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Review

An Evaluation of Ischaemic Preconditioning as a Method of Reducing Ischaemia Reperfusion Injury in Liver Surgery and Transplantation

by
Francis P. Robertson
1,*,
Barry J. Fuller
1 and
Brian R. Davidson
1,2
1
Division of Surgery and Interventional Science, Royal Free Campus, University College London, 9th Floor, Royal Free Hospital, Pond Street, London NW3 2QG, UK
2
Department of Hepaticopancreatobiliary Surgery and Liver Transplantation, Royal Free Foundation Trust, 9th Floor, Royal Free Hospital, Pond Street, London NW3 2QG, UK
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2017, 6(7), 69; https://doi.org/10.3390/jcm6070069
Submission received: 23 May 2017 / Revised: 22 June 2017 / Accepted: 4 July 2017 / Published: 14 July 2017
(This article belongs to the Special Issue Current Research and Advancements in Liver Ischemia and Reperfusion Injury)
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Abstract

:
Liver Ischaemia Reperfusion (IR) injury is a major cause of post-operative liver dysfunction, morbidity and mortality following liver resection surgery and transplantation. There are no proven therapies for IR injury in clinical practice and new approaches are required. Ischaemic Preconditioning (IPC) can be applied in both a direct and remote fashion and has been shown to ameliorate IR injury in small animal models. Its translation into clinical practice has been difficult, primarily by a lack of knowledge regarding the dominant protective mechanisms that it employs. A review of all current studies would suggest that IPC/RIPC relies on creating a small tissue injury resulting in the release of adenosine and l-arginine which act through the Adenosine receptors and the haem-oxygenase and endothelial nitric oxide synthase systems to reduce hepatocyte necrosis and improve the hepatic microcirculation post reperfusion. The next key step is to determine how long the stimulus requires to precondition humans to allow sufficient injury to occur to release the potential mediators. This would open the door to a new therapeutic chapter in this field.

Graphical Abstract

1. Introduction

Ischaemia Reperfusion (IR) injury, the injury that happens to an organ when its blood supply is interrupted and re-established, is a major cause of post operative liver dysfunction, morbidity and mortality following liver transplantation and hepatic resectional surgery. Surgical and oncological advances in the treatment of colorectal liver metastases combined with an increase in obesity and aging populations in the West have led to an increase in major liver resectional surgery being performed on high risk patients. Similarly, the increased demand for liver transplantation combined with its proven success has led to a shortage of donor organs for transplant with the increased use of marginal quality grafts.
The presence of liver steatosis is associated with an increased risk of mortality from 2 to 14% following elective liver resection [1,2] and the use of a graft from a Donor following Circulatory Death (DCD) is associated with a twofold increase in risk of recipient death and graft loss [3]. This increased risk is secondary to the increased susceptibility of these livers to IR injury. There is currently no accepted treatment for IR injury and as such the development of strategies to ameliorate IR injury are necessary to make major liver surgery and liver transplantation safer. This would simultaneously allow the safe implantation of more marginal grafts that are currently rejected for transplantation due to the worry of Primary Graft Non Function (PGNF) resulting from severe IR injury.
Ischaemic Preconditioning (IPC), the process by which short bursts of ischaemia to a vascular bed results in protection during further sustained ischaemic periods, is one such strategy which is directly applicable in the clinical setting. IPC can be either applied directly to the target organ [4] or remotely to a distant vascular bed [5]. Both forms of IPC have been shown to successfully ameliorate IR injury in small animal models. However the translation to clinical practice has led to conflicting results following an initial positive trial by Clavien [6,7] on patients undergoing hepatic resection, there have been several negative trials and some positive trials [8]. A recent meta-analysis failed to identify any benefit resulting from IPC performed in liver resections [9] however a meta-analysis of IPC performed on transplant donor livers prior to graft retrieval found evidence of a reduction in post-operative recipient mortality and graft loss [10]. A key factor in these conflicting results is a lack of understanding of the mechanisms by which IPC exerts its protective effects and as such IPC/RIPC protocols vary between studies and are unlikely to be optimal. Furthermore, IR injury in the setting of humans is more complex than in small animal models as multiple pathways overlap and can be altered secondary to the underlying condition. In small animal models, the animals are healthy and have little genetic variation, IR injury happens in patients often with severe systemic disease and multiple co morbidities. It is well known in cardiac patients and small animal models that diabetes, obesity and increased aged reduce the beneficial effect of preconditioning [11] but the effect of chronic liver disease remains unknown. Further complicating factors include blood loss and the need for transfusion during major liver surgery, as potential humoral factors may be lost or diluted and the type of anaesthetic used. Recently, in the setting of cardiac surgery, two large randomized controlled trials have failed to demonstrate a benefit following RIPC with both trials identifying the use of intravenous propofol (a very common anaesthetic agent used regularly in liver resection and transplantation) as a potential limitation [12,13] and a small trial carried out by our group in the setting of liver transplantation [14] identifying that due to the use of high flow oxygen prevented the creation of true ischaemic conditions in the limb during the RIPC stimulus. As these essential intra-operative factors may impair the protection of RIPC knowledge of the various protective mechanisms is of key importance as this would not only allow IPC protocols in humans to be altered to overcome these hurdles but may also lead to new pathways that can be targeted to ameliorate IR injury bypassing these factors. The majority of basic research into IPC/RIPC has been performed in the myocardium. In this review, we present the mechanistic pathways identified in the protective effect of IPC/RIPC on liver IR injury.

2. Methods

Pubmed, Excerpta Medica Database (EMBASE) and Publicus Ovidus Naso (OVID) were searched between the years of 1986 and 2016 using the search strategy: (((liver) OR (hepatic)) AND ((ischemia) OR (ischemia-reperfusion injury)) AND ((preconditioning) OR (ischemic preconditioning) OR (IPC) OR (remote ischemic preconditioning) OR (RIPC) OR (hepatoprotection))). Key studies investigating the mechanisms of IPC/RIPC are contained in Table 1.

3. Protective Effects of Preconditioning

Although there is clear evidence in the setting of myocardial IR injury to suggest that IPC exerts its maximal effect in the immediate post reperfusion period [44], it is known that IPC has a bimodal duration of protection. There appears to be an early (or classic) window of protection lasting up to 3 h and a later period of protection lasting between 12 and 72 h post preconditioning—the so-called second window of protection (SWOP) [45,46,47]. The mechanisms by which IPC exerts it protection during these phases are poorly understood but have been shown to be very different in the two time periods. The phenomenon of the SWOP, although a focus of cardiac IPC studies has not been the focus of studies in hepatic IR injury, in which IPC/RIPC is generally performed 5 min before IR injury. This review will focus mainly on the classical protective window.
IPC has been postulated to work through three main generic mechanisms (Figure 1). IPC has been shown to release humoral factors into the blood which reduce apoptosis and cell death in the target organ during the IR injury. It has also been shown to reduce the systemic inflammatory response following IR injury further reducing tissue injury. It has been shown in other organs that RIPC relies on a neuronal feedback mechanism to provide protection and that interruption nervous system either physically or pharmacologically can block RIPC [48]. This pathway has not been investigated in the setting of liver IR injury.

4. Adenosine

Adenosine, a nucleotide and component of ATP breakdown, is rapidly released from damaged cells in ischaemic tissue [49] and can bind with four different adenosine receptors (A1R, A2AR, A2BR, and A3R) [50], all of which can be expressed by hepatocytes [51]. As in other organs [51], Adenosine has been shown to play a protective effect in the liver following IR injury through a diverse range of mechanisms (Figure 2). Pharmacological upregulation of endogenous adenosine by R75231 (which prevents adenosine uptake and metabolism) significantly attenuated liver IR injury in a canine model and led to significantly increased survival at two weeks following 2 h of total liver ischaemia [52]. In rats treated with adenosine deaminase (which degrades adenosine) prior to IPC, the protective effect of IPC was abolished in hepatic IR injury as measured by serum transaminases and lactate dehydrogenase [15]. Conversely, administration of a NO donor in these animal reinstated the protective effect which is in keeping with the knowledge that adenosine leads to NO release by the vascular endothelium, resulting in vasodilation [53]. The same group demonstrated that IPC increased levels of adenosine in the hepatic tissue [16] and this has been confirmed in one study [17]. The administration of adenosine deaminase abolished the protective effect of IPC and adenosine infusion prior to IR injury provided protection to a similar level as IPC [16]. An interesting observation by Peralta and colleagues was that 10–15 min of continuous ischaemic stimulus in IPC was the ideal length of time in rats as it lead to sufficient release of adenosine but insufficient release of other toxic metabolites of ischaemia [16]. This is in keeping with studies of IPC on donor livers prior to retrieval in human liver transplantation in which it was demonstrated that 5 min of donor preconditioning was insufficient to provide protection [54] whilst 10 min of donor IPC was associated with a reduction in postoperative transaminases in keeping with a reduction in IR injury [55], a finding also found in patients undergoing RIPC prior to major hepatectomy [8]. There is clear evidence that adenosine is upregulated following IPC/RIPC and that pharmacological degradation of adenosine ablated the protective effect of IPC. Adenosine exerts its anti-apoptotic and vasodilatary effect through its interaction with the adenosine receptors. In keeping with studies into IR injury in other organs, much of the work on these receptors has focused on the A1 and the A2A receptors.

