*2.1.3 IPC in reduced-size orthotopic liver transplantation*

In a reduced-size orthotopic liver transplantation (ROLT) rat model, IPC (10 min ischemia/10 min reperfusion) has been suggested that potentiates hepatocyte proliferation via TNF-α/IL-6-dependent pathway [34]. In addition, authors described that IPC inhibits IL-1 through NO, increases HGF, and reduces TGF-β to finally promote regeneration [34]. In addition, by another pathway independent

#### **Figure 2.**

*Protective mechanisms propose of ischemic preconditioning and remote ischemic preconditioning in the hepatic ischemia-reperfusion injury. A2-R: adenosine 2 receptor; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATF-2: activating transcription factor-2; ATP: adenosine triphosphate; cGMP: guanosine 3*′*,5*′*-cyclic monophosphate; eNOS: endothelial nitric oxide synthase; ER: endoplasmic reticulum; ET-1: endothelin-1; GSH: glutathione; HO-1: heme oxygenase-1; HSF-1: heat shock transcription factor-1; HSP72: heat-shock protein 72; IL: interleukin; iNOS: inducible nitric oxide synthase; JNK: jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MEF2c: myocyte enhancer factor-2; MIF: macrophage migration inhibitory factor; NF-κB: factor nuclear factor-kappa B; NO: nitric oxide; PI3K: phosphatidylinositol 3-kinase; PKC: protein kinase C; PLC: phospholipase C; ROS: reactive oxygen species; STAT3: signal transducer and activator of transcription-3; TNF: tumor necrosis factor; X/XOD: xanthine/ xanthine oxidase.*

**107**

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

through a mechanism at least partially independent of STAT3 [37].

of NO, IPC induced over-expression of heat shock protein 70 (HSP70) and hemeoxigenase-1 (HO-1) [35]. HO-1 protects against I/R injury, whereas the benefits resulting from HSP70 are mainly related to hepatocyte proliferation [35]. In addition, when steatotic grafts from living donors were transplanted applying IPC, the incidence of necrosis was reduced and the expression of both pro-autophagic beclin-1 and LC3 was increased [36]. On the other hand, in a rat model of ROLT with 70 or 90% hepatectomy, IPC (10 min ischemia/15 min reperfusion) impaired hepatic proliferative response by decreasing IL-6 and blunting cell cycle progression

IPC (5 min ischemia/10 min reperfusion) has protected liver grafts in an experimental model of orthotopic liver transplantation (OLT) by modulation of xanthine/ XOD system [38]. IPC reduced cAMP generation, thus ameliorating hepatic injury and survival of recipients with steatotic grafts [39]. In addition, AMPK activation by IPC (5 min ischemia/10 min reperfusion) increased the accumulation of adiponectin in steatotic liver grafts. This increased resistin and activated PI3K/Akt pathway, thus protecting steatotic livers against damage that follows transplantation [40]. However, it should be noted that in experimental liver transplantation from cadaveric donors, brain death abrogates the benefits of IPC (5 min ischemia/10 min reperfusion) in both steatotic and non-steatotic liver transplantation [41, 42]. Indeed, in the setting of liver transplantation, the inflammatory response induced by brain dead, present in the liver before the induction of IPC, would interact with various mechanistic aspects of IPC and block the eventual IPC response. Thus, Jimenez-Castro et al. have demonstrated that the treatment with acetylcholine protected liver grafts from the deleterious effects induced by brain death [41]. Under these conditions, the application of IPC was useful to improve the post-operative

In addition to the liver, the benefits of IPC in experimental models of warm ischemia and liver transplantation have been observed in extrahepatic organs. Thus, IPC protects against lung damage associated with liver transplantation. The application of IPC in liver before I/R can prevent the release of both TNF and xanthine/ XOD from the liver to the circulation. This regulated the P-selectin up-regulation and the neutrophil accumulation in remote organs such as lung and splanchnic

The benefits of IPC observed in experimental models of hepatic resections and liver transplantation [8, 9] prompted human trials of IPC. The benefits of this surgical strategy have been evidenced in patients submitted to liver resections, protecting both steatotic and non-steatotic livers [44]. However, different results have been reported on the effects of IPC in the clinical practice of liver

The first clinical trial testing IPC in patients undergoing major PH was reported by Clavien et al. [47]. Authors conclude that IPC (10 min ischemia/10 min reperfusion) is a protective strategy against hepatic ischemia in humans, particularly

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

*2.1.4 IPC in orthotopic liver transplantation*

outcomes after transplantation.

organs [43].

