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Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia–reperfusion: Therapeutic potential of mitochondrially targeted antioxidants
Author(s) -
PACHER PAL,
Mukhopadhyay Partha,
Horvath Bela,
Zsengeller Zsuzsanna,
Batkai Sandor,
Cao Zongxian,
Kechrid Malek,
Holovac Eileen,
Erdelyi Katalin,
Liaudet Lucas,
Stillman Isaac E,
Joseph Joy,
Kalyanaraman Balaraman
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.650.7
Subject(s) - oxidative stress , reactive oxygen species , inflammation , liver injury , mitochondrion , proinflammatory cytokine , reperfusion injury , mitochondrial ros , infiltration (hvac) , ischemia , medicine , pharmacology , immunology , pathology , chemistry , biochemistry , physics , thermodynamics
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