division of Gastroenterology (Liver Unit), Department of Medicine, University of Alberta, CEGIIR, Edmonton, Alberta, Canada

Publication date: March 1, 2017

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