Reducing Ischaemia/Reperfusion-Induced Organ Injury
Reducing Ischaemia/Reperfusion-Induced Organ Injury
The release of massive amounts of free radicals, lipid hydroperoxides, and their derived products during reperfusion, after a prolonged period of ischaemia, causes cellular damage and cell death. However, their release in smaller amounts after limited, less severe ischaemic and hypoxic insults can confer some degree of protection to the cells to subsequent much more severe insult, and contribute to the condition referred to as preconditioning.
Preconditioning was first described by Murry and colleagues in 1986, in dogs, where the team showed that four cycles of 5 min of ischaemia by coronary occlusion each separated by 5 min of reperfusion before a 40 min of ischaemia produced a 75% reduction in the size of myocardial infarction after reperfusion compared with non-preconditioned hearts.
Subsequent to the discovery of preconditioning, Zhao and colleagues showed, in a heart model in dogs, that after a 60 min period of ischaemia by coronary occlusion, three cycles of 30 s of reperfusion started immediately after reperfusion followed each by 30 s of occlusion produced a 40% reduction in infarct size after a 3 h reperfusion period compared with control which did not undergo the above protocol; this was called post-conditioning. In their model, the amount of protection provided by post-conditioning was similar to a preconditioning protocol. The timing of post-conditioning is crucial as delaying the procedure by a minute after reperfusion is enough to result in complete loss of its protective effects. Post-conditioning is associated with a significant reduction in the release of free radicals during the early period of reperfusion and this is believed to contribute to the reduction in cellular injury during that phase. Both pre- and post-conditioning can confer some clinical benefits, for example, during elective cardiac surgery and during coronary angioplasty after acute myocardial infarction.
Although some of the pathways of cytoprotection have been defined, the definite mechanisms of pre- and post-conditioning still remain unknown. However, the production of small amounts of free radicals is essential for their effects, and furthermore, pre- and post-conditioning confer cellular protection by activating several signalling pathways, which culminate in the inhibition of the opening of mPTPs during reperfusion. Membrane receptors for ligands including adenosine, bradykinin, opioids, cannabinoids, tumour necrosis factor (TNFα), and the ATP-sensitive K channels (KATP channels), protein kinase C (PKC), extracellular receptor protein kinase mitogen-activated protein kinase p42/44, P38 mitogen-activated protein kinase (p38 MAPK), janus kinase (JAK), signal transducer and activating factor of transcription-3 (STAT-3), glycogen synthase kinase 3β (GSK-3β), the Reperfusion Injury Salvage Kinases (RISK) pathway including extracellular-signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase/AKT (PI3-K/AKT) have been implicated in ischaemic conditioning. Recently, the Survivor Activating factor Enhancement (SAFE) kinase pathway has also been linked to these conditions.
Ischaemic Conditioning
The release of massive amounts of free radicals, lipid hydroperoxides, and their derived products during reperfusion, after a prolonged period of ischaemia, causes cellular damage and cell death. However, their release in smaller amounts after limited, less severe ischaemic and hypoxic insults can confer some degree of protection to the cells to subsequent much more severe insult, and contribute to the condition referred to as preconditioning.
Preconditioning was first described by Murry and colleagues in 1986, in dogs, where the team showed that four cycles of 5 min of ischaemia by coronary occlusion each separated by 5 min of reperfusion before a 40 min of ischaemia produced a 75% reduction in the size of myocardial infarction after reperfusion compared with non-preconditioned hearts.
Subsequent to the discovery of preconditioning, Zhao and colleagues showed, in a heart model in dogs, that after a 60 min period of ischaemia by coronary occlusion, three cycles of 30 s of reperfusion started immediately after reperfusion followed each by 30 s of occlusion produced a 40% reduction in infarct size after a 3 h reperfusion period compared with control which did not undergo the above protocol; this was called post-conditioning. In their model, the amount of protection provided by post-conditioning was similar to a preconditioning protocol. The timing of post-conditioning is crucial as delaying the procedure by a minute after reperfusion is enough to result in complete loss of its protective effects. Post-conditioning is associated with a significant reduction in the release of free radicals during the early period of reperfusion and this is believed to contribute to the reduction in cellular injury during that phase. Both pre- and post-conditioning can confer some clinical benefits, for example, during elective cardiac surgery and during coronary angioplasty after acute myocardial infarction.
Although some of the pathways of cytoprotection have been defined, the definite mechanisms of pre- and post-conditioning still remain unknown. However, the production of small amounts of free radicals is essential for their effects, and furthermore, pre- and post-conditioning confer cellular protection by activating several signalling pathways, which culminate in the inhibition of the opening of mPTPs during reperfusion. Membrane receptors for ligands including adenosine, bradykinin, opioids, cannabinoids, tumour necrosis factor (TNFα), and the ATP-sensitive K channels (KATP channels), protein kinase C (PKC), extracellular receptor protein kinase mitogen-activated protein kinase p42/44, P38 mitogen-activated protein kinase (p38 MAPK), janus kinase (JAK), signal transducer and activating factor of transcription-3 (STAT-3), glycogen synthase kinase 3β (GSK-3β), the Reperfusion Injury Salvage Kinases (RISK) pathway including extracellular-signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase/AKT (PI3-K/AKT) have been implicated in ischaemic conditioning. Recently, the Survivor Activating factor Enhancement (SAFE) kinase pathway has also been linked to these conditions.
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