Avila, M.A. (Matías Antonio)

Corrales, F.J. (Fernando José)

Mato, J.M. (José María)

Universidad de Navarra

Heat shock: a barrier to hepatic ischemic injury

Dadun, University of Navarra

EditorialHeat shock: a barrier to hepatic ischemic injuryJose´ M. Mato*, Fernando J. Corrales, Matias A. AvilaDepartment of Medicine, Universidad de Navarra, Pamplona, SpainSee Article, pages 619–627The interruption of tissue oxygenation – ischemia – isprobably the most important problem associated with liversurgery [1,2]. This is especially true for patients withimpaired liver function, such as liver cirrhosis or steatosis,where the effects of ischemic injury may be irreversible evenif the duration of the interruption of blood flow is short.Paradoxically, the generation of reactive oxygen species(ROS) seems to be a key factor in the development of liverdamage in irreversible ischemia. The answer to this apparentparadox lies in that ROS are generated not during the initialperiod of ischemia but upon restoration of blood flow orreperfusion. During ischemia, a variety of cellular and mole-cular events take place in the liver that, upon reoxygenation,result in the massive production of ROS, which inflict directtissue damage and initiate a cascade of deleterious cellularresponses leading to inflammation, cell death, and organ fail-ure. The term ischemia-reperfusion (IR) injury has beencoined to indicate this condition. Therapeutic strategiesaimed to prevent IR injury are focused on controlling ROSgeneration at the time of restoration of blood flow or reperfu-sion, and intervening in the signal cascade initiated by reox-ygenation.Liver injury induced by hepatic IR is characterized byactivation of the transcription factor NF-kB, activation ofKupffer cells, increased production of proinflammatorycytokines, such as tumour necrosis factor-a (TNF-a) andinterleukin-1 (IL-1), liver polymorphonuclear (PMN)leukocyte activation and infiltration, and hepatocellulardamage [2]. TNF-a is an important mediator in PMN leuko-cyte recruitment and activation which in turn are a potentsource of ROS. In view of this critical role played by TNF-ain liver injury, it has been long proposed that suppression ofTNF-a production may attenuate liver injury after IR. Thus,anti-TNF-a antibodies [3] and suppression of cytokinegeneration with FR167653 [4] decrease hepatic IR injuryin experimental models.Recent studies indicate that Kupffer cells play a key rolein the generation of TNF-a during IR liver injury [5]. Forinstance, the inhibition of TNF-a release from Kupffer cellswith gadolinium chloride (GdCl3), previous to the IR treat-ment, maintained low levels of TNF-a attenuating liverinjury, an effect that could be reverted by the administrationof exogenous TNF-a [6,7]. In addition to GdCl3, and otherinhibitors of Kupffer cell activation, a variety of differentpharmacological approaches, such as the administration ofadenosine [8], nitric oxide donors [9], and antioxidants[10,11], have been successfully applied in animal modelsto attenuate liver injury after IR. Identifying the mechan-isms of action by which these and other agents provideischemic tolerance will provide potential targets for thedevelopment of new treatments for IR liver injury.It is known for many years that cellular injury, indepen-dently of its nature (infectious, oxygen deprivation, inflam-matory, heat, etc.), induces an adaptive response.Accordingly, another therapeutic strategy aimed to amelio-rate hepatic IR injury consists in the exposure of the liver tobrief periods of blood flow interruption followed by reper-fusion prior to the prolonged IR treatment, a procedure thatis know as ischemic preconditioning. The protective effectsof ischemic preconditioning were first described in themyocardium and have been also shown experimentally inthe liver. It has been recently demonstrated that ischemicpreconditioning protects sinusoidal endothelial cells andsuppresses Kupffer cell activation after storage and reperfu-sion [12].Heat shock proteins (HSPs) are well known as cytopro-tective proteins. Accordingly, different groups have inves-tigated whether a period of hyperthermia followed byrecovery from this heat treatment is another mechanismfor acquiring ischemic tolerance. Heat shock pretreatmenthas been shown to prevent hepatic ischemic injury causedby Pringle’s manoeuvre [13] and in an isolated rat liverperfusion model [14]. Heat shock preconditioning hasbeen also shown to reduce liver injury induced by carbontetrachloride administration [15] and to improve liver trans-Journal of Hepatology 35 (2001) 663–6650168-8278/01/$20.00 q 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.PII: S0168-8278(01)00224-0www.elsevier.com/locate/jhep* Corresponding author.E-mail address: jmmato@unav.es (J.M. Mato).plant survival in rats [16]. Moreover, geranylgeranylacetone(GGA), a heat shock protein inducer, has been recentlyshown to prevent primary graft malfunction in a model ofrat liver transplantation [17]. Since GGA is a non-toxic anti-ulcer drug, it has been proposed that oral administration ofthis agent may be useful in preventing IR liver injury [17].In this model of liver transplantation, GGA pretreatmentincreased the hepatic mRNA levels of HSP72 and HSP 90and reduced the serum levels of TNF-a after reperfusion(17), suggesting that heat shock preconditioning inducesischemic tolerance acting directly through the liver. In thisissue of the Journal, Yonezawa and colleagues [18] demon-strate