*2.1.1 IPC in warm ischemia without liver resection*

IPC modulates several molecular pathways involving in I/R. When long periods of liver ischemia occur in hepatectomy or transplantation, the lack of oxygenation induces the rapid ATP consume to generate energy for cellular metabolism, resulting in adenosine production. The accumulation of adenosine provokes its transformation to hypoxanthine and xanthine leading to ROS production. IPC (5 min of ischemia/10 min reperfusion) modulates oxidative stress since reduces the accumulation of xanthine and the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO). IPC (5 min of ischemia/10 min reperfusion) inhibits this ROS generating system, xanthine/XOD [11–13]. The activation of adenosine receptor A2 induced by IPC stimulates the activity of various intracellular kinases, like protein kinase C (PKC)-specifically PKC-δ- and p38 mitogen-activated protein kinase (p38MAPK) [20]. The activation of p38 and c-Jun N-terminal kinase (JNK-1) induced by IPC (10 min of ischemia/10 min reperfusion) is associated with increased cyclin D1 expression and entry into the cell cycle [21]. In addition to this, activation of p38 by different pharmacological strategies mimicking IPC effects, including agonists of the adenosine A2 receptor, carbon monoxide (CO), NO, and atrial natriuretic peptide (ANP) has been considered to be a crucial mechanism of hepatoprotection in the setting of liver surgery [22]. Moreover, autophagic flux is enhanced by liver IPC (10 min of ischemia/10 min reperfusion), since endothelial nitric oxide synthase (eNOS)-derived NO activates autophagy via phosphorylation of p38 MAPK [23]. On the other hand, the mechanism involved in the benefits of IPC might be different dependently of the type of the liver [1]. Indeed, in the presence of steatosis, IPC (5 min of ischemia/10 min reperfusion) reduces MAPK activation (JNK and p38), and this is associated with protection against hepatic I/R injury [24, 25]. The involvement of sirtuin-1 (SIRT1) induction in the benefits of IPC (5 min of ischemia/10 min reperfusion) on normothermic hepatic conditions has been reported [26]. Thus, SIRT1 inhibition decreased the expression of extracellular signal-regulated protein kinases (ERK) and augmented p38 protein levels [26]. ERK activation during IPC (5 min of ischemia/10 min reperfusion) protects against I/R injury in steatotic livers, by inhibiting apoptosis [27], whereas treatment with a p38 activator abolished the benefits of IPC on hepatic damage [24]. In addition, inactivation of GSK-3β by IPC (10 min of ischemia/10–15 min reperfusion) induces β-catenin signaling and subsequently up-regulates anti-apoptotic factors, such as Bcl-2 and survivin, leading to a significant amelioration of liver I/R injury [28, 29]. **Figure 2** shows some of the protective mechanisms of IPC in the hepatic I/R injury.
