**4. Brief review of the pathophysiology of IRI**

Fig. 2. Multifaceted mechanism are involved in the causation of hepatic ischemia-reperfusion injury (IRI). Kupffer and endothelial cells produce cytokines and chemokines, recruiting neutrophils that further accentuate injury. EC, endothelial cell. NO (nitric oxide) is decreased as a result of IRI allowing for decreased perfusion and exaggerated injury (Massip-Salcedo, Roselló-Catafau, Prieto, Avíla, & Peralta, 2007). KC, Kuppfer cell. ATP, adenosine triphosphate. TNF, tumor necrosis factor. IL, interleukin. ICAM, intercellular adhesion molecule. PAF, platelet activation factor. LTB4, leukotrien B4. GMS-CSF, granulocyte macrophage colony stimulating factor. INF, interferon. ROS, reactive oxygen species. (Slighty modified with permission of Dr. Joan Rosello-Catafau, Barcelona, Spain)

During the ischemic phase, anaerobic metabolism ensues and produces an inadequate amount of high-energy phosphates which are fundamental to most cellular functions. Low levels of high-energy phosphates affects a myriad of cellular functions: homeostasis, signaling interactions, cellular proliferation and processing of the apoptotic death cycle. Adenosine triphosphate (ATP) depletion impairs the sodium/potassium ATPase (Na+/K+- ATPase) function, resulting in an impairment of the efflux of sodium from the cell. Additionally, toxic metabolites – which are generated during ischemia **–** attract free water into ischemic cells and organelles leading to the formation of cellular edema (Jennings, Shen, Hill, Ganote, & Herdson, 1978). If the ischemic insult lasts greater than 24 hours, it is likely that ATP-synthase activity becomes irreversible after blood restoration, leading to cellular necrosis, apoptosis or necroapoptosis (Sammut et al., 2000). Ischemia also causes an increased expression of adhesion molecules that leads to endothelial cell and neutrophil adhesion resulting in vascular studding and occlusion (Yadav et al., 1998). Furthermore, disequilibrium between NO and endothelin (ET) induces vasoconstriction and subsequent microcirculatory failure even though blood circulation has been re-established (Montalvo-Jave, Escalante-Tattersfield, Ortega-Salgado, Piña, & Geller, 2008). Reestablishment of blood flow will serve to amplify inflammation with consequent injury that is highly variable but dependent on numerous variables that include the extent of mediators produced (i.e. reactive oxygen species), the degree of endothelial and neutrophil adhesive responses and the degree of Kuppfer cell activation.
