title: Oxidative damage in clinical ischemia/reperfusion injury: a reappraisal.
abstract: OBJECTIVE
  Ischemia/reperfusion (I/R) injury is a common clinical problem. Although the pathophysiological mechanisms underlying I/R injury are unclear, oxidative damage is considered a key factor in the initiation of I/R injury. Findings from preclinical studies consistently show that quenching reactive oxygen and nitrogen species (RONS), thus limiting oxidative damage, alleviates I/R injury. Results from clinical intervention studies on the other hand are largely inconclusive. In this study, we systematically evaluated the release of established biomarkers of oxidative and nitrosative damage during planned I/R of the kidney and heart in a wide range of clinical conditions.
  
  
  RESULTS
  Sequential arteriovenous concentration differences allowed specific measurements over the reperfused organ in time. None of the biomarkers of oxidative and nitrosative damage (i.e., malondialdehyde, 15(S)-8-iso-prostaglandin F2α, nitrite, nitrate, and nitrotyrosine) were released upon reperfusion. Cumulative urinary measurements confirmed plasma findings. As of these negative findings, we tested for oxidative stress during I/R and found activation of the nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of oxidative stress signaling.
  
  
  METHODS
  This comprehensive, clinical study evaluates the role of RONS in I/R injury in two different human organs (kidney and heart). Results show oxidative stress, but do not provide evidence for oxidative damage during early reperfusion, thereby challenging the prevailing paradigm on RONS-mediated I/R injury.
  
  
  CONCLUSIONS
  Findings from this study suggest that the contribution of oxidative damage to human I/R may be less than commonly thought and propose a re-evaluation of the mechanism of I/R.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Dorottya K
authors.initials: DK
authors.lastname: de Vries
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Kortekaas
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsikas
authors.forename: Leonie G M
authors.initials: LG
authors.lastname: Wijermars
authors.forename: Cornelis J F
authors.initials: CJ
authors.lastname: van Noorden
authors.forename: Maria-Theresia
authors.initials: MT
authors.lastname: Suchy
authors.forename: Christa M
authors.initials: CM
authors.lastname: Cobbaert
authors.forename: Robert J M
authors.initials: RJ
authors.lastname: Klautz
authors.forename: Alexander F M
authors.initials: AF
authors.lastname: Schaapherder
authors.forename: Jan H N
authors.initials: JH
authors.lastname: Lindeman
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D015232:Dinoprostone / Q000652:urine; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D006351:Heart Valves / Q000601:surgery; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000601:surgery; D016030:Kidney Transplantation; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism; D020218:Response Elements
chemical_list: D015415:Biomarkers; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C075750:8-epi-prostaglandin F2alpha; D008315:Malondialdehyde; D015237:Dinoprost; D015232:Dinoprostone