**2.2 IPC in clinical trials**

transplantation [45, 46].

*2.2.1 IPC in liver resections*

*Ischemic Preconditioning Directly or Remotely Applied on the Liver to Reduce… DOI: http://dx.doi.org/10.5772/intechopen.86148*

of NO, IPC induced over-expression of heat shock protein 70 (HSP70) and hemeoxigenase-1 (HO-1) [35]. HO-1 protects against I/R injury, whereas the benefits resulting from HSP70 are mainly related to hepatocyte proliferation [35]. In addition, when steatotic grafts from living donors were transplanted applying IPC, the incidence of necrosis was reduced and the expression of both pro-autophagic beclin-1 and LC3 was increased [36]. On the other hand, in a rat model of ROLT with 70 or 90% hepatectomy, IPC (10 min ischemia/15 min reperfusion) impaired hepatic proliferative response by decreasing IL-6 and blunting cell cycle progression through a mechanism at least partially independent of STAT3 [37].

#### *2.1.4 IPC in orthotopic liver transplantation*

*Liver Disease and Surgery*

tion up to 48 h [33].

*2.1.2 IPC in liver resections under warm ischemia*

*2.1.3 IPC in reduced-size orthotopic liver transplantation*

The beneficial effects of IPC (10 min of ischemia/5 min reperfusion) in liver partial hepatectomy (PH) have been shown to be linked to better ATP recovery, NO production, antioxidant activities, and regulation of endoplasmic reticulum stress. All of this limited mitochondrial damage and apoptosis. In addition, the ERK1/2 and p38 MAPK activation induced by IPC in PH favors liver regeneration [30]. Furthermore, IPC (10 min of ischemia/10 min of reperfusion) can initiate hepatocyte proliferation action by a signaling mechanism involving TNF-α/IL-6 signal pathway [31]. In contrast, Qian et al. found that IPC impaired residual liver regeneration after major PH without portal blood bypass in rats. In this case, IPC was of 5 min ischemia/10 min reperfusion [32]. Another study testing regenerative capacity of the liver after IPC (10 min ischemia/10 min reperfusion) and PH showed that, despite IPC decreased hepatic injury, it did not influence the regenera-

In a reduced-size orthotopic liver transplantation (ROLT) rat model, IPC (10 min ischemia/10 min reperfusion) has been suggested that potentiates hepatocyte proliferation via TNF-α/IL-6-dependent pathway [34]. In addition, authors described that IPC inhibits IL-1 through NO, increases HGF, and reduces TGF-β to finally promote regeneration [34]. In addition, by another pathway independent

*Protective mechanisms propose of ischemic preconditioning and remote ischemic preconditioning in the hepatic ischemia-reperfusion injury. A2-R: adenosine 2 receptor; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATF-2: activating transcription factor-2; ATP: adenosine triphosphate; cGMP: guanosine 3*′*,5*′*-cyclic monophosphate; eNOS: endothelial nitric oxide synthase; ER: endoplasmic reticulum; ET-1: endothelin-1; GSH: glutathione; HO-1: heme oxygenase-1; HSF-1: heat shock transcription factor-1; HSP72: heat-shock protein 72; IL: interleukin; iNOS: inducible nitric oxide synthase; JNK: jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MEF2c: myocyte enhancer factor-2; MIF: macrophage migration inhibitory factor; NF-κB: factor nuclear factor-kappa B; NO: nitric oxide; PI3K: phosphatidylinositol 3-kinase; PKC: protein kinase C; PLC: phospholipase C; ROS: reactive oxygen species; STAT3: signal transducer and activator of transcription-3; TNF: tumor necrosis factor; X/XOD: xanthine/*

