Hepatic ischemia/reperfusion injury (HIRI) is a pathophysiological condition that occurs when the liver's blood supply is interrupted, resulting in organ hypoxia. It commonly happens when blood supply to the liver is reduced during liver resection due to prolonged obstruction of blood flow, shock, trauma, or heart failure. Prolonged hepatic ischemia followed by reperfusion, which occurs following a liver transplant, causes serious harm and contributes to increased morbidity and death. Several HIRI treatments, including pharmacological preconditioning, ischemic preconditioning, and remote ischemic preconditioning, have been proposed based on the further study on hepatic ischemia-reperfusion injury. Pharmacological preconditioning has demonstrated promising benefits in the prevention of liver injury in experimental models and a few randomised controlled human studies. The current state of pharmacological preconditioning for hepatic ischemia and reperfusion injury is discussed in this study

Huang, Chi

Qin, Peiyang

Sung, Tszching

English

Advanced Emergency Medicine (E-Journal)

Advanced Emergency Medicine- 98 -AReview of Pharmacological Preconditioning for HepaticIschemia-Reperfusion InjuryPeiyang Qin1, Chi Huang2, Tszching Sung31. Institute of Biomedicine & Guangdong Provincial Key Laboratory of Bioengineering Medicine,College of Stomatology, Jinan University, Guangzhou 510632, China.2. Fujian Provincial Key Laboratory of Innovative Drug Target Research and State KeyLaboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University,Xiamen 361102, China.3. Institute of New Drug Research and Guangdong Province Key Laboratory of PharmacodynamicConstituents of Traditional Chinese Medicine & New Drug Research, College of Pharmacy, JinanUniversity, Guangzhou 510632, China.Abstract: Hepatic ischemia/reperfusion injury (HIRI) is a pathophysiological condition that occurs when the liver's bloodsupply is interrupted, resulting in organ hypoxia. It commonly happens when blood supply to the liver is reduced during liverresection due to prolonged obstruction of blood flow, shock, trauma, or heart failure. Prolonged hepatic ischemia followedby reperfusion, which occurs following a liver transplant, causes serious harm and contributes to increased morbidity anddeath. Several HIRI treatments, including pharmacological preconditioning, ischemic preconditioning, and remote ischemicpreconditioning, have been proposed based on the further study on hepatic ischemia-reperfusion injury. Pharmacologicalpreconditioning has demonstrated promising benefits in the prevention of liver injury in experimental models and a fewrandomised controlled human studies. The current state of pharmacological preconditioning for hepatic ischemia andreperfusion injury is discussed in this study.Keywords: Ischemic Preconditioning; Ischemia-Reperfusion Injury; Hepatectomy; Liver Transplant; DrugIntroductionIschemia-reperfusion injury (IRI) is a joint experimental and clinical finding that tissue ischemia with insufficientoxygen supply followed by successful reperfusion triggers a broad and complex array of inflammatory responses involvingmultifactorial metabolic mechanisms pathways, ultimately leading to severe ischemia-reperfusion injury, circulatorydysfunction, organ failure, and death. Ischemia-reperfusion injury to the liver is a type of injury that occurs when the liver isdeprived of oxygen and nutrients (HIRI) is a multi-factorial pathologic process that leads to post-ischemic organ failure andcell death.Following liver surgery, there is an increased risk of death, resulting in an increase in morbidity and mortality. Forirreversible acute and chronic liver disorders, a liver transplant has been the most effective treatment option so far. Theprimary cause of primary non-function or insufficiency of the transplanted liver after liver transplantation isischemia-reperfusion damage. It is also the most common reason for liver transplantation and mortality. As a result, livertransplantation research is a prominent topic.Ischemic preconditioning (IPC) is described as a brief period of ischemia followed by tissue reperfusion in order toincrease ischemic tolerance for a prolonged length of ischemia. The adaptive pathophysiological process in the targetedorgan allows IPC to reduce the size of IRI. Ischemic preconditioning can lower the severity