that hyperthermic preconditioning attenuates IR liverinjury acting at the organ level through the suppression ofKupffer cell activation and neutrophil infiltration, whileproviding a protective effect on the parenchymal cells.The authors first found that heat shock preconditioningmarkedly induced HSP72 expression in the different typesof cells that exist in the liver -hepatocytes, Kupffer cells andendothelial cells. Then, they observed that the increase inplasma TNF-a and in hepatic TNF-a mRNA during reper-fusion was significantly suppressed by heat shock precondi-tioning. In these experiments, Yonezawa and colleaguesimmersed a group of rats in a hot water bath for 15 min tomaintain their rectal temperature at 428C. The control groupof rats was immersed in a bath maintained at 378C for thesame period of time. After 48 h recovery, partial hepaticischemia was induced by clamping the vessels of the lefthepatic lobes; and after a 90 min ischemia, the vessels wereunclamped. Plasma was collected and the left lobes of thelivers were removed before clamping, at reperfusion and atvarious times after reperfusion. They also found that theincrease in plasma alanine amino transferase (ALT) levelsduring the reoxygenation period was less marked in the heatshock pretreated animals than in the control rats. Histologi-cal examination of the livers confirmed that heat shockpretreatment preserved the tissue integrity during reperfu-sion. The production of cytokine-induced neutrophilchemoattractant, a potent chemoattractant for neutrophilsin rats, was also suppressed in the heat shock pretreatedanimals. Consistently, while reperfusion induced an intenseinfiltration of PMNs in the hepatic parenchyma of thecontrol group, particularly in necrotic areas, in the heatshock pretreated group the number of PMNs was smallerand were only found in the hepatic triad.In summary, the studies of Yonezawa and colleaguesdemonstrate that the stress produced by hyperthermicpreconditioning induces tolerance to a future ischemic insultacting directly on the various cell types of the liver – hepa-tocytes, Kupffer cells and endothelial cells. But how doesheat shock preconditioning works its protective effect onliver cells? One possibility is that HSP72, the major heatshock protein, may prevent Kupffer cells from activation inresponse to IR injury by suppressing NF-kB activation. NF-kB is normally kept in an inactive state outside the nucleusby its binding partner, I-kB. Phosphorylation of this inhibi-tor by the I-kB kinases leads to its degradation and therelease of NF-kB, which can then migrate to the nucleusand activate target genes. Although Yonezawa and collea-gues did not determine NF-kB activation or I-kB phosphor-ylation in their experimental model, different studiesindicate that hyperthermia suppresses I-kB phosphorylationand NF-kB activation in a variety of cellular systems includ-ing astroglial cells, RAW 264.7 murine macrophages, ratand human islets, murine lung epithelium and rat hepato-cytes [19–23]. Recently, Frossard and colleagues havedemonstrated that hyperthermia in rats decreases the sever-ity of cerulein-induced pancreatitis by reducing TNFaexpression in the pancreas through the stabilization I-kBand the suppression of NF-kB activation [24]. Suppressionby heat shock preconditioning of NF-kB activation inresponse to IR may be then the mechanism by which theproduction of TNF-a from Kupffer cells is inhibited. Thereduced production of TNF-a by Kupffer cells in responseto IR after heat shock preconditioning will reduce, in itsturn, the cytotoxic effect of this cytokine on the hepatocytes(which depends also on the activation of NF-kB), limit theinfiltration of PMNs to the liver and ameliorate tissuedamage.Based on these studies about how heat shock precondi-tioning protects the liver from IR injury, Yonezawa andcolleagues propose that, although hyperthermia is still anexperimental treatment, patients undergoing liver surgerymay benefit from the future improvement of extracorporeallocal hyperthermic technologies using, for instance, radiofrequency irradiation. However, as reviewed recently byDeMeester and colleagues [25], it should be rememberedthat when cells or animals have been previously ‘primed’ byexposure to endotoxins a subsequent heat stress may preci-pitate cell death by apoptosis – a phenomenon which hasbeen named ‘the heat shock paradox’ [25]. Therefore, aclear understanding of the signaling pathways activated byheat shock and inflammation and how these stress responsesinteract seems necessary before evaluation of the therapeu-tic potential of hyperthermia.References[1] Hui AM, Kawasaki S, Makuuchi M, Nakayama J, Ikegami T, Miya-gawa S. Liver injury following normothermic ischemia in steatotic ratliver. Hepatology 1994;20:1287–1293.[2] Serracino-Inglott F, Habib NA, Mathie RT. Hepatic ischemia-reper-fusion injury. Am J Surg 2001;181:160–166.[3] Colletti LM, Remick DG, Burtch GD, Kunkel SL, Strieter RM,Campbell Jr DA. Role of tumour necrosis factor-alpha in the patho-physiologyc alterations after hepatic ischemia/reperfusion injury inthe rat. J Clin Invest 1990;85:1936–1943.[4] Hato S, Urakami A, Yamano T, Uemura T, Ota T, Hirai R, Shimizu N.Attenuation of liver and lung injury after hepatic ischemia and reper-fusion by a cytokine-suppressive agent, fr167653. 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Heat shock: a barrier to hepatic ischemic injury

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