From the Guidelines
Free radicals form during reperfusion injury due to the sudden restoration of oxygen to previously ischemic tissues, leading to the formation of reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radicals 1. When tissues are deprived of oxygen during ischemia, cellular metabolism shifts to anaerobic pathways, causing accumulation of metabolites and damage to mitochondria. Upon reperfusion, the damaged mitochondrial electron transport chain cannot properly process the influx of oxygen, leading to incomplete reduction of oxygen molecules and formation of ROS. Additionally, the enzyme xanthine oxidase, which accumulates during ischemia, rapidly generates superoxide radicals when oxygen returns, as noted in the context of cardioprotective strategies to limit myocardial ischemia-reperfusion injury 1. The sudden calcium influx during reperfusion further damages mitochondria, exacerbating ROS production, and neutrophils that infiltrate the reperfused tissue also contribute by releasing free radicals as part of the inflammatory response. These free radicals cause oxidative damage to cellular proteins, lipids, and DNA, triggering cell death pathways and extending tissue injury beyond the initial ischemic damage. The mechanisms leading to myocardial injury seem to be free radical formation, calcium overload, and impairment of the coronary vasculature, highlighting the importance of cardioprotective agents and strategies to prevent or diminish the extent of perioperative ischaemia-reperfusion-induced myocardial dysfunction 1. Some studies suggest that postconditioning, an intervention applied within the first minute of reperfusion, may salvage myocardium previously made ischemic by inhibiting the mitochondrial permeability transition pore, a common end effector of conditioning 1. However, the uncertainty regarding the magnitude, time course, and nature of lethal reperfusion injury and how it can be modulated represents an important gap of knowledge that may hinder the appropriate design of clinical trials 1. Key points to consider in the context of reperfusion injury and free radical formation include:
- The role of mitochondrial damage and dysfunction in ROS production
- The contribution of xanthine oxidase and neutrophils to free radical generation
- The impact of calcium influx on mitochondrial damage and ROS production
- The potential benefits and limitations of cardioprotective strategies, including postconditioning, in preventing or diminishing myocardial injury.
From the Research
Formation of Free Radicals in Reperfusion Injury
- Free radicals form in reperfusion injury due to the imbalance between the cellular formation of free radicals and cells' capacity to defend against them 2.
- The restoration of blood flow after ischemia leads to the production of reactive oxygen species (ROS), which play an essential role in both organ injury and repair processes 2, 3.
- ROS can be produced from several sources, including xanthine oxidase, cytochrome oxidase, cyclooxygenase, mediated unsaturated fatty acid oxidation, oxidation of catecholamines, mitochondrial oxidation, activation of leukocyte nicotinamide adenine dinucleotide phosphate oxidase, iron release, and reduction-oxidation reaction cycling 2.
Mechanisms of Free Radical Formation
- The opening of the mitochondrial permeability transition pore (mPTP) is a determining factor in causing loss of cardiomyocyte function and viability in reperfusion injury 3.
- Mitochondrial damage is a major mechanism of mitochondrial dysfunction, and oxidative stress resulting from the formation of ROS contributes to this damage 3.
- The infiltration of inflammatory leukocytes, such as macrophages and neutrophils, into the myocardium causes further ROS production beyond the initiation of the inflammatory cascade 2.
Role of Oxygen Free Radicals
- Oxygen free radicals play a major role in the pathogenesis of post-ischemic reperfusion injury in the heart 4, 5.
- The timely administration of oxygen radical scavengers can reduce the quantity of free radicals generated following reperfusion and improve recovery of post-ischemic ventricular function and metabolism 4.
- Oxygen free radicals participate in the injury process, and their generation is viewed as contributing to post-ischemic reperfusion injury 5.