of the ischemia-reperfusioninjury and increase the success rate of liver transplantation.Ischemic preconditioning has been proven to be a promising technique for improving postoperative outcomes after liverVolume 11 | Issue 3 - 99 -resections in a number of experimental investigations and a few clinical series. Furthermore, many pharmacologicalintervention and preconditioning methods, such as remote preconditioning, heat shock, and hyperbaric oxygen, have beendeveloped to reduce the functional impairment associated with ischemia-reperfusion injury. The primary mechanisms ofpharmacological preconditioning for liver ischemia/reperfusion injury are currently: (1) reducing cellular calcium excess; (2)reducing oxidative stress; (3) reducing inflammatory factor production; and (4) modulating apoptosis, pyroptosis, orautophagy. The majority of HIRI pretreatment medicines reduce tissue and cell damage by one or more of the mechanismslisted above, enhance liver tissue and cell resistance to ischemia-reperfusion (IR), maintain liver function, and preventpostoperative liver damage.1. Substances that are anti-inflammatoriesAlthough the inflammatory response is protective in the repair of tissue damage, an overabundance of it can harm tissueand organ function. Activated Kupffer cells produce a lot of reactive oxygen species, proinflammatory cytokines,chemokines, and adhesion molecules during HIRI. During liver resection, neutrophils aggregate in ischemic parts of the liver,promoting the inflammatory response of liver parenchyma cells, thanks to ROS-activated inflammatory pathways.1.1Antagonizers of the adrenergic receptorMohammed et al. proposed that carvedilol can selectively antagonise α1ARs and non-selectively β1ARs and β2ARs asan adrenergic receptor antagonist[1], inhibit G protein-coupled receptor signalling pathway and reduce the expression ofprotein kinase C. level, thereby reducing the release of NF-κB and reducing the inflammatory response. CF102 is a highlyselective α3 adrenergic receptor antagonist. Ohana et al. [2] believed that CF102 exerted a practical anti-inflammatory effectby down-regulating the expression of the PI3K/NF-κB signalling pathway.1.2Dipeptidyl peptidase-4 inhibitorSherif et al. [3] discovered that vildagliptin, a dipeptidyl peptidase-4 inhibitor, lowers HIRI, primarily by inhibiting highmobility group protein 1 (HMGB-1). TNF- levels also reduce the expression of the TLR4/NF-B signalling pathway, whichhelps to reduce inflammation. By activating the Nrf-2/HO-1 pathway, Abdel-Gaber et al. [4] discovered that sitagliptin mightenhance the expression of Nrf-2 mRNA and the content of HO-1 and so have an anti-inflammatory impact.1.3AnestheticsYang et al. [5] found that remifentanil, as an opioid receptor agonist, could activate β-arrestin and reduce theinflammatory response of HIRI. Dexmedetomidine, an α2 receptor agonist, commonly used in clinical anaesthesia, cantrigger the presynaptic α2A receptor on Kupffer cells' surface, inhibiting the expression of norepinephrine, inhibiting theinflammatory response, and reducing HIRI during hepatectomy.1.4Endogenous active substancesNot only exogenous drugs can reduce HIRI damage, but many endogenous active substances can also play an importantprotective role. The Ang II/AT1R pathway, as a critical hypoxic/ischemic organ damage regulatory axis, activation of AT1Rincreases oxidative stress and the expression of inflammatory cytokines. Ye et al. [6] also found that pretreatment withgalectin-1 (Gal-1), mainly expressed in macrophages, neutrophils, dendritic cells, and other cells, can increaseanti-inflammatory cells. The expression of factor IL-10, while significantly attenuating the expression of pro-inflammatorycytokines and chemokines (CXCL-1, CXCL-10) such as TNF-α, IL-1β, IL-6 and IFN-γ, and reducing the inflammatoryresponse.In addition to the drugs included in the above categories, new drugs are continually being demonstrated to exertanti-inflammatory effects during HIRI. Kamel et al. [7] proposed that the angiotensin-converting enzyme inhibitor perindoprilcan alleviate the impact of Nrf-2-related signalling pathways, TLR4/NF-κB, JAK1/STAT-3, PI3k/Akt/mTOR and othersignalling pathways. Yu et al. [8] found that L-tetrahydropalmatine can directly reduce the production of inflammatoryAdvanced Emergency Medicine- 100 -cytokines TNF-α and IL-6, further