Derangements of liver tissue bioenergetics in Concanavalin A-induced hepatitis

• Main Authors: Al-Shamsi Mariam, Shahin Allen, Mensah-Brown Eric PK, Souid Abdul-Kader
• Format: Article
• Language: English
• Published: BMC 2013-01-01
• Series: BMC Gastroenterology
• Subjects: Concanavalin A (ConA); Hepatitis; Caspase; AST; ALT; IFN-γ
• Online Access: http://www.biomedcentral.com/1471-230X/13/6

<p>Abstract</p> <p>Background</p> <p>A novel <it>in vitro</it> system was employed to investigate liver tissue respiration (mitochondrial O₂ consumption) in mice treated with concanavalin A (Con A). This study aimed to investigate hepatocyte bioenergetics in this well-studied hepatitis model.</p> <p>Methods</p> <p>C57Bl/6 and C57Bl/6 <it>IFN-γ</it>^{<it>−/−</it>} mice were injected intravenously with 12 mg ConA/kg. Liver specimens were collected at various timepoints after injection and analyzed for cellular respiration and caspase activation. Serum was analyzed for interferon-gamma (IFN-γ) and aminotransferases. Fluorescence activated cell sorting analysis was used to determine the phenotype of infiltrating cells, and light and electron microscopy were used to monitor morphological changes. Phosphorescence analyzer that measured dissolved O₂ as function of time was used to evaluate respiration.</p> <p>Results</p> <p>In sealed vials, O₂ concentrations in solutions containing liver specimen and glucose declined linearly with time, confirming zero-order kinetics of hepatocyte respiration. O₂ consumption was inhibited by cyanide, confirming the oxidation occurred in the respiratory chain. Enhanced liver respiration (by ≈68%, p<0.02) was noted 3 hr after ConA treatment, and occurred in conjunction with limited cellular infiltrations around the blood vessels. Diminished respiration (by ≈30%, <it>p</it>=0.005) was noted 12 hr after ConA treatment, and occurred in conjunction with deranged mitochondria, areas of necrosis, and prominent infiltrations with immune cells, most significantly, CD3⁺NKT⁺ cells. Increases in intracellular caspase activity and serum IFN-γ and aminotransferase levels were noted 3 hr after ConA treatment and progressed with time. The above-noted changes were less pronounced in C57Bl/6 IFN-γ^−/− mice treated with ConA.</p> <p>Conclusions</p> <p>Based on these results, liver tissue bioenergetics is increased 3 hr after ConA exposure. This effect is driven by the pathogenesis of the disease, in which IFN-γ and other cytokines contribute to. Subsequent declines in liver bioenergetics appear to be a result of necrosis and active caspases targeting the mitochondria within hepatocytes.</p>