Reperfusion tissue injury

In vivo roles of CXCR1 and CXCR2 and their ligands were investigated using rabbits in which the orthologues of IL-8 and its two receptors have been identified. Intravenous injection of a neutralizing anti-IL-8 antibody prevented neutrophil accumulation and activation in a model of reperfusion tissue injury... 

Moriwaki etal. (1996) observed xanthine oxidase staining in infiltrating lymphocytes (probably T-lymphocytes but not B-lymphocytes) in inflammatory lesions of the human small and large intestine. Its ubiquitous localization suggests that xanthine oxidase is involved in the pathogenesis of reperfusion tissue injury. 

High antioxidative activity carvedilol has been shown in isolated rat heart mitochondria [297] and in the protection against myocardial injury in postischemic rat hearts [281]. Carvedilol also preserved tissue GSL content and diminished peroxynitrite-induced tissue injury in hypercholesterolemic rabbits [298]. Habon et al. [299] showed that carvedilol significantly decreased the ischemia-reperfusion-stimulated free radical formation and lipid peroxidation in rat hearts. Very small I50 values have been obtained for the metabolite of carvedilol SB 211475 in the iron-ascorbate-initiated lipid peroxidation of brain homogenate (0.28 pmol D1), mouse macrophage-stimulated LDL oxidation (0.043 pmol I 1), the hydroxyl-initiated lipid peroxidation of bovine pulmonary artery endothelial cells (0.15 pmol U1), the cell damage measured by LDL release (0.16 pmol l-1), and the promotion of cell survival (0.13 pmol l-1) [300]. SB 211475 also inhibited superoxide production by PMA-stimulated human neutrophils. 

XOR is a cytoplasmic enzyme and a ready source of electrons for transfer to molecular oxygen to form reactive oxygen species such as superoxide and peroxide. It is therefore thought to be involved in free radical-generated tissue injury and has been implicated in the pathogenesis of ischemia-reperfusion damage. Moreover, it has recently been implicated in the production of peroxynitrite (89), and carbonate radical anion (92), both potent biological oxidants. Its exact role in lipid peroxidation, inflammation, and infection needs... 

Exerts beneficial effects against ischemia/reperfusion-induced injury through its abilities to release CO which mediates a cardioprotective action by regulating tissue Na+, K+ and Ca2+ levels [152]... 

Several studies have indicated that the early measurement of the water ADC provides a valuable predictor of final tissue injury (reviewed in Hoehn-Berlage 1995). This notion has to be extended by adding information on the perfusion status of the tissue in models of permanent vessel occlusion, DWI may indeed be an excellent surrogate marker for chronic tissue damage. However, if reperfusion is installed either by using a reversible occlusion model or by administration of recanalizing drugs such correlations become much weaker as recently demonstrated (van Dorsten et al. 2002). 

The specific choice of treatments to be used in combination with hypothermia could be based on a variety of different approaches. First, there could be a direct synergistic effect between hypothermia and the other proposed treatment modality, presumably as a result of a complementary mode of action. For example, combining hypothermia with thrombolytic therapy might be an appropriate pairing in which the hypothermia prolongs the therapeutic window for subsequent definitive reperfusion. Similarly, hypothermia could be used just after thrombolysis, to prevent reperfusion induced injury and prolonging the viability of injured but not irreversibly damaged tissue. 

The inflammation response to tissue injury involves infiltration of damaged areas by leukocytes from the blood stream (1-4). Unregulated extravasation of leukocytes can result in inflammatory disorders such as reperfusion injuries, stroke, psoriasis, rheumatoid arthritis and respiratory diseases. An early step in the cascade of events leading to influx of leukocytes is the recognition of the tetrasaccharide sLex 1 (found on the terminus of leukocyte surface glycoproteins), by E, P and L selectins that are expressed by endothelial cells... 