inhibiting the ERK/NF-κB signalling pathway and playing a protective role in the processof IR.2. Medications to reduce cellular calcium overloadWhen IR occurs, the production of adenosine triphosphate (ATP) is reduced, the sodium-potassium pump activity isdecreased, and the intracellular Ca2+ concentration is abnormally increased, that is, calcium overload. In addition, thedamage to mitochondrial structure and function caused by cellular ischemia and hypoxia can also cause intracellular calciumoverload. Calcium overload mainly induces cell death or apoptosis by activating calcium-dependent enzymes such as neutralprotease and protein kinase C [1]. The current common drugs specifically reduce the cellular calcium overload during HIRIby protecting the structure and function of mitochondria. Neda et al. [2] proposed that silibinin can neutralise a large amountof ROS to maintain mitochondrial membrane integrity, reduce mitochondrial membrane fusion, reduce calcium overload,and reduce HIRI while regulating the expression of OPA1 and MFN1 genes. Gu et al. [11] [3] confirmed through experimentsthat ursodeoxycholic acid lysophosphatidylethanolamide could protect mitochondria, maintain ATP production, balancemitochondrial fission and fusion, reduce the reduction of mitochondrial fission and fusion calcium overload, and inhibitmitochondria-mediated apoptosis pathway and play a role in lowering HIRI.3. Medications to reduce oxidative stressUnder physiological conditions, the reactive oxygen species (ROS) produced by hepatocytes maintain a dynamicbalance with the superoxide dismutase (SOD) they contain. In the process of IR, Kupffer cells and neutrophils generate alarge amount of ROS. The SOD produced by the body cannot be removed entirely, resulting in mitochondrial dysfunction,destruction of protein, cell membrane integrity and lipid peroxidation to produce propanediol. Aldehydes and other lipidperoxides. Therefore, scavenging excess ROS or increasing SOD expression can inhibit the occurrence of oxidative stressduring IR, thereby alleviating HIRI.De Almeida et al. [6] confirmed that methylene blue (MB) could exert its reducing properties at low concentrations,replacing oxygen molecules as the electron acceptor of xanthine oxidase in the electron transfer of IR, thereby reducing theamount of ROS.4. Multi-mechanism medicinesNobiletin, a natural flavonoid, is a beneficial antioxidant with anti-inflammatory and anti-cancer activities. In recentyears nobiletin has received extensive attention due to its various medicinal properties and biological effects. Dusabimana etal. found that nobiletin can activate the SIRT1/FOXO3α signalling pathway to induce autophagy. Recent studies have shownthat liver-selective MMP-9 inhibitors can reduce HIRI and accelerate liver tissue regeneration.In the latest study, PPAR-γ agonists, the diabetes treatment drugs, were also found to play a protective role during liverischemia/reperfusion. Oral administration of PPAR-γ agonists 1-3 days before liver surgery can effectively alleviate HIRI byactivating the FAM3A-ATP-Akt signalling pathway, reducing oxidative stress and reducing the inflammatory mediatorNF-κB . In addition, petrolatum can also reduce oxidative stress and inflammation by up-regulating the expression ofPPAR-γ, regulating the downstream NF-κB-p65 and JAK2/STAT1 pathways .Irisin, a newly discovered hormone, appears to be a novel and potential HIRI treatment. This kind of protein, which isreleased by skeletal and cardiac muscle after exercise, has many protective benefits in HIRI. After hepatic I/R, exogenousirisin treatment improved liver function, reduced liver necrosis and cell apoptosis, and lowered inflammatory response[14]. Inhepatic I/R, exogenous irisin significantly reduced the expression of the mitochondrial fission related proteinsdynamin-related protein 1 (drp-1) and fission 1 (Fis-1). Exogenous irisin therapy also boosted mitochondrial content as wellas peroxisome proliferative activated receptor (PPAR) co-activator 1 (PGC-1) and mitochondrial transcription factor (TFAM)expression, all of which are associated to mitochondrial biogenesis. Irisin also reduced oxidative stress in the hepatic I/R byupregulating the production of uncoupling proteins (UCP) 2. Exogenous irisin therapy reduced hepatic I/R injury byinhibiting mitochondrial fission, boosting