ABSTRACT
Angiotensin converting enzyme 2 (ACE2) which breaks down profibrotic peptide angiotensin II to antifibrotic peptide angiotensin-(1-7) is a potential therapeutic target in liver fibrosis. We therefore investigated the long-term therapeutic effect of recombinant ACE2 using a liver-specific adeno-associated viral genome 2 serotype 8 vector (rAAV2/8-ACE2) with a liver-specific promoter in three murine models of chronic liver disease, including carbon tetrachloride-induced toxic injury, bile duct ligation-induced cholestatic injury, and methionine- and choline-deficient diet-induced steatotic injury. A single injection of rAAV2/8-ACE2 was administered after liver disease has established. Hepatic fibrosis, gene and protein expression, and the mechanisms that rAAV2/8-ACE2 therapy associated reduction in liver fibrosis were analyzed. Compared with control group, rAAV2/8-ACE2 therapy produced rapid and sustained upregulation of hepatic ACE2, resulting in a profound reduction in fibrosis and profibrotic markers in all diseased models. These changes were accompanied by reduction in hepatic angiotensin II levels with concomitant increases in hepatic angiotensin-(1-7) levels, resulting in significant reductions of NADPH oxidase assembly, oxidative stress and ERK1/2 and p38 phosphorylation. Moreover, rAAV2/8-ACE2 therapy normalized increased intrahepatic vascular tone in fibrotic livers. We conclude that rAAV2/8-ACE2 is an effective liver-targeted, long-term therapy for liver fibrosis and its complications without producing unwanted systemic effects.
Subject(s)
Dependovirus/genetics , Genetic Therapy , Genetic Vectors/genetics , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Peptidyl-Dipeptidase A/genetics , Angiotensin I/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Cytokines/metabolism , Dependovirus/classification , Disease Models, Animal , Enzyme Activation , Gene Expression , Genetic Therapy/methods , Genetic Vectors/administration & dosage , Hepatic Stellate Cells/metabolism , Inflammation Mediators/metabolism , Injections, Intraperitoneal , Lipid Peroxidation/genetics , Liver Cirrhosis/chemically induced , Liver Cirrhosis/pathology , Liver Cirrhosis/therapy , Liver Function Tests , MAP Kinase Signaling System , Male , Methoxamine/pharmacology , Mice , NADPH Oxidases/metabolism , Neovascularization, Pathologic/genetics , Organ Specificity/genetics , Oxidative Stress , Peptidyl-Dipeptidase A/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
PURPOSE: To describe a methodology for surgical audit and feedback based on hospital-level indicators of the quality of colorectal cancer care. METHODS: Process and outcome indicators were identified from a population-based database (N = 3095 patients treated by 258 surgeons at 130 hospitals across New South Wales between February 1, 2000 and January 31, 2001). Hospitals were ranked on each indicator, with those in the lowest 20th percentile receiving a score of 0 and the remainder receiving a score of 1. Scores for individual indicators were then summed for each hospital and divided by the number of relevant indicators to provide an evidence-based score (EBS) and a clinical outcome score. RESULTS: Ten process and six clinical outcome indicators were identified. Hospital-level summary scores ranged from 0.14 to 1.0 for evidence-based processes and from 0.17 to 1.0 for clinical outcomes. Evidence-based score and clinical outcome score were independent (r = 0.12, P = 0.32). There was a small positive association between evidence-based score and caseload (r = 0.33, P = 0.005) but clinical outcome score and caseload were unrelated (r = 0.11, P = 0.36). CONCLUSIONS: Evidence-based score and clinical outcome score address different aspects of quality of care. The wide variability of hospitals' outcome scores and an association of evidence-based score and caseload indicate that simple scores may be useful in audit and feedback.
