Oxidative Damage in Clinical Ischemia/Reperfusion Injury: A Reappraisal

Abstract

Aims: 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 F2a, 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. Innovation: 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. Conclusion: 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. Antioxid. Redox Signal. 19,[535][536][537][538][539][540][541][542][543][544][545]

Hypothermic machine perfusion in liver transplantation

“…Metabolic pathways are responsible for mitochondrial ROS production in a large range of tissues, including livers, kidneys, hearts, and brain [52][53][54]. ].…”

Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane‐mediated thromboxane A2 receptor activation

“…The generation of isoprostanes resulting from lipid peroxidation seems to occur immediately after reperfusion because no further increase in the isoprostane concentration could be observed in subsequent post-operative period Ulus et al, 2003). In contrast, in clinical ischaemia/ reperfusion injury, no increase of 8-iso-PGF 2α levels in plasma and urine during early reperfusion of the ischaemic kidney or heart has been described, indicating a highly complex and sensitive process of isoprostane formation under ischaemic conditions (de Vries et al, 2013). Furthermore, in patients with ischaemic chronic heart failure, levels of 8-iso-PGF2α correlated significantly with indices of remodelling (Radovanovic et al, 2008).…”

Ischemia-reperfusion injury: evidences for translational research

“…In the last years, many promising compounds showing antioxidant properties have been under investigation for the prevention and treatment of neural IRI. However, some evidences on other tissues, albeit proving oxidative stress, suggest that the contribution of oxidative damage to human IRI may be less than commonly thought and propose a reevaluation of the mechanism of IRI (15). It is conceivable that the beneficial properties of riluzole in neural IRI may be the result of a combination of different mechanisms.…”