protein levels, a plasma marker of inflammation, and decreases in the production of inflammatory cytokines such as interleukin-6. Using an intravital microscopic approach to examine postischemic leukocyte rolling, adhesion, and emigration in postcapillary venules in real time, we have demonstrated that antecedent ethanol exposure prevents adhesive interactions between circulating leukocytes and the endothelium from developing in tissues exposed to I/R. The temporal expression of this protected or preconditioned state induced by ethanol ingestion is biphasic. The first or acute phase is short-lived, first becoming apparent within 1 hour after ingestion, with peak anti-inflammatory effects occurring 2 to 3 hours after intake, and then disappearing by 4 hours after consumption. The second or delayed phase of ischemic tolerance induced by ethanol becomes evident 18 to 24 hours after ethanol consumption and is notable for its magnitude of protection, being much more powerful than the acute phase (Figure 1). In these studies, plasma ethanol levels peaked at 45mg/dL within 30 minutes of gastric instillation by gavage and returned to control levels within 60 minutes of ingestion. This observation indicates that neither the acute phase of protection that arises within 1 to 3 hours of alcohol ingestion nor the late phase that reemerges 18 to 24 hours later are due to direct effects of ethanol. Indeed, ethanol must be absent from the blood before the cardioprotective effects of the alcohol become apparent. Interestingly, continued presence of ethanol prevents the infarct-sparing effects of other interventions that induce a preconditioned, protected state such as antecedent exposure to short bouts of ischemia or prior treatment with agents that activate mitochondrial ATP-sensitive potassium channels.
Late Phase o
Time Interval between Ethanol Ingestion and Prolonged Ischemia (hours)
Based on the large body of evidence indicating that leukocyte infiltration into postischemic tissues plays an essential role in the production of reperfusion injury, it was suggested that ethanol may exert anti-inflammatory actions in the setting of I/R. Indeed, ethanol consumption at low to moderate levels is associated with reduced C-reactive
Figure 1 Antecedent ethanol ingestion produces two temporal phases of protection against the proinflammatory effects of ischemia/reperfusion. The early or acute phase develops within 1 hour after ingestion and is relatively short-lived, persisting for 1 to 3 hours and then disappearing. This is followed by the emergence of a second window of protection 12 to 24 hours later; this is more potent and persists for at least 2 days. The second wave of protection is termed late phase or delayed ethanol preconditioning.
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