5. The A1 Receptor

Genetic knockout mice lacking the A1 receptor are more susceptible to hepatic IR injury than wild type mice with a normal A1R [56]. This was linked to a significant increase in the level of apoptosis and neutrophil infiltration seen within the liver at 12 and 24 h. Selective blockade of A1R with 8-Cyclopentyl-1, 3-dpropylxanthine (DPCPX) also increased IR injury as measured by serum transaminases and hepatic necrosis [56]. In contrast, beagles administered the A1R antagonist (KW3902) had reduced transaminases, better hepatic blood flow upon reperfusion and significantly improved two-week survival following hepatic IR injury (83% vs. 17%, p < 0.05) [57]. It is unclear why there is such a striking difference between the studies on the A1 receptor but this may reflect the different species or the use of a different A1R antagonist.
Adenosine or its receptors may also play a role in the protective effect of IPC. However some of the results have been conflicting. Ajemieh and colleagues [19] demonstrated that in rats treated with the A1R antagonist, DPCPX, the protective effect of IPC was ablated. Similarly treatment of rats with CCPA (an A1R agonist) provided a similar level of protection following IR injury as garnered by IPC. This was in contrast to findings from Peralta and colleagues [18] who demonstrated that, although adenosine depletion negated the protective effects of IPC and improved hepatic blood flow post reperfusion, pharmacological inhibition of the A1R with DPCPX did not affect the protection produced by IPC. The timing of DPCPX administration between these studies differs. It was administered 5 min prior to IPC by Perlata [18] and 24 h prior to IPC by Ajemieh and colleagues [19] which may explain the different results. Both studies used a dose of 0.1 mg/kg. In none of the above studies did treatment of the animals with an A1R agonist lead to protection of the liver during IR injury prompting the suggestion that IPC required the presence or upregulation of endogenous adenosine [19] or other mediators.

6. The A2A Receptor

The A2A Receptor has been shown to play a key role in hepatic IR injury as the administration of the A2AR agonist γ-glutamylcysteine synthase (GCS) to isolated rat livers immediately prior to reperfusion reduced the level of apoptosis and degree of liver IR injury as measured by transaminases and degree of hepatocyte apoptosis [58].
IPC has been shown indirectly to exert protection through the A2AR in several studies. Perlata and colleagues [18] demonstrated that the use of DMPX, an A2R antagonist (at this time point, there was no distinction between A2AR and A2BR), ablated the protective effect of IPC in a rat model. Thurman and colleagues [59] demonstrated again that the administration of DMPX ablated the protective effect of IPC but also they were one of few groups who demonstrated that the administration of CGS-21680, an A2R agonist, protected the liver against IR injury. Their results would suggest that IPC prevented sinusoidal epithelial cell death through the adenosine receptors. However, in contrast, Schaeur and colleagues [20] demonstrated that the use of DMPX had no effect on the protective effect of IPC. Adenosine has been shown to exert its protective effect through reduced hepatocyte apoptosis and increased hepatic blood flow post reperfusion. It has also been shown to play a role in directing the early immune response post reperfusion [60] and mice treated with an A2AR agonist (ATL146e) not only had a significantly reduced IR injury but also had less upregulation of pro-inflammatory cytokines including IL-6 and MCP-1. The activation of Natural Killer T cells was inhibited through activation of the A2AR [61] again suggesting that adenosine is able to suppress the post reperfusion inflammatory response. Whether this is as a result of reduced necrosis or directly suppressing inflammation remains to be elucidated as the effect of IPC on NKT cell differentiation and activation has not been investigated.

7. The A2B Receptor

Few studies have investigated the role of the A2BR in hepatic IR injury. Zimmerman and colleagues [62] demonstrated that the A2BR was upregulated on human hepatocytes in post reperfusion liver biopsies when compared to the same livers pre implantation. Furthermore, they showed that mice lacking the A2BR suffered significantly worse IR injury following 45 min of warm IR injury and that this was associated with higher levels of IL-6 and TNFα production in the liver and distant end organs. Analysis using cell culture demonstrated that activation of the A2BR reduced NF-κB activation and stabilization in hepatocytes and that pharmacological stabilisation of NF-κB reconstituted the injury in A2BR deficient mice. In a study of global hypoxic preconditioning in which mice were subjected to 10% Oxygen for 10 min prior to hepatic IR injury, it was shown that mice lacking the A2BR were not protected while mice lacking each of the other three receptors were still protected [21]. Although reduction in IR injury was associated a reduction in IL-6, TNFα levels and neutrophil infiltration, no down stream mechanisms were explored.

8. The A3 Receptor

There is no evidence as yet regarding the role of the A3R either in hepatic IR injury or in IPC of the liver.

9. Adenosine and Its Receptors

The seemingly conflicting results from studies investigating the individual adenosine receptors would suggest that it is more likely that the mechanism of protection of IPC is related to increased adenosine release rather than upregulation of an individual receptor.

10. Nitric Oxide and Nitric Oxide Synthase

Nitric oxide (NO), a potent vasodilator, is a colourless gas synthesized by the action of Nitric Oxide Synthase (NOS) on l-arginine [63] and has been shown to exert a protective effect during hepatic IR injury [64] by inhibiting synthesis of endothelin, a potent vasoconstrictor [65]. There are three isoforms of NOS. Only two are believed to play a role in hepatic IR injury: endothelial nitric oxide syntase (eNOS) and inducible nitric oxide syntase (iNOS).
There is robust evidence demonstrating that NO derived from eNOS is hepatoprotective following IR injury. Transgenic mice lacking eNOS have been shown to suffer a more significant IR injury [66,67,68,69,70] whilst genetic over expression of eNOS in mice is associated with a significant reduction in IR injury [71].
In the setting of IPC, eNOS expression and circulating levels of l-arginine were upregulated in the rodent liver following IPC and this was associated with increased nitrate levels in the portal vein [22]. Pre treatment with DMPX, an adenosine A2 inhibitor, abolished the protective effect of IPC. There was no upregulation of eNOS and the results were similar to those seen when rats were treated with l-NAME, a NOS inhibitor, suggesting that eNOS upregulation and function is reliant on the A2R pathway [64]. These results were similar to the findings of Mathie and colleagues [72] who demonstrated that administration of adenosine was able to ameliorate IR injury but that when combined with l-NA, an eNOS inhibitor, adenosine was unable to provide protection [72]. Transgenic mice lacking eNOS that underwent RIPC displayed the same level of hepatic IR injury as those undergoing IR injury without RIPC again confirming the key role eNOS in the early protection of RIPC [23].
The effect of NO from iNOS in hepatic IR injury is more variable. Some studies have suggested that the effect of iNOS activation is dependent on the length of the ischaemic period and temperature maintained during ischaemia [63], however several studies have shown that NO derived from iNOS is a key mechanism of liver injury following IR injury [73,74]. Targeting eNOS rather than NO may therefore be more beneficial.
IPC of the liver has not been shown to affect iNOS levels [22] suggesting the iNOS does not play a role in the protective mechanisms of IPC/RIPC.

11. Protein Kinase C

The term protein kinase C (PKC) encompasses a family of intracellular enzymes that can be classified as signal transducers that direct the processing of downstream proteins. PKC induction in hepatocytes has been shown to be significantly elevated in rodent livers following reperfusion [75]. PKC has been identified as a downstream signalling pathway of adenosine receptors [76,77]. Pharmacological inhibition of PKC has been shown to reduce hepatic IR injury [26,78,79].
Interestingly, studies investigating the effect of IPC on PKC activity have shown that the protective effect of IPC is not associated with inhibition of PKC but actually with an increase in PKC activity. In an isolated hepatocyte model, it was shown that the protective effect of hypoxic preconditioning was ablated by the use of a PKC inhibitor chelerythrine [24]. Further similar work by the same group on isolated rodent hepatocytes confirmed these findings but also linked PKC activation to the A2R [77]. In pig livers undergoing IPC, prior to cold storage, PKC was shown to be activated in the hepatocytes of livers undergoing IPC prior to cold storage [26]. Treatment of livers with chelerythrine was shown to abolish the protective effects of IPC [26]. Other intracellular kinases have been implicated including tyrosine kinase [80], mitogen activated protein kinase [77]. Although PKC has been postulated as a potential mechanism for IPC, it would seem more likely that PKC and other intracellular kinases play a key role in indiscriminately transferring the extracellular signal generated by IPC/RIPC to the cell nucleus.

12. Nuclear Factor Kappa-Light-Chain-Enhancer of B Cells (NF-κB)

NF-κB is a transcription factor that is rapidly upregulated in ischaemic cells and has been shown to play a role in hepatic IR injury and to promote upregulation of iNOS and pro-inflammatory cytokines [75,81]. NF-κB levels were significantly upregulated within the first 4 h post IR injury in a murine model.
In mice that underwent IPC, NF-κB levels were significantly lower than those that did not [38]. This was associated with a reduction in TNFα mRNA levels. In porcine grafts undergoing IPC prior to cold storage, NF-κB translocation was upregulated early following IPC, prior to cold storage [27] suggesting that similar to PKC, NF-κB is more likely to be an intracellular messenger that is affected by extracellular molecules upregulated during IPC/RIPC.