**106**

*xanthine oxidase.*

**Figure 2.**

IPC (5 min ischemia/10 min reperfusion) has protected liver grafts in an experimental model of orthotopic liver transplantation (OLT) by modulation of xanthine/ XOD system [38]. IPC reduced cAMP generation, thus ameliorating hepatic injury and survival of recipients with steatotic grafts [39]. In addition, AMPK activation by IPC (5 min ischemia/10 min reperfusion) increased the accumulation of adiponectin in steatotic liver grafts. This increased resistin and activated PI3K/Akt pathway, thus protecting steatotic livers against damage that follows transplantation [40]. However, it should be noted that in experimental liver transplantation from cadaveric donors, brain death abrogates the benefits of IPC (5 min ischemia/10 min reperfusion) in both steatotic and non-steatotic liver transplantation [41, 42]. Indeed, in the setting of liver transplantation, the inflammatory response induced by brain dead, present in the liver before the induction of IPC, would interact with various mechanistic aspects of IPC and block the eventual IPC response. Thus, Jimenez-Castro et al. have demonstrated that the treatment with acetylcholine protected liver grafts from the deleterious effects induced by brain death [41]. Under these conditions, the application of IPC was useful to improve the post-operative outcomes after transplantation.

In addition to the liver, the benefits of IPC in experimental models of warm ischemia and liver transplantation have been observed in extrahepatic organs. Thus, IPC protects against lung damage associated with liver transplantation. The application of IPC in liver before I/R can prevent the release of both TNF and xanthine/ XOD from the liver to the circulation. This regulated the P-selectin up-regulation and the neutrophil accumulation in remote organs such as lung and splanchnic organs [43].

#### **2.2 IPC in clinical trials**

The benefits of IPC observed in experimental models of hepatic resections and liver transplantation [8, 9] prompted human trials of IPC. The benefits of this surgical strategy have been evidenced in patients submitted to liver resections, protecting both steatotic and non-steatotic livers [44]. However, different results have been reported on the effects of IPC in the clinical practice of liver transplantation [45, 46].

#### *2.2.1 IPC in liver resections*

The first clinical trial testing IPC in patients undergoing major PH was reported by Clavien et al. [47]. Authors conclude that IPC (10 min ischemia/10 min reperfusion) is a protective strategy against hepatic ischemia in humans, particularly

in young patients requiring a prolonged period of inflow occlusion and in the presence of steatosis [44, 47]. Other clinical trials also suggest that IPC (10 min ischemia/10 min reperfusion) provides both better intraoperative hemodynamic stability and anti-ischemic effects compared with intermittent clamping [48, 49]. Regarding the molecular basis of IPC (10 min ischemia/10 min reperfusion) in clinical PH, its beneficial effects have been shown to be linked to the down-regulation of potentially cytotoxic functions of PMNLs elicited by the Pringle Maneuver [50]. In addition, IPC (10 min ischemia/15 min reperfusion) increased the generation of adenosine and attenuated the degradation of purines in patients undergoing PH. Moreover, IPC appeared to attenuate apoptotic response of the liver remnant after resection [51]. Other clinical trial revealed that IPC (10 min ischemia/10 min reperfusion) stimulated the expression of the IL-1-RA, inducible nitric oxide synthase (iNOS), and Bcl-2 which decreased the inflammatory response and abrogated liver I/R injury [52]. Interestingly, since the ischemic period and pathophysiology are similar in partial hepatectomy and living donor liver transplantation, IPC could reduce damage and improve liver regeneration failure, a relevant risk factor in living donor liver transplantation [34]. Moreover, IPC could be implemented as an appropriate surgical strategy for the use of suboptimal livers, such as steatotic ones, in the clinical practice. Different results indicate that in patients with liver cirrhosis, IPC (5 min ischemia/5 min reperfusion) has been a suitable method to decrease liver I/R injury [53, 54]. Recently, the protective mechanism of IPC in patients with liver cirrhosis subjected to PH has been associated with changes in MAPK pathways [54]. In contrast, IPC applied for 15 min followed by 5 min reperfusion did not improve liver tolerance to I/R injury after PH in patients with liver cirrhosis [55]. In fact, RIPC did not induce changes in the postoperative levels of transaminases, bilirubin, and albumin nor reduced the morbidity and mortality rates and the duration of hospitalization [55].