mitochondrial biogenesis, and alleviating oxidative stress, according to theVolume 11 | Issue 3 - 101 -findings.ConclusionIschemia-reperfusion damage is a serious side effect of liver surgery that is linked to a high rate of morbidity andmortality. Many studies have shown that pharmacological preconditioning can protect the liver by significantly reducing orpreventing reperfusion injury throughout the last few years. However, most of these researches have been conducted onanimals, and despite encouraging outcomes in experimental models, the majority of the findings cannot be applied tohumans. Despite the fact that I/R injury appears to be reduced in terms of biochemical indices, most trials, particularly in theclinical situation, have failed to show any reduction in morbidity and mortality. As a result, the positive impacts onbiochemical indicators must be translated into better clinical outcomes and validated in larger human investigations. Morecriteria, such as the patients' age, the pathology of the liver, the duration of ischemia, and the amount of the surviving liver,must also be investigated. On the following points, pharmacological preconditioning research and application still need to beimproved: (1) The medication pretreatment study is currently in the early stages of development. (2) Based on themechanism of action and pharmacokinetic characteristics of different drugs, what method and when to administer themedication during the perioperative period of liver surgery can exert the best protective effect of the drug is still beingexplored in the clinical application; (3) Whether pretreatment drugs with differing mechanisms of action andpharmacokinetic characteristics can exert the best protective effect of the drug is still being explored in the clinicalapplication.References[1] Mohammed SG., Ibrahim I, Mahmoud MF, & Mahmoud A. (2019). Carvedilol protects against hepaticischemia/reperfusion injury in high-fructose/high-fat diet-fed mice: Role of G protein-coupled receptor kinase 2 and 5.Toxicology and applied pharmacology, 382, 114750.[2] Ohana G, Cohen S, Rath-Wolfson L, & Fishman P. (2016). A3 adenosine receptor agonist, CF102, protects againsthepatic ischemia/reperfusion injury following partial hepatectomy. Molecular medicine reports, 14(5), 4335–4341.[3] Sherif IO, &Al-Shaalan NH. (2018). Vildagliptin Attenuates Hepatic Ischemia/Reperfusion Injury via the TLR4/NF-κBSignaling Pathway. Oxidative medicine and cellular longevity, 2018, 3509091.[4] Abdel-Gaber SA, Geddawy A, & Moussa RA. (2019). The hepatoprotective effect of sitagliptin against hepatic ischemiareperfusion-induced injury in rats involves Nrf-2/HO-1 pathway. Pharmacological reports : PR, 71(6), 1044–1049.[5] Yang Y, Chen C, Cui C, et al (2019). Indispensable role of β-arrestin2 in the protection of remifentanil preconditioningagainst hepatic ischemic reperfusion injury. Scientific reports, 9(1), 2087.[6] Ye Y, Wang W, Zhang W. et al (2019). Galectin-1 attenuates hepatic ischemia reperfusion injury in mice. Internationalimmunopharmacology, 77, 105997.[7] Kamel E O, Hassanein E, Ahmed MA, &Ali F. (2020). Perindopril Ameliorates Hepatic Ischemia Reperfusion Injury ViaRegulation of NF-κB-p65/TLR-4, JAK1/STAT-3, Nrf-2, and PI3K/Akt/mTOR Signaling Pathways. Anatomical record(Hoboken, N.J. : 2007), 303(7), 1935–1949.[8] Yu Q, Wu L, Liu T, et al (2019). Protective effects of levo-tetrahydropalmatine on hepatic ischemia/reperfusion injury aremediated by inhibition of the ERK/NF-κB pathway. International immunopharmacology, 70, 435–445.About the Author：1. Qin Peiyang（2002-）,Female,Han nationality,Henan Province ,Bachelor of stomatology in reading,Jinan University,Reaserch Interest: Clinical science and oral science2. Huang Chi,Male（2002-）,Han nationality, Hunan Province,Bachelor of pharmaceutical science in reading,XiamenUniversity,Reaserch Interest: Pharmaceutical Chemistry3. Tszching Sung（1999-）,Female, Han nationality,Guangdong Province,Bachelor of pharmacy,Jinan University,ReaserchInterest: PharmaceuticsPeiyang Qin and Chi Huang contributed equally to this work.

A Review of Pharmacological Preconditioning for Hepatic Ischemia-Reperfusion Injury

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A Review of Pharmacological Preconditioning for Hepatic Ischemia-Reperfusion Injury

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