13. Haem-Oxygenase-1 (HO-1)

Haem-oxygenase is an enzyme that catalyses the degradation of heme resulting in the production of anti-oxidant biliverdin and carbon monoxide [82] another gaseous signalling agent which has vasodilatory effects. Expression of HO-1 has been shown to be upregulated in hepatocytes following hepatic IR injury [28] and it has been shown to reduce hepatocyte apoptosis following IR injury, increase the availability of anti-oxidants, improve hepatic blood flow and to have anti-inflammatory effects [83] all of which have been suggested may ameliorate IR injury. Treatment of mice with gadolinium choride has been shown to upregulate HO-1 expression of Kupffer cells promoting an anti-inflammatory phenotype in Kupffer cells that was absent in HO-1 genetic knock out mice, and was associated with reduced liver injury [84]. Pharmacological upregulation of HO-1 with isoproterenol has been shown to reduce cytokine release from macrophage cell culture via down regulation of NF-κB following lipopolysaccharide stimulation and to reduce HMGB-1 release (a key driver of liver IR injury). This was associated with a significantly increased seven-day survival from 30 to 70% in a rat model of peritonitis [85]. Similar findings have been shown in a rat model of cardiac IR injury, in which again treatment with isoproterenol prior to occlusion of the left anterior descending artery for 30 min significantly increased circulating levels of HO-1 and HO-1 activity which was associated with significantly reduced levels of IL-6, TNFα and HMGB1 and significantly reduced infarct size [86]. Transduction experiments of rat livers with a viral vector for HO-1 injected into the portal vein prior to graft harvest have shown upregulation of HO-1 up to 90 days post transplantation and is associated with increased survival and immune tolerance [87] as demonstrated by an increased level of Tregs, Il-10 and TGF-β in both the liver and the periphery.
RIPC of the hind limb has been shown to significantly upregulate HO-1 expression and activity on hepatocytes. This was measured after 4 h but prior to IR injury and was associated with a significant reduction in IR injury as measured by transaminases [28]. In contrast at 2 h post direct IPC and IR injury, although IR injury was ameliorated and HO-1 mRNA levels were upregulated, HO-1 was not detectable on hepatocytes, but was by 24 h, suggesting that upregulation of HO-1 takes several hours and may not be the earliest protective mechanism of IPC [29]. Interestingly, although HO-1 was upregulated on hepatocytes, there was no change identified in circulating lymphocytes [28]. The same group demonstrated in mice that HO-1 expression is upregulated following IR injury suggesting that the upregulation of HO-1 is necessary pre IR injury to be effective [30]. Upregulation of HO-1 in the liver following RIPC was seen to increase the incidence of autophagy [30]. This is the process by which cells envelop and degrade damaged cellular components within the cytoplasm preventing them from leaking in to the surrounding extracellular space where they act as damage associated molecular patterns (DAMPs) and may explain why RIPC can be associated with a reduction in HMGB1 release following IR injury [86].

14. The Immune System

IR injury is an example of sterile inflammation. Following reperfusion, the release of DAMPS into the extra cellular space provokes an intense inflammatory activation and several cell types have been implicated in this process.

15. CD4+ T Cells

CD4+ T cells are a component of the lymphocyte populations and are rapidly recruited to post ischaemic tissue. There is clear evidence that CD4+ T cells play a key role in IR injury as mice lacking CD4+ T cells, although suffering a similar ischaemic injury, are protected from the reperfusion injury [74]. This phenomenon has not only been shown in the murine liver, but is evident in the murine kidney [88], and in the murine lung [89]. The CD4+ T cell population is composed of both pro inflammatory effector T cells and anti-inflammatory T cells. The effect of IPC on effector T cells has not been investigated as research has focused on the anti-inflammatory subgroup—regulatory T cells (Tregs). Three studies have looked at the effect of IPC on Treg recruitment and function, two in the kidney [31,32] and one in the liver [33]. The study protocols for the two studies in the kidney were very similar and IPC was performed seven days prior to the IR injury. Both studies demonstrated similar findings that not only did IPC ameliorate renal IR injury but also that Treg numbers in the ischaemic kidneys were upregulated. This upregulation of Tregs was not seen when the IR injury was performed three days or 14 days post IPC, suggesting that it is a delayed and transient phenomenon [31]. Treg function was measured by IL-10 production as measured by intracellular flow cytometry and this was significantly upregulated by IPC. Antibody depletion of Tregs by anti-CD25 antibody [32] or PC61 [31] ablated the protective effect of IPC. Furthermore adoptive transfer of Tregs obtained from mice that underwent IPC provided protection in naive mice [32]. In contrast, when IPC was performed immediately prior to IR injury, despite protection during IR injury, there was no evidence of Treg mobilization to the liver [33]. Furthermore depletion of Tregs did not ablate the protective effect of IPC and transfer of pre-activated Tregs into mice did not protect against IR injury and the authors came to the conclusion that the protection gained by IPC is independent of Tregs. The experiment they failed to perform was to augment Tregs into preconditioned mice and to add Tregs from preconditioned mice into naive mice. IPC has been shown to result in a reduction in circulating cytokines especially IL-6 which is known to act as a brake of Treg activation, proliferation and function [90] and to promote CD4+ effector T cell migration [91]. It is most likely that key factor in the differences between these studies is the timing between the preconditioning stimulus and IR injury. It is perhaps unrealistic to expect IPC to have a profound effect of T cells populations within such a short period of time. However, IPC/RIPC is more likely to alter the cytokine milieu that may affect early T cell responses and direct the later T cell response.

16. Macrophages

Kupffer Cells are resident liver macrophages and have been shown to be activated early following IR injury [92,93]. However experiments blocking macrophage activity have had varied results with some studies demonstrating that Kupffer cell blockade or modulation attenuated IR injury [94,95] whilst other models have shown increased IR injury following Kupffer cell depletion [96].
IPC has been shown to reduce Kupffer cell activation following IR injury as measured by reduced phagocytosis of latex particles [36] reduced reactive oxygen species secretion [34] and reduced TNFα secretion leading not only to reduced hepatic IR injury [34] but also reduced neutrophil accumulation in distant end organs [35]. However, arguably the most important study is a study from Tejima and colleagues in which the results suggest that IPC directly reduced hepatocycyte injury and death rather than through suppressing Kupffer cell activation [37]. Interestingly though they found in the absence of Kupffer cells, this protection was not gained suggesting a key role for macrophages in the preconditioning stimulus. This is in keeping with the theory that IPC/RIPC works by causing limited tissue injury resulting in protective mechanisms being activated.

17. Monocytes

Inflammatory monocytes are rapidly recruited to sites of tissue injury from the bone marrow by chemokine ligand 2 (CCL2) [97]. Few studies have looked at the role of inflammatory monocytes in hepatic IR injury, however they have been shown to play a key role in acetaminophen liver injury in small animal models [98]. One study using genetic CCL2 knock out mice has demonstrated that these are protected from hepatic IR injury leading to the suggestion that inflammatory monocytes play a key role in the pathogenesis of IR injury [99]. No studies have investigated the effect of IPC/RIPC on inflammatory monocytes.

18. Cytokines

Hepatic IR injury is associated with the early release of several pro-inflammatory cytokines. IL-2 [100], IL-6 [100,101], IL-17 [102], and TNFα [100,101] have been shown to be upregulated following hepatic IR injury and to be associated with increased hepatocyte apoptosis and neutrophil infiltration into the post ischaemic liver. TNFα is a key pro inflammatory cytokine that has been shown to play a role in hepatic IR injury and treatment of mice with anti-TNFα prior to IR injury is associated with a significant reduction in injury [100].
Serum cytokines have been measured in many small animal models of IPC/RIPC and there is strong evidence to show that IPC and RIPC are associated with a reduction in TNFα production in the liver in the first few hours following reperfusion [39,43]. Pre-treatment of mice undergoing IPC with DPCPX, an A1R antagonist abolished the protective effect of IPC and the reduction in serum TNFα levels suggesting that adenosine signalling may dampen down the immune response [19]. Furthermore, inhibition of NF-κB translocation by IPC led to a reduction TNFα mRNA in murine livers following IR injury [38].
IL-6 levels have similarly been shown to be reduced in the early hours post IR injury in mice undergoing IPC [40,42]. However, IPC is associated with a spike in IL-6 levels within the first hour post IR injury [42]. Although no studies of IPC/RIPC in hepatic IR injury have been performed in either IL-6 or TNFα deficient mice, studies have suggested that both IL-6 and TNFα are essential for hepatic regeneration and studies of hepatectomy in IL-6 deficient mice have demonstrated a more significant IR injury with increased mortality [40,103,104]. It should be noted that this model purposefully used a small for size liver remnant and several studies have shown that IPC is protective in normal livers. Similar results have been seen with TNF receptor deficient mice [105]. This may be explained by the fact that some immune cells have been shown to be pleiotropic and inflammatory monocytes recruited to sites of sterile inflammation in the liver were seen to phenotypically change and become alternative monocytes which are essential to tissue regeneration [106].
There has been much interest in IL-10, a potent anti-inflammatory cytokine both in terms of whether its supplementation may ameliorate IR injury and whether it is upregulated by IPC/RIPC. Treatment of mice with recombinant IL-10 prior to IR injury significantly attenuated IR injury and interestingly was associated with a reduction in TNFα production in the liver [105]. IL-10 depletion has been shown to result in increased liver injury and increased production of TNFα and IL-6 (89) [95] again demonstrating an interplay between these pro-inflammatory and anti-inflammatory cytokines and suggesting that manipulating cytokine production could alter IR injury. The effect of IPC on IL-10 levels post IR injury have been conflicting. In a rodent model, of direct RIPC, although IR injury was attenuated, IL-10 levels were not upregulated [42]. In contrast, in a trial of donor IPC in human liver transplantation, recipients that received a liver that underwent IPC prior to retrieval has significantly higher serum levels of Il-10 at three hours post reperfusion [41]. This was not associated with a reduction in IR injury but was associated with a significant reduction in both moderate and severe acute rejection episodes.
Although IL-6, IL-10 and TNFα knockout mice do exist as do neutralizing antibodies, these experiment have not to our knowledge been performed and as such, although IPC has been shown to alter levels of these cytokines, it remains unknown as to whether this is necessary for the protection garnered by IPC or as a consequence of IPC reducing hepatocyte death.

