**2. Ischemic preconditioning**

Preconditioning the liver with ischemia involves a brief period of portal triad clamping usually between 5 and 15 min followed by a brief period of reperfusion (10–20 min) before a prolonged period of ischemia [10] (**Figure 1**). The exact mode of action of the IPC in the prevention of post-operative hepatic complication has not yet been fully comprehended. The molecular basis for IPC consists of a sequence of events in which in response to the triggers of IPC, a signal must be generated and transduced into an intracellular message leading to the effector mechanism

**105**

*Ischemic Preconditioning Directly or Remotely Applied on the Liver to Reduce…*

of protection [11, 12]. As in the pathophysiology of hepatic I/R, in the modulation of hepatic injury induced by IPC, there is a complex interaction between different

Over the years, studies with experimental animal models have reported numerous positive effects of IPC on the alleviation of hepatic I/R injury and improvements of post-operative liver functioning. Various combinations of ischemia and reperfusion periods have been tested showing similar beneficial effects: lower aminotransferase levels, reduced hepatocellular injury, and higher survival rates [14]. IPC protected against mitochondrial ROS and thus reduce the oxidative stressmediated damage in liver I/R injury [15–18]. However, Rüdiger et al. showed that IPC is beneficial in liver submitted to an ischemic period of up to 75 min, but not for

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

*DOI: http://dx.doi.org/10.5772/intechopen.86148*

mechanisms and cell types [13].

**2.1 IPC in experimental models**

more prolonged ischemia [19].

*2.1.1 IPC in warm ischemia without liver resection*

protective mechanisms of IPC in the hepatic I/R injury.

#### **Figure 1.**

*Schematic illustration of ischemic preconditioning and remote ischemic preconditioning.*

of protection [11, 12]. As in the pathophysiology of hepatic I/R, in the modulation of hepatic injury induced by IPC, there is a complex interaction between different mechanisms and cell types [13].
