The Role of Neutrophils and Reactive Oxygen Metabolites in Reperfusion Injury
John J. Lemasters, Constance Oliver in Cell Biology of Trauma, 2020
There have been numerous reports that have implicated oxygen radicals as mediators of the microvascular and parenchymal cell dysfunction induced by reperfusion of ischemic tissues. Studies of ischemia/reperfusion in the intestine, performed in our laboratory and by other investigators, implicate both xanthine oxidase-derived oxidants and neutrophils in the pathogenesis of this disorder. Over the past decade we have demonstrated that xanthine oxidase-derived oxidants elicit the production of inflammatory mediators, which attract and activate polymorphonuclear leukocytes (neutrophils) into postischemic tissue. The activated neutrophils then mediate the vascular injury that is associated with reperfusion. This review summarizes the evidence that provides the basis for the xanthine oxidase/neutrophil hypothesis of reperfusion injury. When a tissue is subjected to ischemia, a sequence of chemical reactions is initiated that may ultimately lead to cellular dysfunction and necrosis. Although no single process can be identified as the critical event in ischemia-induced tissue injury, most studies indicate that depletion of cellular energy stores and accumulation of toxic metabolites may contribute to cell death. It is undeniable that re-establishing blood flow is necessary in rescuing ischemic tissues; however, reperfusion of ischemic tissues also leads to a sequence of events that paradoxically injures tissues. Parks and Granger have shown that relatively little injury to the intestinal mucosa occurs during the ischemic period and that the majority of the injury occurs upon reperfusion. This observation implicated some reaction initiated by the return of oxygenated blood to the ischemic tissue, which led to the concept that reperfusion injury may be mediated, at least in part, through the formation of reactive oxygen metabolites.
Extremity Trauma
Stephen M. Cohn, Alan Lisbon, Stephen Heard in 50 Landmark Papers, 2021
Vascular injury in patients suffering from trauma to the extremity can lead to death from exsanguination, shock, tissue injury, and metabolic derangements. Vascular assessment of injured extremities is thus a critical component of the evaluation and management of trauma patients with blunt or penetrating trauma. Hard signs of vascular injury include active hemorrhage, an expanding hematoma, bruit over the wound, an absence of distal pulse, and ischemia in the extremity. In an observational study of penetrating extremity trauma at an urban trauma center, all patients that were taken immediately to surgery as a result of hard signs ultimately had a major arterial injury requiring repair, implying a 100% positive predictive value for when penetrating trauma shows hard signs of arterial injury. For patients who do not present with hard signs of vascular injury, an injured extremity index (IEI), which is analogous to the ankle-brachial index (ABI) and arterial pressure index (API) but applies to any extremity, should be performed. The IEI can be computed as follows: IEI = highest systolic pressure in extremity that is injured/systolic pressure in proximal vessel of an uninjured extremity, where an abnormal IEI measures less than 0.9. In studies exploring the predictive value for ABI and API in identifying vascular injury requiring surgical intervention, the sensitivity, specificity, and positive predictive value of an ABI lower than 0.90 were 100%, and an API less than 0.90 had a sensitivity of 87% and a specificity of 97% for arterial disruption. Patients who undergo revascularization of an injured extremity are at risk for ischemia reperfusion injury as reperfusion paradoxically can cause further damage, ultimately threatening the viability of organs, and can cause significant metabolic derangement such as hyperkalemia and acidosis. There are several therapeutic strategies being explored to limit ischemia reperfusion injury including ischemic preconditioning. However, when these strategies have been applied to clinical practice, outcomes have been ambiguous. Timely reperfusion of the ischemic area at risk is the most widely accepted strategy to prevent ischemia reperfusion injuries and related complications such as multiorgan dysfunction syndrome (MODS).
