Abstract
Whole body exposure of wild type control littermates and A2A adenosine receptor (A2AR) gene deleted mice to low oxygen containing inspired gas mixture allowed the investigation of the mechanism that controls inflammatory liver damage and protects the liver using a mouse model of T cell-mediated viral and autoimmune hepatitis. We tested the hypothesis that the inflammatory tissue damage-associated hypoxia and extracellular adenosine --> A2AR signaling plays an important role in the physiological anti-inflammatory mechanism that limits liver damage during fulminant hepatitis. After induction of T cell-mediated hepatitis, mice were kept in modular chambers either under normoxic (21% oxygen) or hypoxic (10% oxygen) conditions for 8 h. It was shown that the whole body exposure to hypoxic atmosphere caused tissue hypoxia in healthy animals as evidenced by a decrease in the arterial blood oxygen tension and increase of the plasma adenosine concentration (P < 0.05). This "hypoxic" treatment resulted in significantly reduced hepatocellular damage and attenuated levels of serum cytokines in mice with acute liver inflammation. The anti-inflammatory effects of hypoxia were not observed in the absence of A2AR in studies of A2AR gene-deficient mice or when A2AR have been pharmacologically antagonized with synthetic antagonist. The presented data demonstrate that total body hypoxia-triggered pathway provides protection in acute hepatitis and that hypoxia (upstream) and A2AR (downstream) function in the same immunosuppressive and liver tissue-protecting pathway.
Highlights
Acute or chronic hepatitis due to viral infections or autoimmune hepatitis affects millions of patients and results in high long-term morbidity [1,2,3,4]
We examined a tissue-protective effect of hypoxia via A2A adenosine receptor (A2AR) in a welldocumented model of autoimmune and viral hepatitis which is triggered by i.v. injection of concanavalin A (Con A)
It was found that Con A-induced levels of alanine transaminase (ALT), AST, as well as lactate dehydrogenase (LDH) were significantly higher in animals that were pre-treated by the adenosine A2 receptor antagonist ZM241385 (Figure 1)
Summary
Acute or chronic hepatitis due to viral infections or autoimmune hepatitis affects millions of patients and results in high long-term morbidity [1,2,3,4]. For example, hepatitis B virus-specific T cell responses contribute to viral clearance and clinical recovery, and to immune-mediated acute and chronic necro-inflammatory liver disease [5,6]. It was suggested that the extracellular adenosine levels in the inflamed area was sufficiently high to trigger signaling by A2A and/or A2B adenosine receptors (A2AR and A2BR) and to suppress immune attack by surrounding cells, including activated T cells. This chain of events culminates in inhibition of overactive immune cells in a delayed negative feedback blockade due to the well-
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