19. Conclusions

IPC/RIPC are an inexpensive and easily applied mechanism depending on intrinsic survival responses for protection during IR injury. Despite being first described in 1986 [4] and 1996 [5], the mechanisms by which they provide protection remain unclear and this has hampered their clinical translation. The release of adenosine from the ischaemic tissue during the preconditioning stimulus would appear to be the earliest and potentially the initial mechanism for signalling protection. Work from Peralta and colleagues [16] demonstrates that the optimal length of the preconditioning stimulus requires a delicate balance between being long enough to release sufficient quantities of adenosine but not too long that it simultaneously releases toxic metabolites. No studies have been done to date in humans to investigate the optimal time required for the preconditioning stimulus however studies measuring adenosine release in the organ undergoing the preconditioning stimulus may shed light on this. Following adenosine release and stimulation of the various adenosine receptors, there is evidence of decreased apoptosis and enhanced autophagy reducing release of DAMPS. Intracellular signalling via protein kinases and NF-κB leads to upregulation of pro survival pathways including HO-1. ENOS is upregulated along with l-arginine levels and the resulting NO produced has been shown to improve hepatic microcirculation and reduce the reperfusion injury. It is difficult to identify the predominant method of protection in these small animal studies as each study has only investigated one pathway and blockade/genetic knockdown of that pathway has abrogated the protective effect of IPC/RIPC. In humans, the picture is more complicated by the interplay of all of the pathways and the effect of chronic disease on these pathways. The next key step is to measure how long the IPC/RIPC stimulus requires to be applied in humans to release adequate adenosine/l-arginine as this may allow IPC/RIPC to be more successfully translated to clinical practice.

Acknowledgments

We gratefully acknowledge the Wellington Hospital, London/HCA for the fellowship for Francis Robertson.

Author Contributions

F.R. performed the literature search and wrote the manuscript. B.F. and B.D. contributed to writing the manuscript and reviewed the final draft.

