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Chronic intermittent hypoxia and acetaminophen induce synergistic liver injury

Obstructive sleep apnea (OSA) leads to chronic intermittent hypoxia (CIH) during sleep. OSA has been associated with liver injury. Our goal was to examine whether CIH increases liver injury induced by acetaminophen (APAP) treatment. C57BL/6J mice were exposed to CIH or intermittent air (IA) for 4 weeks while being treated with APAP i.p. (200 mg/kg) or normal saline daily. A combination of CIH and APAP caused liver injury with increases in serum alanine aminotransferase, aspartate aminotransferase (AST), gamma glutamyl transferase and total bilirubin levels, whereas CIH alone induced only elevation in serum AST levels. APAP alone did not affect serum levels of liver enzymes. Histopathology revealed hepatic necrosis and increased apoptosis in mice exposed to CIH and APAP, whereas the liver remained intact in all other groups. Mice exposed to CIH and APAP exhibited decreased hepatic glutathione and a five‐fold increase in nitrotyrosine levels. APAP or CIH alone had no effect on either glutathione or nitrotyrosine. A combination of CIH and APAP caused marked increases in monocyte chemoattractant protein‐1 and macrophage inflammatory protein‐2, which were not observed in mice exposed to CIH or APAP alone. We conclude that CIH and chronic APAP treatment lead to synergistic liver injury, which may have clinical implications for patients with OSA.