Heart Microcirculation
John H. Barker, Gary L. Anderson, Michael D. Menger in Clinically Applied Microcirculation Research, 2019
Besides ischemic heart disease, myocardial ischemia can occur during thrombolytic therapy, angioplasty, and open heart surgery. Prolonged deprivation of blood flow in conjunction with hypoxia can lead to irreversible cellular injury, resulting from energy depletion, lactic acidosis, and inhibition of both glucose and fatty acid utilization. Reperfusion following ischemia causes additional tissue damage, which is characterized by reperfusion injury. Neutrophils have been found to accumulate in the reperfused region of the myocardium. Adherence of neutrophils to the endothelial cells during ischemia-reperfusion is believed to be mediated by locally decreased shear stress (driving force) and upregulated neutrophil-endothelial adhesion molecules such as CD11/CD18 membrane glycoprotein. Once the neutrophils are activated, they release a variety of vasoactive and cytotoxic metabolites, of which reactive oxygen radicals are the major factor thought to cause myocardium injury. Ischemia-induced changes of microvascular hemodynamics include dilation of small coronary arterioles and subsequent drop of perfusion pressure, increase of functional intercapillary distances, leukocyte capillary plugging, platelet aggregation, and microvascular hyperpermeability. Also, endothelium-dependent vasodilatation is compromised during ischemia-reperfusion injury. The structural and functional conditions of the microvascular bed in the ischemic-reperfused myocardium may be an important factor in determining the final outcome and reversibility of cellular injury to the myocardium. The microvascular endothelial cell has been proposed as a major source of free radical production, and more importantly, is one of the primary targets of these radicals. Recent studies in canine beating hearts by Defily and Chilian demonstrate that ischemia-reperfusion significantly attenuates endothelium-dependent vasodilation of coronary arterioles, and importantly, preconditioning reduces arteriolar endothelial dysfunction after the injury (Figure 2). Therefore, preservation of microvascular function may reduce the amount of tissue necrosis and limit the reperfusion injury. (For further details, see Chapter 6 of this volume.)
Quercetin protects rat skeletal muscle from ischemia reperfusion injury
Published in Journal of Enzyme Inhibition and Medicinal Chemistry
Fazile Nur Ekinci Akdemir, İlhami Gülçin, Berna Karagöz, Recep Soslu
In this study, we investigated the potential beneficial effects of quercetin on skeletal muscle ischemia reperfusion injury. Twenty-four Sprague–Dawley type rats were randomly divided into four groups. In the sham group, only gastrocnemius muscle were removed and given no quercetin. In ischemia group, all the femoral artery, vein and collaterals were occluded in the left hindlimb by applying tourniquate under general anaesthesia for three hours but reperfusion was not done. In the Quercetin + Ischemia reperfusion group, quercetin (200 mg kg−1 dose orally) was given during one-week reoperation and later ischemia reperfusion model was done. Finally, gastrocnemius muscle samples were removed to measure biochemical parameters. The biomarkers, MDA levels, SOD, CAT and GPx activities, were evaluated related to skeletal muscle ischemia reperfusion injury. MDA levels reduced and SOD, CAT and GPx activities increased significantly in Quercetin + Ischemia reperfusion group. Results clearly showed that Quercetin have a protective role against oxidative damage induced by ischemia reperfusion in rats.
Picroside II decreases the development of fibrosis induced by ischemia/reperfusion injury in rats
Published in Renal Failure
Lei Wang, Xiu-Heng Liu, Hui Chen, Zhi-Yuan Chen, Xiao-Dong Weng, Tao Qiu, Lin Liu
In kidney transplantation, renal ischemia and reperfusion injury was one of the leading factors to the development of renal fibrosis, which was the main cause of graft loss. The fibrogenic changes were associated with the long term inflammation elicited by ischemia and reperfusion injury. In the present study, we investigated the role of the Picroside II, the main active constituents of the extract of picrorrhiza scrophulariiflora roots, in attenuating renal fibrosis in a renal ischemia and reperfusion injury model. We induced ischemia and reperfusion injury in kidneys treated with or without Picroside II. We observed that inflammation and tissue fibrosis were increased in ischemia and reperfusion injury group compared to Picroside II group, however, these changes were significantly decreased by the treatment with Picroside II. We concluded that Picroside II can protect the ischemic kidney against renal fibrosis and its mechanism may be through the inhibition of the long term inflammation.
Targeting reperfusion injury in acute myocardial infarction: a review of reperfusion injury pharmacotherapy
Published in Expert Opinion on Pharmacotherapy
Vikram Sharma, Robert M Bell, Derek M Yellon
Introduction: Acute myocardial infarction (AMI) (secondary to lethal ischemia–reperfusion [IR]) contributes to much of the mortality and morbidity from ischemic heart disease. Currently, the treatment for AMI is early reperfusion; however, this itself contributes to the final myocardial infarct size, in the form of what has been termed ‘lethal reperfusion injury’. Over the last few decades, the discovery of the phenomena of ischemic preconditioning and postconditioning, as well as remote preconditioning and remote postconditioning, along with significant advances in our understanding of the cardioprotective pathways underlying these phenomena, have provided the possibility of successful mechanical and pharmacological interventions against reperfusion injury. Areas covered: This review summarizes the evidence from clinical trials evaluating pharmacological agents as adjuncts to standard reperfusion therapy for ST-elevation AMI. Expert opinion: Reperfusion injury pharmacotherapy has moved from bench to bedside, with clinical evaluation and ongoing clinical trials providing us with valuable insights into the shortcomings of current research in establishing successful treatments for reducing reperfusion injury. There is a need to address some key issues that may be leading to lack of translation of cardioprotection seen in basic models to the clinical setting. These issues are discussed in the Expert opinion section.