Conflicts of Interest

The authors declare no conflict of interest

References

  1. Veteläinen, R.; van Vliet, A.; Gouma, D.J.; van Gulik, T.M. Steatosis as a risk factor in liver surgery. Ann. Surg. 2007, 245, 20–30. [Google Scholar] [CrossRef] [PubMed]
  2. Selzner, M.; Clavien, P.-A. Fatty liver in liver transplantation and surgery. Semin. Liver Dis. 2001, 21, 105–113. [Google Scholar] [CrossRef] [PubMed]
  3. Callaghan, C.J.; Charman, S.C.; Muiesan, P.; Powell, J.J.; Gimson, A.E.; van der Meulen, J.H.P. Outcomes of transplantation of livers from donation after circulatory death donors in the UK: A cohort study. BMJ Open 2013, 3, e003287. [Google Scholar] [CrossRef] [PubMed]
  4. Murry, C.E.; Jennings, R.B.; Reimer, K.A. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986, 74, 1124–1136. [Google Scholar] [CrossRef] [PubMed]
  5. Przyklenk, K.; Bauer, B.; Ovize, M.; Kloner, R.A.; Whittaker, P. Regional ischemic “preconditioning” protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 1993, 87, 893–899. [Google Scholar] [CrossRef] [PubMed]
  6. Clavien, P.A.; Yadav, S.; Sindram, D.; Bentley, R.C. Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans. Ann. Surg. 2000, 232, 155–162. [Google Scholar] [CrossRef] [PubMed]
  7. Clavien, P.-A.; Selzner, M.; Rüdiger, H.A.; Graf, R.; Kadry, Z.; Rousson, V.; Jochum, W. A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning. Ann. Surg. 2003, 238, 843–852. [Google Scholar] [CrossRef] [PubMed]
  8. Kanoria, S.; Robertson, F.P.; Mehta, N.N.; Fusai, G.; Sharma, D.; Davidson, B.R. Effect of Remote Ischaemic Preconditioning on Liver Injury in Patients Undergoing Major Hepatectomy for Colorectal Liver Metastasis: A Pilot Randomised Controlled Feasibility Trial. World J. Surg. 2016. [Google Scholar] [CrossRef] [PubMed]
  9. O’Neill, S.; Leuschner, S.; McNally, S.J.; Garden, O.J.; Wigmore, S.J.; Harrison, E.M. Meta-analysis of ischaemic preconditioning for liver resections. Br. J. Surg. 2013, 100, 1689–1700. [Google Scholar] [CrossRef] [PubMed]
  10. Robertson, F.P.; Magill, L.J.; Wright, G.P.; Fuller, B.; Davidson, B.R. A systematic review and meta-analysis of donor ischaemic preconditioning in liver transplantation. Transpl. Int. 2016. [Google Scholar] [CrossRef] [PubMed]
  11. McCafferty, K.; Forbes, S.; Thiemermann, C.; Yaqoob, M.M. The challenge of translating ischemic conditioning from animal models to humans: The role of comorbidities. Dis. Model. Mech. 2014, 7, 1321–1333. [Google Scholar] [CrossRef] [PubMed]
  12. Hausenloy, D.J.; Candilio, L.; Evans, R.; Ariti, C.; Jenkins, D.P.; Kolvekar, S.; Knight, R.; Kunst, G.; Laing, C.; Nicholas, J.; et al. Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery. N. Engl. J. Med. 2015, 373, 1408–1417. [Google Scholar] [CrossRef] [PubMed]
  13. Meybohm, P.; Bein, B.; Brosteanu, O.; Cremer, J.; Gruenewald, M.; Stoppe, C.; Coburn, M.; Schaelte, G.; Böning, A.; Niemann, B.; et al. A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery. N. Engl. J. Med. 2015, 373, 1397–1407. [Google Scholar] [CrossRef] [PubMed]
  14. Robertson, F.P.; Goswami, R.; Wright, G.P.; Imber, C.; Sharma, D.; Malago, M.; Fuller, B.J.; Davidson, B.R. Remote ischaemic preconditioning in orthotopic liver transplantation (RIPCOLT trial): A pilot randomized controlled feasibility study. HPB 2017. [Google Scholar] [CrossRef] [PubMed]
  15. Peralta, C.; Hotter, G.; Closa, D.; Gelpí, E.; Bulbena, O.; Rosello-Catafau, J. Protective effect of preconditioning on the injury associated to hepatic ischemia-reperfusion in the rat: Role of nitric oxide and adenosine. Hepatology 1997, 25, 934–937. [Google Scholar] [CrossRef] [PubMed]
  16. Peralta, C.; Closa, D.; Xaus, C.; Gelpí, E.; Roselló-catafau, J.; Hotter, G. Hepatic preconditioning in rats is defined by a balance of adenosine and xanthine. Hepatology 1998, 28, 768–773. [Google Scholar] [CrossRef] [PubMed]
  17. Nakayama, H.; Yamamoto, Y.; Kume, M.; Yamagami, K.; Yamamoto, H.; Kimoto, S.; Ishikawa, Y.; Ozaki, N.; Shimahara, Y.; Yamaoka, Y. Pharmacologic stimulation of adenosine A2 receptor supplants ischemic preconditioning in providing ischemic tolerance in rat livers. Surgery 1999, 126, 945–954. [Google Scholar] [CrossRef]
  18. Peralta, C.; Hotter, G.; Closa, D.; Prats, N.; Xaus, C.; Gelpí, E.; Roselló-Catafau, J. The protective role of adenosine in inducing nitric oxide synthesis in rat liver ischemia preconditioning is mediated by activation of adenosine A2 receptors. Hepatology 1999, 29, 126–132. [Google Scholar] [CrossRef] [PubMed]
  19. Ajamieh, H.H.; Candelario-Jalil, E.; Fernández, O.S.L.; Gerbes, A.L. Ischaemic and pharmacological preconditionings protect liver via adenosine and redox status following hepatic ischaemia/reperfusion in rats. Clin. Sci. 2008, 115, 69–77. [Google Scholar] [CrossRef] [PubMed]
  20. Schauer, R.; Gerbes, A.L.; Vonier, D.; op den Winkel, M.; Fraunberger, P.; Bilzer, M. Induction of cellular resistance against Kupffer cell–derived oxidant stress: A novel concept of hepatoprotection by ischemic preconditioning. Hepatology 2003, 37, 286–295. [Google Scholar] [CrossRef] [PubMed]
  21. Chouker, A.; Ohta, A.; Martignoni, A.; Lukashev, D.; Zacharia, L.C.; Jackson, E.K.; Schnermann, J.; Ward, J.M.; Kaufmann, I.; Klaunberg, B.; et al. In Vivo Hypoxic Preconditioning Protects From Warm Liver Ischemia-Reperfusion Injury Through the Adenosine A2B Receptor. Transplantation 2012, 94, 894–902. [Google Scholar] [CrossRef] [PubMed]
  22. Koti, R.S.; Tsui, J.; Lobos, E.; Yang, W.; Seifalian, A.M.; Davidson, B.R. Nitric oxide synthase distribution and expression with ischemic preconditioning of the rat liver. FASEB J. 2005, 19, 1155–1157. [Google Scholar] [CrossRef] [PubMed]
  23. Abu-Amara, M.; Yang, S.Y.; Quaglia, A.; Rowley, P.; Fuller, B.; Seifalian, A.; Davidson, B. Role of endothelial nitric oxide synthase in remote ischemic preconditioning of the mouse liver. Liver Transpl. 2011, 17, 610–619. [Google Scholar] [CrossRef] [PubMed]
  24. Carini, R.; De Cesaris, M.G.; Splendore, R.; Bagnati, M.; Albano, E. Ischemic preconditioning reduces Na+ accumulation and cell killing in isolated rat hepatocytes exposed to hypoxia. Hepatology 2000, 31, 166–172. [Google Scholar] [CrossRef] [PubMed]
  25. Carini, R.; De Cesaris, M.G.; Splendore, R.; Vay, D.; Domenicotti, C.; Nitti, M.P.; Paola, D.; Pronzato, M.A.; Albano, E. Signal pathway involved in the development of hypoxic preconditioning in rat hepatocytes. Hepatology 2001, 33, 131–139. [Google Scholar] [CrossRef] [PubMed]
  26. Ricciardi, R.; Meyers, W.C.; Schaffer, B.K.; Kim, R.D.; Shah, S.A.; Wheeler, S.M.; Donohue, S.E.; Sheth, K.R.; Callery, M.P.; Chari, R.S. Protein kinase C inhibition abrogates hepatic ischemic preconditioning responses. J. Surg. Res. 2001, 97, 144–149. [Google Scholar] [CrossRef] [PubMed]
  27. Ricciardi, R.; Shah, S.A.; Wheeler, S.M.; Quarfordt, S.H.; Callery, M.P.; Meyers, W.C.; Chari, R.S. Regulation of NFκB in hepatic ischemic preconditioning. J. Am. Coll. Surg. 2002, 195, 319–326. [Google Scholar] [CrossRef]
  28. Lai, I.-R.; Chang, K.-J.; Chen, C.-F.; Tsai, H.-W. Transient limb ischemia induces remote preconditioning in liver among rats: The protective role of heme oxygenase-1. Transplantation 2006, 81, 1311–1317. [Google Scholar] [CrossRef] [PubMed]
  29. Datta, G.; Luong, T.V.; Fuller, B.J.; Davidson, B.R. Endothelial nitric oxide synthase and heme oxygenase-1 act independently in liver ischemic preconditioning. J. Surg. Res. 2014, 186, 417–428. [Google Scholar] [CrossRef] [PubMed]
  30. Wang, Y.; Shen, J.; Xiong, X.; Xu, Y.; Zhang, H.; Huang, C.; Tian, Y.; Jiao, C.; Wang, X.; Li, X. Remote ischemic preconditioning protects against liver ischemia-reperfusion injury via heme oxygenase-1-induced autophagy. PLoS ONE 2014, 9, e98834. [Google Scholar] [CrossRef] [PubMed]
  31. Kinsey, G.R.; Huang, L.; Vergis, A.L.; Li, L.; Okusa, M.D. Regulatory T cells contribute to the protective effect of ischemic preconditioning in the kidney. Kidney Int. 2010, 77, 771–780. [Google Scholar] [CrossRef] [PubMed]
  32. Cho, W.Y.; Choi, H.M.; Lee, S.Y.; Kim, M.G.; Kim, H.-K.; Jo, S.-K. The role of Tregs and CD11c(+) macrophages/dendritic cells in ischemic preconditioning of the kidney. Kidney Int. 2010, 78, 981–992. [Google Scholar] [CrossRef] [PubMed]
  33. Devey, L.R.; Richards, J.A.; O’Connor, R.A.; Borthwick, G.; Clay, S.; Howie, A.F.; Wigmore, S.J.; Anderton, S.M.; Howie, S.E.M. Ischemic preconditioning in the liver is independent of regulatory T cell activity. PLoS ONE 2012, 7, e49647. [Google Scholar] [CrossRef] [PubMed]
  34. Peralta, C.; Prats, N.; Xaus, C.; Gelpí, E.; Roselló-Catafau, J. Protective effect of liver ischemic preconditioning on liver and lung injury induced by hepatic ischemia-reperfusion in the rat. Hepatology 1999, 30, 1481–1489. [Google Scholar] [CrossRef] [PubMed]