At present it is difficult to distinguish between the different oxygen-radical generating systems in relation to ischaemia/reperfusion-induced tissue injury. It is likely that the formation of oxygen radicals occurs as a result of metabolic processes and that redox-active metal catalysed reactions and the beneficial effects of iron chelators are due to both chelation of the metal and their radicalscavenging properties. 

PBN failed to exert a cardioprotective role in our model of ischemia and reperfusion. There are a number of possibilities that may explain the absence of any protective effect. Firstly, PBN may not have gained access to the site where the hydroxyl radical is generated. Failure to deliver PBN to this locus of radical production would exclude any possible protective effect for this spin trap. Secondly, the kinetic reaction between a radical species and the spin trap is rather inefficient. Thus PBN may trap only a small fraction of the total amount of hydroxyl radical produced. Thirdly, in the aqueous environment of the myocardial cell the PBN/ OH adduct formed is unstable and spontaneously decomposes into benzaldehyde and the tert-butylhydroaminoxyl radical. These toxic breakdown products are more stable than the parent molecule and may diffuse from their site of production to other areas, resulting in an extension of tissue injury. Fourthly, we must acknowledge the possibility that the hydroxyl radical contributes only minimally to myocardial cell injury in this model. 

It is considered that tissue injury following ischemia and reperfusion is mediated by reactive oxygen derived-species (ROS) and pools of redox active iron and copper. The role of free iron and copper is visualized mainly as causing the conversion of low reactive species, such as superoxide radical anion, to the highly reactive hydroxyl radicals. The significance of iron in ischemia and reperfusion is supported by studies showing that metal chelation protected post-ischemic tissue [8], whereas the addition of iron to the perfusate increased the rate of injury [9]. 

The inflammatory response is initiated by stimuli released from sites of tissue injury that results in the expression of selectins on the endothelial layer. These selectins (E(endothelial)-selectin and P(platelet)-selectin) function through recognition of oligosaccharides on the opposing leukocyte cell surface [194]. This interaction eventually weakly tethers the leukocyte to the endothelial layer, at which point integrin binding events lead to firm adhesion and extravasation of the leukocyte into the tissue. In certain disease processes, excessive leukoc)4e infiltration becomes deleterious to the body, and inhibitors of this process are desirable. Rheumatoid arthritis, asthma, organ transplant rejection, and reperfusion injury are just a few of the cases in which these events occur [27]. 

Cardiomyocyte death occurs during ischemia as well as during the subsequent reperfusion,69 with both necrosis and apoptosis contributing to cell death.70 Loss of cardiomyocyte volume regulation contributes to irreversible ischemic tissue injury,71 and open hemichannels might contribute to the ischemia/reperfusion-induced osmotic imbalance in cardiomyocytes.72,73... 

Cerebral ischaemia is responsible for approximately 85% of strokes (cerebrovascular accidents) irrespective of whether they are thrombotic or embolic in nature.4 Reestablishment of blood flow (reperfusion) in the postischaemic period is often accompanied by further tissue injury that is associated with aberrant microvascular function, damage to endothelial cells, and inflammatory cell exudates.5-6 In recent years, particular attention has focused upon the contribution of neutrophils to the pathogenesis of the reperfusion injury seen in cerebral ischaemia. 

Reperfusion to restore the flow of oxygenated blood to ischaemic tissue is essential for its survival but it produces oxygen free radicals, which are thought to be responsible for reperfusion-induced injury. 

Ischemia-reperfusion causes severe tissue injury when the blood is reperfused into an ischemic organ. This injury is pathologically characterized by massive sequestration of neutrophils into the injured tissue (46). This injury occurs because of the generation of reactive oxygen intermediates produced by neutrophils (47), and is observed in several clinical conditions such as myocardial infarction, cerebral infarction, and multiple organ failure. 

In this model, pathologically, no cerebral tissue injury was observed during ischemia alone. However, reperfusion for 6 h caused margination and intravascular aggregation of neutrophils with edematous change in parenchyma. Reperfusion for up to 12 h induced massive neutrophil infiltration into the parenchyma, with severe hemorrhagic and edematous change. 

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