**3. Remote ischemic preconditioning**

RIPC is a surgical technique by which preconditioning of one organ or vascular bed provides protection to distant organs or vascular beds during a sustained period of ischaemia (**Figure 1**). Few experimental and clinical studies, most of them from the last years, have addressed the effects of RIPC in livers submitted to I/R.

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

When RIPC is applied in the hind limb, it reduced hepatic warm I/R injury of mice, rats, and rabbits. RIPC (5–10 min ischemia/5–10 min reperfusion) has been shown to improve hepatic oxygenation and microcirculation and to reduce hepatic acidosis and damage [59, 60]. RIPC (4 min ischemia/4 min reperfusion) induced eNOS activation, leading to NO production to preserve sinusoidal structure and blood flow [61]. In addition, RIPC (5 min ischemia/5 min reperfusion) regulated the expressions of iNOS and eNOS and the expressions of miR-34a, miR-122, and miR-27b injury related miRs in fatty livers, thus attenuating I/R injury [62, 63]. RIPC (10 min ischemia/10 min reperfusion) also induced the up-regulation of HO-1, induced autophagy, and then reduced the damaged mitochondria to inhibit apoptosis and eventually protect hepatic cells from I/R injury [64, 65]. Moreover, RIPC (5 min ischemia/5 min reperfusion) reduced neutrophil activation and adhesion and TNF-α [66]. Controversial results have been described in a rat model in which RIPC protocol included 3 cycles of 10 min ischemia interspersed with 10 min of reperfusion periods [67]. Regarding the hemodynamic and microcirculatory alterations, RIPC protocol had beneficial effect; however, the histopathological findings were paradox [67, 68]. In addition to RIPC in the hind limb, when RIPC (5 min ischemia/5 min reperfusion) is applied in kidney, it has also been shown to protect liver against I/R injury, improving blood flow, histology, and redox-state [69]. **Figure 2** shows some of the protective mechanisms of RIPC in the

A recent study in mice showed that RIPC (3 cycles of 5 min of ischemia each followed by 5 min of reperfusion) applied in the right femoral vascular bundle did not affect regeneration after 70%-PH [70]. However, of clinical interest, the same protocol of RIPC improved liver weight gain and hepatocyte mitoses after 90%-PH [70].

In an experimental model of OLT, RIPC based on 4 cycles of 5 min of ischemia

and 5 min of reperfusion was applied on the infrarenal aorta. The results suggested that RIPC might confer potent protection against the detrimental effects of I/R injury including apoptosis and inflammation [71]. In addition, authors suggest that HO-1 overexpression could play an orchestrating role in RIPC (5 min ischemia/5 min reperfusion)-mediated organ protection [71]. In addition, a recent study showed that the same protocol of RIPC also exhibits protective effects, as indicated by increased portal venous flow and microcirculation, as well as decreased AST and ALT levels and a reduced Suzuki score in a model of OLT [72]. Authors suggest that the RIPC inhibited the macrophage migration inhibitory factor (MIF), which resulted in the modulation of further downstream pro-survival

mechanisms (iNOS, RISK-, SAFE-pathways), protecting graft injury [72].

Only three studies dated in 2017 and 2018 have addressed the effects of RIPC in

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

*3.1.1 RIPC in warm ischemia without liver resection*

**3.1 RIPC in experimental models**

hepatic I/R injury.

*3.1.2 RIPC in liver resections*

**3.2 RIPC in clinical trials**

the clinical liver surgery.

*3.1.3 RIPC in orthotopic liver transplantation*

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