Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia–reperfusion: Therapeutic potential of mitochondrially targeted antioxidants

Mitochondrial reactive oxygen species generation has been implicated in the pathophysiology of ischemia‐reperfusion (I/R) injury; however, its exact role with inflammation are elusive. Herein we explore the spatial‐temporal relationship of oxidative/nitrative stress and inflammatory response during the course of hepatic I/R and the possible therapeutic potential of mitochondrial‐targeted antioxidants, using a mouse model of segmental hepatic ischemia‐reperfusion injury. Hepatic I/R was characterized by early mitochondrial injury, decreased complex I activity, increased oxidant generation in the liver or liver mitochondria, and profound hepatocellular injury/dysfunction with acute proinflammatory response without inflammatory cell infiltration, followed by marked neutrophil infiltration and a more pronounced secondary wave of oxidative stress in the liver. Mitochondrially targeted antioxidants, MitoQ or Mito‐CP, dose‐dependently attenuated I/R‐induced liver dysfunction, the early and delayed oxidative stress response, and mitochondrial and histopathological injury/dysfunction, as well as delayed inflammatory cell infiltration and cell death. Mitochondrially generated oxidants play a central role in triggering the deleterious cascade of events associated with hepatic I/R, which may be targeted by novel antioxidants for therapeutic advantage