  35. Peralta, C.; Fernández, L.; Panés, J.; Prats, N.; Sans, M.; Piqué, J.M.; Gelpí, E.; Roselló-Catafau, J.; Roselló-Catafau, J. Preconditioning protects against systemic disorders associated with hepatic ischemia-reperfusion through blockade of tumor necrosis factor–induced P-selectin up-regulation in the rat. Hepatology 2001, 33, 100–113. [Google Scholar] [CrossRef] [PubMed]
  36. Glanemann, M.; Vollmar, B.; Nussler, A.K.; Schaefer, T.; Neuhaus, P.; Menger, M.D. Ischemic preconditioning protects from hepatic ischemia/reperfusion-injury by preservation of microcirculation and mitochondrial redox-state. J. Hepatol. 2003, 38, 59–66. [Google Scholar] [CrossRef]
  37. Arai, M.; Ikeda, H.; Tomiya, T.; Yanase, M.; Inoue, Y.; Nagashima, K.; Nishikawa, T.; Watanabe, N.; Omata, M.; Fujiwara, K.; et al. Ischemic preconditioning protects hepatocytes via reactive oxygen species derived from Kupffer cells in rats. Gastroenterology 2004, 127, 1488–1496. [Google Scholar] [CrossRef]
  38. Funaki, H.; Shimizu, K.; Harada, S.-I.; Tsuyama, H.; Fushida, S.; Tani, T.; Miwa, K. Essential role for nuclear factor kappaB in ischemic preconditioning for ischemia-reperfusion injury of the mouse liver. Transplantation 2002, 74, 551–556. [Google Scholar] [CrossRef] [PubMed]
  39. Zhang, S.-J.; Zhu, C.-J.; Zhao, Y.-F.; Li, J.; Guo, W.-Z. Different ischemic preconditioning for rat liver graft: Protection and mechanism. Hepatobiliary Pancreat. Dis. Int. 2003, 2, 509–512. [Google Scholar] [PubMed]
  40. Yao, A.; Li, X.; Pu, L.; Zhong, J.; Liu, X.; Yu, Y.; Zhang, F.; Kong, L.; Sun, B.; Wang, X.; et al. Impaired hepatic regeneration by ischemic preconditioning in a rat model of small-for-size liver transplantation. Transpl. Immunol. 2007, 18, 37–43. [Google Scholar] [CrossRef] [PubMed]
  41. Koneru, B.; Shareef, A.; Dikdan, G.; Desai, K.; Klein, K.M.; Peng, B.; Wachsberg, R.H.; de la Torre, A.N.; Debroy, M.; Fisher, A.; et al. The ischemic preconditioning paradox in deceased donor liver transplantation—Evidence from a prospective randomized single blind clinical trial. Am. J. Transplant. 2007, 7, 2788–2796. [Google Scholar] [CrossRef] [PubMed]
  42. Guimarães Filho, M.A.C.; Cortez, E.; Garcia-Souza, É.P.; Soares, V.M.; Moura, A.S.; Carvalho, L.; Maya, M.C.A.; Pitombo, M.B. Effect of remote ischemic preconditioning in the expression of IL-6 and IL-10 in a rat model of liver ischemia-reperfusion injury. Acta Cir. Bras. 2015, 30, 452–460. [Google Scholar] [CrossRef] [PubMed]
  43. Li, D.-Y.; Shi, X.-J.; Li, W.; Sun, X.-D.; Wang, G.-Y. Ischemic preconditioning and remote ischemic preconditioning provide combined protective effect against ischemia/reperfusion injury. Life Sci. 2016, 150, 76–80. [Google Scholar] [CrossRef] [PubMed]
  44. Hausenloy, D.; Yellon, D.M. New directions for protecting the heart against ischaemia–reperfusion injury: Targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc. Res. 2004, 61, 448–460. [Google Scholar] [CrossRef] [PubMed]
  45. Marber, M.S.; Latchman, D.S.; Walker, J.M.; Yellon, D.M. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation 1993, 88, 1264–1272. [Google Scholar] [CrossRef] [PubMed]
  46. Kuzuya, T.; Hoshida, S.; Yamashita, N.; Fuji, H.; Oe, H.; Hori, M.; Kamada, T.; Tada, M. Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ. Res. 1993, 72, 1293–1299. [Google Scholar] [CrossRef] [PubMed]
  47. Hausenloy, D.J.; Yellon, D.M. The second window of preconditioning (SWOP) where are we now? Cardiovasc. Drugs Ther. 2010, 24, 235–254. [Google Scholar] [CrossRef] [PubMed]
  48. Lim, S.Y.; Hausenloy, D.J. Remote ischemic conditioning: From bench to bedside. Front. Physiol. 2012, 3, 27. [Google Scholar] [CrossRef] [PubMed]
  49. Fredholm, B.B. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ. 2007, 14, 1315–1323. [Google Scholar] [CrossRef] [PubMed]
  50. Fredholm, B.B.; IJzerman, A.P.; Jacobson, K.A.; Klotz, K.N.; Linden, J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 2001, 53, 527–552. [Google Scholar] [PubMed]
  51. Laubach, V.E.; French, B.A.; Okusa, M.D. Targeting of adenosine receptors in ischemia-reperfusion injury. Expert Opin. Ther. Targets 2011, 15, 103–118. [Google Scholar] [CrossRef] [PubMed]
  52. Todo, S.; Zhu, Y.; Zhang, S.; Jin, M.B.; Ishizaki, N.; Tanaka, H.; Subbotin, V.; Starzl, T.E. Attenuation of ischemic liver injury by augmentation of endogenous adenosine. Transplantation 1997, 63, 217–223. [Google Scholar] [CrossRef] [PubMed]
  53. Li, J.M.; Fenton, R.A.; Cutler, B.S.; Dobson, J.G. Adenosine enhances nitric oxide production by vascular endothelial cells. Am. J. Physiol. 1995, 269, C519–C523. [Google Scholar] [PubMed]
  54. Koneru, B.; Fisher, A.; He, Y.; Klein, K.M.; Skurnick, J.; Wilson, D.J.; de la Torre, D.N.; Merchant, A.; Arora, R.; Samanta, A.K.; et al. Ischemic preconditioning in deceased donor liver transplantation: A prospective randomized clinical trial of safety and efficacy. Liver Transplant. 2005, 11, 196–202. [Google Scholar] [CrossRef] [PubMed]
  55. Jassem, W.; Fuggle, S.V.; Cerundolo, L.; Heaton, N.D.; Rela, M. Ischemic preconditioning of cadaver donor livers protects allografts following transplantation. Transplantation 2006, 81, 169–174. [Google Scholar] [CrossRef] [PubMed]
  56. Kim, J.; Kim, M.; Song, J.H.; Lee, H.T. Endogenous A1 adenosine receptors protect against hepatic ischemia reperfusion injury in mice. Liver Transplant. 2008, 14, 845–854. [Google Scholar] [CrossRef] [PubMed]
  57. Magata, S.; Taniguchi, M.; Suzuki, T.; Shimamura, T.; Fukai, M.; Furukawa, H.; Fujita, M.; Todo, S. The Effect of Antagonism of Adenosine A1 Receptor Against Ischemia and Reperfusion Injury of the Liver. J. Surg. Res. 2007, 139, 7–14. [Google Scholar] [CrossRef] [PubMed]
  58. Ben-Ari, Z.; Pappo, O.; Sulkes, J.; Cheporko, Y.; Vidne, B.A.; Hochhauser, E. Effect of adenosine A2A receptor agonist (CGS) on ischemia/reperfusion injury in isolated rat liver. Apoptosis 2005, 10, 955–962. [Google Scholar] [CrossRef] [PubMed]
  59. Thurman, R.G.; Lemasters, J.J.; Arai, M.; Thurman, R.G.; Lemasters, J.J. Contribution of adenosine A(2) receptors and cyclic adenosine monophosphate to protective ischemic preconditioning of sinusoidal endothelial cells against Storage/Reperfusion injury in rat livers. Hepatology 2000, 32, 297–302. [Google Scholar] [CrossRef]
  60. Day, Y.-J.; Marshall, M.A.; Huang, L.; McDuffie, M.J.; Okusa, M.D.; Linden, J. Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction. AJP Gastrointest. Liver Physiol. 2004, 286, G285–G293. [Google Scholar] [CrossRef] [PubMed]
  61. Lappas, C.M.; Day, Y.-J.; Marshall, M.A.; Engelhard, V.H.; Linden, J. Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation. J. Exp. Med. 2006, 203, 2639–2648. [Google Scholar] [CrossRef] [PubMed]
  62. Zimmerman, M.A.; Grenz, A.; Tak, E.; Kaplan, M.; Ridyard, D.; Brodsky, K.S.; Mandell, M.S.; Kam, I.; Eltzschig, H.K. Signaling through hepatocellular A2B adenosine receptors dampens ischemia and reperfusion injury of the liver. Proc. Natl. Acad. Sci. USA 2013, 110, 12012–12017. [Google Scholar] [CrossRef] [PubMed]
  63. Abu-Amara, M.; Yang, S.Y.; Seifalian, A.; Davidson, B.; Fuller, B. The nitric oxide pathway—Evidence and mechanisms for protection against liver ischaemia reperfusion injury. Liver Int. 2012, 32, 531–543. [Google Scholar] [CrossRef] [PubMed]
  64. Abu-Amara, M.; Yang, S.Y.; Quaglia, A.; Rowley, P.; Tapuria, N.; Seifalian, A.M.; Fuller, B.J.; Davidson, B.R. Effect of remote ischemic preconditioning on liver ischemia/reperfusion injury using a new mouse model. Liver Transpl. 2011, 17, 70–82. [Google Scholar] [CrossRef] [PubMed]
  65. Peralta, C.; Rull, R.; Rimola, A.; Deulofeu, R.; Roselló-Catafau, J.; Gelpí, E.; Rodés, J. Endogenous nitric oxide and exogenous nitric oxide supplementation in hepatic ischemia-reperfusion injury in the rat. Transplantation 2001, 71, 529–536. [Google Scholar] [CrossRef] [PubMed]
  66. Hines, I.N.; Kawachi, S.; Harada, H.; Pavlick, K.P.; Hoffman, J.M.; Bharwani, S.; Wolf, R.E.; Grisham, M.B. Role of nitric oxide in liver ischemia and reperfusion injury. Mol. Cell. Biochem. 2002, 234, 229–237. [Google Scholar] [CrossRef] [PubMed]
  67. Hines, I.N.; Harada, H.; Flores, S.; Gao, B.; McCord, J.M.; Grisham, M.B. Endothelial nitric oxide synthase protects the post-ischemic liver: potential interactions with superoxide. Biomed. Pharmacother. 2005, 59, 183–189. [Google Scholar] [CrossRef] [PubMed]
  68. Kawachi, S.; Hines, I.N.; Laroux, F.S.; Hoffman, J.; Bharwani, S.; Gray, L.; Leffer, D.; Grisham, M.B. Nitric Oxide Synthase and Postischemic Liver Injury. Biochem. Biophys. Res. Commun. 2000, 276, 851–854. [Google Scholar] [CrossRef] [PubMed]
  69. Lee, V.G.; Johnson, M.L.; Baust, J.; Laubach, V.E.; Watkins, S.C.; Billiar, T.R. The roles of iNOS in liver ischemia-reperfusion injury. Shock 2001, 16, 355–360. [Google Scholar] [CrossRef] [PubMed]
