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

• Published in: Free radical biology & medicine Vol. 53; no. 5; pp. 1123 - 1138
• Main Authors: Mukhopadhyay, Partha, Horváth, Bėla, Zsengellėr, Zsuzsanna, Bátkai, Sándor, Cao, Zongxian, Kechrid, Malek, Holovac, Eileen, Erdėlyi, Katalin, Tanchian, Galin, Liaudet, Lucas, Stillman, Isaac E., Joseph, Joy, Kalyanaraman, Balaraman, Pacher, Pál
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2012
• Subjects: animal models; Animals; Antioxidants; Antioxidants - pharmacology; Antioxidants - therapeutic use; cell death; chemokine CXCL2; Cyclic N-Oxides - pharmacology; Cyclic N-Oxides - therapeutic use; Dose-Response Relationship, Drug; Free radicals; histopathology; inflammation; Inflammation - drug therapy; Inflammation - metabolism; Ischemia–reperfusion; liver; Liver Diseases - drug therapy; Liver Diseases - metabolism; Liver Diseases - physiopathology; Male; malondialdehyde; Mice; Mice, Inbred C57BL; mitochondria; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; neutrophils; Organophosphorus Compounds - pharmacology; Organophosphorus Compounds - therapeutic use; oxidants; Oxidative stress; Oxidative Stress - drug effects; pathophysiology; Reactive oxygen and nitrogen species; reactive oxygen species; Reactive Oxygen Species - metabolism; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - physiopathology; stress response; tumor necrosis factor-alpha; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacology; Ubiquinone - therapeutic use; Antioxidants; Oxidative stress; Free radicals; Ischemia–reperfusion; Reactive oxygen and nitrogen species
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.05.036

Mitochondrial reactive oxygen species generation has been implicated in the pathophysiology of ischemia–reperfusion (I/R) injury; however, its exact role and its spatial–temporal relationship 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 (at 2h of reperfusion) mitochondrial injury, decreased complex I activity, increased oxidant generation in the liver or liver mitochondria, and profound hepatocellular injury/dysfunction with acute proinflammatory response (TNF-α, MIP-1α/CCL3, MIP-2/CXCL2) without inflammatory cell infiltration, followed by marked neutrophil infiltration and a more pronounced secondary wave of oxidative/nitrative stress in the liver (starting from 6h of reperfusion and peaking at 24h). Mitochondrially targeted antioxidants, MitoQ or Mito-CP, dose-dependently attenuated I/R-induced liver dysfunction, the early and delayed oxidative and nitrative stress response (HNE/carbonyl adducts, malondialdehyde, 8-OHdG, and 3-nitrotyrosine formation), 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.
[Display omitted]
▸ Ischemia–reperfusion (I/R) injury is a pivotal mechanism of organ damage/dysfunction. ▸ The exact role and timing of mitochondrial oxidant generation in liver I/R are elusive. ▸ Mitochondrial oxidant generation triggers I/R-induced liver inflammation and injury. ▸ Mitochondrial antioxidants (MTAs) prevent I/R-induced oxidative/nitrative injury. ▸ MTAs prevent I/R-induced acute/delayed inflammatory response and cell death.