Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia–reperfusion: Therapeutic potential of mitochondrially targeted antioxidants
| Autor: | Isaac E. Stillman, Partha Mukhopadhyay, Eileen Holovac, Galin Tanchian, Balaraman Kalyanaraman, Joy Joseph, Zongxian Cao, Malek Kechrid, Zsuzsanna Zsengellėr, Bėla Horváth, Katalin Erdėlyi, Lucas Liaudet, Sandor Batkai, Pal Pacher |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Ubiquinone Mitochondria Liver Inflammation Mitochondrion Pharmacology Biology medicine.disease_cause Biochemistry Article Antioxidants Proinflammatory cytokine Cyclic N-Oxides Mice chemistry.chemical_compound Organophosphorus Compounds Physiology (medical) medicine Animals chemistry.chemical_classification Reactive oxygen species MitoQ Dose-Response Relationship Drug Liver Diseases medicine.disease Malondialdehyde Mice Inbred C57BL Oxidative Stress chemistry Reperfusion Injury Immunology medicine.symptom Reactive Oxygen Species Reperfusion injury Oxidative stress |
| Zdroj: | Free Radical Biology and Medicine, vol. 53, no. 5, pp. 1123-1138 |
| ISSN: | 0891-5849 |
| DOI: | 10.1016/j.freeradbiomed.2012.05.036 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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