Seek and Hide Phosphatidylserine: A New Approach to Prevent Hepatic Ischemia/Reperfusion Injury

Events responsible for the pathogenesis of hepatic ischemia/reperfusion injury and mechanisms of action of some pharmacologic agents that have been reported to confer protection against liver damage. Hypoxia causes the depletion of cellular ATP, mitochondrial de-energization, alterations of H⁺, Na⁺, and Ca²⁺ homeostasis and conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XOD). Upon re-oxygenation, the formation of ROS by uncoupled mitochondria and XOD promotes oxidative stress and mitochondrial permeability transition that leads to cell death by either necrosis or apoptosis. Concomitantly, the activation of Kupffer cells releases ROS, NO, eicosanoids and pro-inflammatory cytokines/chemokines (TNF-α, IL-6, IL-1β, MCP-1, IL-12, IL-8). These pro-inflammatory mediators, in concert with the increased expression of adhesion molecules (ICAM-1, VCAM-1 P- and E-selectins) by sinusoidal endothelial cells, promote liver infiltration by granulocytes and monocytes. CD4⁺ T lymphocytes can also contribute to hepatic reperfusion injury.