Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia-reperfusion: therapeutic potential of mitochondrially targeted antioxidants. Free Radic Biol Med 2012 Sep 01;53(5):1123-38
Date
06/12/2012Pubmed ID
22683818Pubmed Central ID
PMC3432152DOI
10.1016/j.freeradbiomed.2012.05.036Scopus ID
2-s2.0-84864956266 (requires institutional sign-in at Scopus site) 114 CitationsAbstract
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 2 h 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 6 h of reperfusion and peaking at 24 h). 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.
Author List
Mukhopadhyay P, Horváth B, Zsengellėr Z, Bátkai S, Cao Z, Kechrid M, Holovac E, Erdėlyi K, Tanchian G, Liaudet L, Stillman IE, Joseph J, Kalyanaraman B, Pacher PAuthor
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntioxidants
Cyclic N-Oxides
Dose-Response Relationship, Drug
Inflammation
Liver Diseases
Male
Mice
Mice, Inbred C57BL
Mitochondria, Liver
Organophosphorus Compounds
Oxidative Stress
Reactive Oxygen Species
Reperfusion Injury
Ubiquinone