  70. Theruvath, T.P.; Zhong, Z.; Currin, R.T.; Ramshesh, V.K.; Lemasters, J.J. Endothelial nitric oxide synthase protects transplanted mouse livers against storage/reperfusion injury: Role of vasodilatory and innate immunity pathways. Transplant. Proc. 2006, 38, 3351–3357. [Google Scholar] [CrossRef] [PubMed]
  71. Duranski, M.R.; Elrod, J.W.; Calvert, J.W.; Bryan, N.S.; Feelisch, M.; Lefer, D.J. Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury. AJP Hear. Circ. Physiol. 2006, 291, H2980–H2986. [Google Scholar] [CrossRef] [PubMed]
  72. Serracino-Inglott, F.; Virlos, I.T.; Habib, N.A.; Williamson, R.C.N.; Mathie, R.T. Adenosine preconditioning attenuates hepatic reperfusion injury in the rat by preventing the down-regulation of endothelial nitric oxide synthase. BMC Gastroenterol. 2002, 2, 22. [Google Scholar] [CrossRef]
  73. Wang, L.-M.; Tian, X.-F.; Song, Q.-Y.; Gao, Z.-M.; Luo, F.-W.; Yang, C.-M. Expression and role of inducible nitric oxide synthase in ischemia-reperfusion liver in rats. Hepatobiliary Pancreat. Dis. Int. 2003, 2, 252–258. [Google Scholar] [PubMed]
  74. Zwacka, R.M.; Zhang, Y.; Halldorson, J.; Schlossberg, H.; Dudus, L.; Engelhardt, J.F. CD4(+) T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J. Clin. Investig. 1997, 100, 279–289. [Google Scholar] [CrossRef] [PubMed]
  75. Bradham, C.A.; Stachlewitz, R.F.; Gao, W.; Qian, T.; Jayadev, S.; Jenkins, G.; Hannun, Y.; Lemasters, J.J.; Thurman, R.G.; Brenner, D.A. Reperfusion after liver transplantation in rats differentially activates the mitogen-activated protein kinases. Hepatology 1997, 25, 1128–1135. [Google Scholar] [CrossRef] [PubMed]
  76. Nakano, A.; Cohen, M.V.; Downey, J.M. Ischemic preconditioning: from basic mechanisms to clinical applications. Pharmacol. Ther. 2000, 86, 263–275. [Google Scholar] [CrossRef]
  77. Carini, R.; Grazia De Cesaris, M.; Splendore, R.; Domenicotti, C.; Nitti, M.P.; Pronzato, M.A.; Albano, E. Signal pathway responsible for hepatocyte preconditioning by nitric oxide. Free Radic. Biol. Med. 2003, 34, 1047–1055. [Google Scholar] [CrossRef]
  78. Yamaguchi, K.; Kawahara, T.; Kumakura, S.; Hua, J.; Kugimiya, T.; Nagaoka, I.; Inada, E. Effect of olprinone, a phosphodiesterase iii inhibitor, on hepatic ischemia-reperfusion injury in rats. Shock 2010, 33, 436–441. [Google Scholar] [CrossRef] [PubMed]
  79. Meng, G.-X.; Yuan, Q.; Wei, L.-P.; Meng, H.; Wang, Y.-J. Protein kinase C-β inhibitor treatment attenuates hepatic ischemia and reperfusion injury in diabetic rats. Exp. Ther. Med. 2016, 11, 565–570. [Google Scholar] [CrossRef] [PubMed]
  80. Ricciardi, R.; Schaffer, B.K.; Kim, R.D.; Shah, S.A.; Donohue, S.E.; Wheeler, S.M.; Quarfordt, S.H.; Callery, M.P.; Meyers, W.C.; Chari, R.S.; et al. Protective effects of ischemic preconditioning on the cold-preserved liver are tyrosine kinase dependent. Transplantation 2001, 72, 406–412. [Google Scholar] [CrossRef] [PubMed]
  81. Hur, G.M.; Ryu, Y.S.; Yun, H.Y.; Jeon, B.H.; Kim, Y.M.; Seok, J.H.; Lee, J.H. Hepatic Ischemia/Reperfusion in Rats Induces iNOS Gene Transcription by Activation of NF-κB. Biochem. Biophys. Res. Commun. 1999, 261, 917–922. [Google Scholar] [CrossRef] [PubMed]
  82. Choi, A.M.K.; Alam, J. Heme Oxygenase-1: Function, Regulation, and Implication of a Novel Stress-inducible Protein in Oxidant-induced Lung Injury. Am. J. Respir. Cell Mol. Biol. 1996, 15, 9–19. [Google Scholar] [CrossRef] [PubMed]
  83. Origassa, C.S.T.; Câmara, N.O.S. Cytoprotective role of heme oxygenase-1 and heme degradation derived end products in liver injury. World J. Hepatol. 2013, 5, 541–549. [Google Scholar] [PubMed]
  84. Devey, L.; Ferenbach, D.; Mohr, E.; Sangster, K.; Bellamy, C.O.; Hughes, J.; Wigmore, S.J. Tissue-resident macrophages protect the liver from ischemia reperfusion injury via a heme oxygenase-1-dependent mechanism. Mol. Ther. 2009, 17, 65–72. [Google Scholar] [CrossRef] [PubMed]
  85. Ha, Y.M.; Ham, S.A.; Kim, Y.M.; Lee, Y.S.; Kim, H.J.; Seo, H.G.; Lee, J.H.; Park, M.K.; Chang, K.C. β1-Adrenergic receptor-mediated HO-1 induction, via PI3K and p38 MAPK, by isoproterenol in RAW 264.7 cells leads to inhibition of HMGB1 release in LPS-activated RAW 264.7 cells and increases in survival rate of CLP-induced septic mice. Biochem. Pharmacol. 2011, 82, 769–777. [Google Scholar] [CrossRef] [PubMed]
  86. Wang, J.; Hu, X.; Fu, W.; Xie, J.; Zhou, X.; Jiang, H. Isoproterenol-mediated heme oxygenase-1 induction inhibits high mobility group box 1 protein release and protects against rat myocardial ischemia/reperfusion injury in vivo. Mol. Med. Rep. 2014. [Google Scholar] [CrossRef] [PubMed]
  87. Sun, L.; Shi, T.; Qiao, H.; Jiang, X.; Jiang, H.; Krissansen, G.W.; Sun, X. Hepatic Overexpression of Heme Oxygenase-1 Improves Liver Allograft Survival by Expanding T Regulatory Cells. J. Surg. Res. 2011, 166, e187–e194. [Google Scholar] [CrossRef] [PubMed]
  88. Burne, M.J.; Daniels, F.; El Ghandour, A.; Mauiyyedi, S.; Colvin, R.B.; O’Donnell, M.P.; Rabb, H. Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure. J. Clin. Investig. 2001, 108, 1283–1290. [Google Scholar] [CrossRef] [PubMed]
  89. Yang, Z.; Sharma, A.K.; Linden, J.; Kron, I.L.; Laubach, V.E. CD4+ T lymphocytes mediate acute pulmonary ischemia-reperfusion injury. J. Thorac. Cardiovasc. Surg. 2009, 137, 695–702. [Google Scholar] [CrossRef] [PubMed]
  90. Dienz, O.; Rincon, M. The effects of IL-6 on CD4 T cell responses. Clin. Immunol. 2009, 130, 27–33. [Google Scholar] [CrossRef] [PubMed]
  91. Nish, S.A.; Schenten, D.; Wunderlich, F.T.; Pope, S.D.; Gao, Y.; Hoshi, N.; Yu, S.; Yan, X.; Lee, H.K.; Pasman, L.; et al. T cell-intrinsic role of IL-6 signaling in primary and memory responses. Elife 2014, 3, e01949. [Google Scholar] [CrossRef] [PubMed]
  92. Caldwell-Kenkel, J.C.; Currin, R.T.; Tanaka, Y.; Thurman, R.G.; Lemasters, J.J. Kupffer cell activation and endothelial cell damage after storage of rat livers: effects of reperfusion. Hepatology 1991, 13, 83–95. [Google Scholar] [PubMed]
  93. Shiratori, Y.; Kiriyama, H.; Fukushi, Y.; Nagura, T.; Takada, H.; Hai, K.; Kamii, K. Modulation of ischemia-reperfusion-induced hepatic injury by Kupffer cells. Dig. Dis. Sci. 1994, 39, 1265–1272. [Google Scholar] [CrossRef] [PubMed]
  94. Bailey, S.M.; Reinke, L.A. Antioxidants and gadolinium chloride attenuate hepatic parenchymal and endothelial cell injury induced by low flow ischemia and reperfusion in perfused rat livers. Free Radic. Res. 2000, 32, 497–506. [Google Scholar] [CrossRef] [PubMed]
  95. Liang, J.; Yamaguchi, Y.; Matsumura, F.; Goto, M.; Akizuki, E.; Matsuda, T.; Okabe, K.; Ohshiro, H.; Ishihara, K.; Yamada, S.; et al. Calcium-Channel Blocker Attenuates Kupffer Cell Production of Cytokine-Induced Neutrophil Chemoattractant Following Ischemia–Reperfusion in Rat Liver. Dig. Dis. Sci. 2000, 45, 201–209. [Google Scholar] [CrossRef] [PubMed]
  96. Kobayashi, T.; Hirano, K.; Yamamoto, T.; Hasegawa, G.; Hatakeyama, K.; Suematsu, M.; Naito, M. The protective role of Kupffer cells in the ischemia-reperfused rat liver. Arch. Histol. Cytol. 2002, 65, 251–261. [Google Scholar] [CrossRef] [PubMed]
  97. Muller, W.A. New Mechanisms and Pathways for Monocyte Recruitment. J. Exp. Med. 2001, 194, F47–F52. [Google Scholar] [CrossRef] [PubMed]
  98. Krenkel, O.; Mossanen, J.C.; Tacke, F. Immune mechanisms in acetaminophen-induced acute liver failure. Hepatobiliary Surg. Nutr. 2014, 3, 331–343. [Google Scholar] [CrossRef] [PubMed]
  99. Bamboat, Z.Z.M.; Ocuin, L.M.; Balachandran, V.P.; Obaid, H.; Plitas, G.; DeMatteo, R.R.P.; Lotze, M.; Clavien, P.; Harvey, P.; Strasberg, S.; et al. Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion. J. Clin. Investig. 2010, 120, 559–569. [Google Scholar] [CrossRef] [PubMed]
  100. Colletti, L.M.; Remick, D.G.; Burtch, G.D.; Kunkel, S.L.; Strieter, R.M.; Campbell, D.A., Jr. Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J. Clin. Investig. 1990, 85, 1936–1943. [Google Scholar] [CrossRef] [PubMed]
  101. Tsung, A.; Sahai, R.; Tanaka, H.; Nakao, A.; Fink, M.P.; Lotze, M.T.; Yang, H.; Li, J.; Tracey, K.J.; Geller, D.A.; et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J. Exp. Med. 2005, 201, 1135–1143. [Google Scholar] [CrossRef] [PubMed]
  102. Caldwell, C.C.; Okaya, T.; Martignoni, A.; Husted, T.; Schuster, R.; Lentsch, A.B. Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 289, G969–G976. [Google Scholar] [CrossRef] [PubMed]
  103. Camargo, C.A.; Madden, J.F.; Gao, W.; Selvan, R.S.; Clavien, P. Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology 1997, 26, 1513–1520. [Google Scholar] [CrossRef] [PubMed]
  104. Cressman, D.E.; Greenbaum, L.E.; DeAngelis, R.A.; Ciliberto, G.; Furth, E.E.; Poli, V.; Taub, R. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 1996, 274, 1379–1383. [Google Scholar] [CrossRef] [PubMed]
