OBJECTIVE:: Liver injury and cell death are prominent features in the pathogenesis of acute liver failure. Mitochondrial uncoupling protein 2 plays a controversial role in liver cell death through its involvement in the production of reactive oxygen species and adenosine triphosphate. DESIGN:: This randomized controlled animal study was designed to investigate the exact role of uncoupling protein 2 in the pathogenesis of endotoxemic acute liver failure. SETTING:: Research laboratory of an academic institution. SUBJECTS, INTERVENTIONS, AND MEASUREMENTS:: Uncoupling protein 2+/+ and uncoupling protein 2-/- mice were challenged with d-galactosamine (Gal, 720 mg/kg intraperitoneally) and Escherichia coli lipopolysaccharide (10 μg/kg intraperitoneally) and studied 6 hrs thereafter (n = 5 per group). Control mice received physiologic saline (n = 5 per group). Analysis included in vivo fluorescence microscopy of hepatic microcirculation and hepatocellular apoptosis as well as plasma malondialdehyde concentrations as reactive oxygen species-dependent lipid peroxidation product and hepatic adenosine triphosphate levels. MAIN RESULTS:: Administration of Gal-lipopolysaccharide in uncoupling protein 2+/+ mice caused systemic cytokine release and malondialdehyde production. Further, it provoked marked hepatic damage, characterized by intrahepatic leukocyte recruitment (10.5 ± 1.3 n/mm vs. 3.3 ± 0.5 n/mm), microvascular perfusion failure (33.1% ± 1.6% vs. 2.3% ± 0.4%), and adenosine triphosphate depletion (3.4 ± 0.9 μmol/g vs. 6.4 ± 0.9 μmol/g). Furthermore, uncoupling protein +/+ mice revealed a huge rise in cell apoptosis, given by high numbers of hepatocytes exhibiting nuclear chromatin fragmentation (44.9 ± 11.5 n/mm vs. 0.0 ± 0.0 n/mm) and cleaved caspase-3 expression (1.24 ± 0.24 vs. 0.06 ± 0.04). Liver injury was coexistent with enzyme release (alanine aminotransferase 442 ± 126 U/L vs. 57 ± 12 U/L) and necrotic cell death. Of interest, Gal-lipopolysaccharide-exposed uncoupling protein 2-/- mice exhibited higher rates of hepatocellular apoptosis (135.6 ± 46.0 n/mm) as well as cleaved caspase-3 expression (1.75 ± 0.25), however, preserved hepatic adenosine triphosphate (6.4 ± 1.7), milder perfusion failure (24.5 ± 2.4) and decreased leukocyte recruitment (2.7 ± 0.2), less necrotic injury, lower transaminase levels (340 ± 91), and finally better survival rates. CONCLUSION:: The higher adenosine triphosphate availability in uncoupling protein 2-deficient mice might allow hepatocytes to undergo apoptosis as an energy-consuming mode of cell death, while at the same time cellular adenosine triphosphate levels seem to increase hepatic resistance against harmful effects upon Gal-lipopolysaccharide exposure. As net result, uncoupling protein 2 deficiency provided protection under endotoxemic stress conditions, underlining the significant role of the bioenergetic status in critical illness.
Strategische Forschungsbereiche und Zentren
- Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)