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 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.
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Partha
P
Mukhopadhyay
Bėla
B
Horváth
Zsuzsanna
Z
Zsengellėr
Sándor
S
Bátkai
Zongxian
Z
Cao
Malek
M
Kechrid
Eileen
E
Holovac
Katalin
K
Erdėlyi
Galin
G
Tanchian
Lucas
L
Liaudet
Isaac E
IE
Stillman
Joy
J
Joseph
Balaraman
B
Kalyanaraman
Pál
P
Pacher
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D000975:Antioxidants; D003497:Cyclic N-Oxides; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; C571715:mito-carboxy proxyl; D014451:Ubiquinone; C429014:mitoquinone