  105. Yamada, Y.; Kirillova, I.; Peschon, J.J.; Fausto, N. Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. Proc. Natl. Acad. Sci. USA 1997, 94, 1441–1446. [Google Scholar] [CrossRef] [PubMed]
  106. Dal-Secco, D.; Wang, J.; Zeng, Z.; Kolaczkowska, E.; Wong, C.H.Y.; Petri, B.; Ransohoff, R.M.; Charo, I.F.; Jenne, C.N.; Kubes, P. A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury. J. Exp. Med. 2015, 212, 447–456. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Previously identified mechanism of IPC. Mechanisms identified in the setting of liver IR injury are in black whilst those not implicated/researched are in white.
Figure 1. Previously identified mechanism of IPC. Mechanisms identified in the setting of liver IR injury are in black whilst those not implicated/researched are in white.
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Figure 2. Protective mechanisms of adenosine release following Ischaemic Preconditioning (IPC).
Figure 2. Protective mechanisms of adenosine release following Ischaemic Preconditioning (IPC).
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Table
Table 1. Studies investigating the mechanism of Ischaemic Preconditioning (IPC)/ Ischaemia Reperfusion Preconditioning (RIPC) in the setting of hepatic IR injury.
Table 1. Studies investigating the mechanism of Ischaemic Preconditioning (IPC)/ Ischaemia Reperfusion Preconditioning (RIPC) in the setting of hepatic IR injury.
Study GroupYearSpeciesIPC Time (min)Ischaemic Time (min)Reperfusion Time (min)Hepatic IschaemiaPharmacological ManipulationsParameters AssessedOutcome of IPCProposed Mechanism
Adenosine
Peralta [15]1997rat109090partialAdenosine and NOLFTs↓ LFTsAdenosine/NO
Hepatic blood flow↑ blood flow
Peralta [16]1998ratVariable9090partialAdenosine and NOLFTs
Adenosine
Inosine
Xanthine		↓ LFTs
↑ Adenosine		Adenosine
Nakayama [17]1999rat1045Up to 7 daysunclearA1 and A2 receptorsLFTs↑ 7 day survivalAdenosine via A2 receptor
7 day survival↓ LFTs
Adenosine↑ Adenosine
A1 receptor
Peralta [18]1999rat109090partialA1, A2 receptors and NOLFTs↓ LFTsNO production through action of adenosine on A2R
Hepatic blood flow↑ blood flow
NO production↑ NO production
Ajamieh [19] 2008rat109024 hpartialA1 receptorLFTs↓ LFTsA1 receptor
TNFα levels↓ TNFα levels
MPO activity↓ oxidative stress
A2A receptor
Perlata [18]1999rat109090partialA1, A2 receptors and NOLFTs↓ LFTsNO production through action of adenosine on A2R
Hepatic blood flow↑ blood flow
NO production↑ NO production
Schaeur [20]2003rat1090120partialA2A receptor and p38 MAPKLFTs↓ LFTsp38 MAPK stimulation not A2A receptor
Hepatic perfusion↓ KC induce liver damage
A2B receptor
Chouker [21]2012mouse1045240partialA2A, A2B receptors LFTs↓ LFTsA2B receptor but not A2A receptor
TNFα levels↓ TNFα levels
IL-6 levels↓ IL-6 levels
A3 receptor
None
eNOS
Koti [22]2005rat545120partiall-arginine and NOLFTs↓ LFTsNO formed from eNOS is hepatoprotective
NO↑ NO levels
eNOS↑ eNOS
iNOSno change in iNOS
Abu-Amara [23]2011mouse440120partialeNOS genetic knockoutLFTs
Hepatic blood flow
Pathological injurye
NOS expression		↓ LFTs
↓ injury
eNOS expression not upregulated in wild type mice.		RIPC provided no protection in eNOS−/− mice
RIPC did not upregulate eNOS expression in wild type mice
iNOS
Koti [22]2005rat545120partiall-arginine and NOLFTs↓ LFTsNO formed from eNOS is hepatoprotective
NO↑ NO levels
eNOS↑ eNOS
iNOSno change in iNOS
PKC
Carini [24]2000rat10900hepatocytesPKCIntracellular pH↑ cell survivalPKC necessary to allow IPC
Intracellular Na↓ pH
Cell viability↓ Na accumulation
Carini [25]2001rat109090hepatocytesA2A receptor and PKCCell viability↑ cell survivalPKC activation following A2A receptor stimulation
PK levels↑ p38 MAPK phosphorylation
Ricciardi [26]2001pig15120240totalPKCGraft function↑ Graft functionPKC translocation to nucleus is necessary for IPC
Hepatic perfusion↑ Hepatic perfusion
Graft injury↓ Graft injury
NF-κB
Ricciardi [27]2002pig15120240totalPKCNF-κB↑NF-κBIPC increases translocation of NF-κB
HO-1
Lai [28]2006rat1045240partialHO-1LFTs↓ LFTsRIPC increases HO-1 expression and activity
HO-1 expression↑ HO-1 expression
HO activity↑ HO activity
Datta [29]2014mouse545120partialeNOS genetic knockoutLFTs
Hepatic perfusion
HO-1 expression		↓ LFTs
↑ Hepatic perfusion		eNOS−/− mice had reduced effect from IPC. HO-1 mRNA no significantly increased by IPC
Wang [30]2014mouse44524 hpartialHO-1LFTs↓ LFTsRIPC lead to increased autophagy in a HO-1 dependant manner
HO-1 expression↑ HO-1 expression
Autophagy↑ Autophagy
Tregs
Kinsey [31]2010mouse24 (bilateral)28 (7 days post IPC)unclearRenal (1 kidney)Treg depletion and adoptive transferSerum creatinine
Renal Treg number and IL-10 production		↓ Creatinine
↑ Treg accumulation
↑ Treg IL-10 production		Treg accumulation took 7 days. Treg depletion ablated effect of IPC
Cho [32]2010mouse24 (bilateral)28 (7 days post IPC)24 hRenal (1 kidney)Treg depletion and adoptive transferSerum creatinine↓ CreatinineTreg depletion ablated effect of IPC.
Stimulated lymphocytes from mice undergoing IPC were less pro-inflammatory.
Treg number↑ Treg accumulation
Splenocytes cytokine and proliferation↓ Splenocyte proliferation and cytokine production
Devey [33]2012mouse155024 hpartialTreg depletion and adoptive transferLFTs
Treg numbers
Circulating cytokines		↓ LFTs
Treg recruitment		IPC mechanism not related to Tregs
Macrophages
Peralta [34]1999rat109090partialTNFα treatment and macrophage depletion with Gadolinium Chloride.LFTs↓ LFTsTNFα production by macrophages drives hepatic IR injury
Hepatic oedema↓ TNFα release
TNFα release↓ hepatic oedema
Peralta [35]2001rat199090partialAntibody inhibition of I-CAM and macrophage depletion with Gadolinium ChlorideLFTs
Neutrophil accumulation and activity in distant organs		↓ neutrophil accumulation and activity in distant end organsIPC reduce neutrophil infiltration into distant organs but not the liver itself. Likely secondary to macrophage TNFα production
Glanemann [36]2003rat54590globalNilLFTs↓ LFTsIPC reduction macrophage activation in early staged of IR injury
Kupffer cell phagocytosis↓ Kupffer cell activation
Hepatic perfusion and oxygenation↑ hepatic perfusion and oxygenation
Tejima [37]2004rat104060partialMacrophage depletion with Gadolinium Chloride and treatment with anti-oxidantsLFTs↓ LFTsMacrophages were essential for the preconditioning stimulus to be effective
Sinusoidal epithelial cell injuryno change in sinusoidal epithelial cell injury
Cytokines
Funaki [38]2002mouse1570240globalNF-κB an tyrosine kinase inhibitionHepatic TNFα↓ TNFαIPC reduced hepatic TNFα levels
Zhu [39]2003rat10240 (cold)24 hglobalnilLFTs↓ LFTsIPC lead to reduced apoptosis and TNFα release
Serum TNFα↓ TNFα
Apoptosis↓ Apoptosis
Yao [40]2007rat10557 daysglobalnilSurvivalNo change in survivalIPC increased IR injury in small for size grafts
LFTs↑ LFTs
Hepatic IL-6No change in TNFα
Hepatic TNFα↓ IL-6
Koneru [41]2007human10329-505n/aglobalnilSurvival
LFTs
Post-op complications
Serum TNFα
Serum IL-6
Serum IL-10		No change in survival
↑ LFTs in the first 2 days
↓ episodes of acute rejection
↑ IL-10 levels post reperfusion
No change in TNFα or IL-6 levels
Ajamieh [19]2008rat109024 hpartialA1 receptorLFTs↓ LFTsA1 receptor
TNFα levels↓ TNFα levels
MPO activity↓ oxidative stress
Guimaraes [42]2015rat445180partialnilLFTs
Serum IL-6
Serum IL-10		↓ LFTs
↑ IL-6 at 1 h
↓ IL-6 at 3 h		IL-6 levels were raised 1 h post IPC but were significantly less at 3 h
Li [43]2016mouse10120 (cold)3 daysglobalnilSurvivalNo change in survivalIPC reduced liver injury but did not improve survival
LFTs↓ LFTs
Serum TNFα↓ TNFα
Innate immune response↓ Apoptosis
Abbreviations used: eNOS (endothelial Nitric Oxide Synthase), HO-1 (Heam-oxygenase-1)iNOS (inducible Nitric Oxide Syntase), KC (Kupffer Cells), LFT’s (Liver Function Tests), MAPK (Mitogen-activated Protein Kinases), MPO (Myeloperoxidase), NF-κB (Nuclear Factor kappa-light-chain-enhancer-of B cells), NO (Nitric Oxide), PK (Protein Kinase) TNFα (Tumour Necrosis Factor alpha), Tregs (regulatory T cells).

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Robertson, F.P.; Fuller, B.J.; Davidson, B.R. An Evaluation of Ischaemic Preconditioning as a Method of Reducing Ischaemia Reperfusion Injury in Liver Surgery and Transplantation. J. Clin. Med. 2017, 6, 69. https://doi.org/10.3390/jcm6070069

AMA Style

Robertson FP, Fuller BJ, Davidson BR. An Evaluation of Ischaemic Preconditioning as a Method of Reducing Ischaemia Reperfusion Injury in Liver Surgery and Transplantation. Journal of Clinical Medicine. 2017; 6(7):69. https://doi.org/10.3390/jcm6070069

Chicago/Turabian Style

Robertson, Francis P., Barry J. Fuller, and Brian R. Davidson. 2017. "An Evaluation of Ischaemic Preconditioning as a Method of Reducing Ischaemia Reperfusion Injury in Liver Surgery and Transplantation" Journal of Clinical Medicine 6, no. 7: 69. https://doi.org/10.3390/jcm6070069

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