Akciğerlerde İskemi-Reperfüzyon Hasarı ve İskemik Önkoşullama

Year 2005, Issue: 1, 35 - 49, 01.01.2005

Hilmi Burak Kandilci Bülent Gümüşel

Abstract

İskemi-reperfüzyon İ/R , doku veya organa giden kan akımında bir süre azalma ve sonrasında yeniden kanlanma olarak tanımlanmaktadır. İ/R ile indüklenen akciğer hasarı akciğer tranplantasyonunda sık karşılaşılan bir durumdur. Son yıllarda klinikte akciğer İ/R hasarını engellemeye yönelik kompleman inhibisyonu, sürfaktan tedavisi, nitrik oksit inhalasyonu gibi farklı yaklaşımlar kullanılmaktadır. 1986 yılında Murry ve arkadaşları tarafından miyokardda İ/R hasarına karşı güçlü endojen koruma oluşturan bir mekanizma iskemik önkoşullama gösterilmiştir. İskemik önkoşullama, doku veya hücrelerin iskemi ve reperfüzyona kısa süreli maruz kalmasını takiben daha uzun süreli iskemi ile oluşan doku hasarında belirgin bir azalmadır. Kalpte gösterilmesinden sonra beyin, omurilik, iskelet kası, karaciğer, böbrek, akciğer, gibi pek çok farklı dokuda önkoşullama oluşturulabileceği gösterilmiştir. Bu derlemede akciğerlerde İ/R hasarı, iskemik önkoşullama ve olası etki mekanizmaları değerlendirilmiştir.

Keywords

Akciğer, iskemi-reperfüzyon, iskemik önkoşullama

Ischemia-Reperfusion Injury and Ischemic Preconditioning in the Lungs

Abstract

Ischemia-reperfusion I/R is defined as the condition of inadequate blood supply to a tissue or organ for a limited time which is followed by the restoration of blood flow. I/R- induced lung injury is a common situation occurring in lung transplantation. In recent years, multiple clinical strategies are suggested to prevent I/R injury such as complement inhibition, surfactant therapy, nitric oxide inhalation. In 1986, Murry and coworkers was the first to demonstrate that ischemic preconditioning was a protective mechanism against I/R injury in the hearth. A short period of ischemia-reperfusion protects against detrimental effects of subsequent prolonged ischemia; this endogenous mechanism of protection has been termed as ischemic preconditioning IP . After its demonstration in myocardium, several studies have addressed that IP may also occur in brain, skeletal muscle, liver, kidney and the lung. In this review, I/R injury, IP and its possible mechanisms in the lung were evaluated.

Keywords

Lung, Ischemia-reperfusion, Ischemic preconditioning

References

• Siemionow M, Arslan E.: Ischemia/reperfusion injury: A review in relation to free tissue transfers. Microsurgery, 24, 468-475 (2004).
• Maxwell, S.R.J., Lip, G.Y.H.: Reperfusion injury: a review of the pathophysiology,clinical manifestations and therapeutic options. Int. J. Cardiol., 58, 95-117 (1997)
• Carden, D.L., Granger, D.N.: Pathophysiology of ischemia-reperfusion injury. J. Pathol., 190, 255-66 (2000).
• Collard, C.D., Gelman, S.: Pathophysiology, Clinical Manifestations, and Prevention of Ischemia-Reperfusion Injury. Anesthesiology, 94, 1133-1138 (2001).
• Nakamura, T., Vollmar, B., Winning, J., Ueda M., Menger, M.D., Schäfers, H.-J.: Hepa- rin and the nonanticoagulant N-acetyl heparin attenuate capillary no-reflow after nor- mothermic ischemia of the lung. Ann. Thorac. Surg., 72, 1183-1189 (2001).
• Crestani, B., Cornillet, P., Dehoux, M., Rolland, C., Guenounou, M., Aubier, M.: Al- veolar type II epithelial cells produce interleukin-6 in vitro and in vivo: regulation by alveolar macrophage secretory products. J. Clin. Invest., 94, 731-740 (1994).
• Levinson, R.M., Shure, D., Moser, K.M.: Reperfusion pulmonary edema after pulmo- nary artery thromboendarterectomy. Am. Rev. Respir. Dis., 134, 1241-1245 (1986).
• Vural, K.M., Öz, M.C.: Endothelial adhesivity , pulmonary hemodynamics and ni- tric oxide synthesis in ischemia-reperfusion. Eur. J. Cardiothorac. Surg., 18, 348-352 (2000).
• Krishnadasan B, Naidu BV, Byrne K,et al.: The role of proinflammatory cytokines in lung ischemia-reperfusion injury. J. Thorac. Cardiovasc Surg., 125, 261-272 (2003).
• Connaughton, P.J., Bahuth, J.J., Lewis, F.J.: Lung ischemia up to six hours; influence of topical cooling in situ on subsequent pulmonary function. Dis. Chest., 41, 404-408 (1962).
• McCord JM.: Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med., 312, 159-163 (1985).
• McCord JM.: Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med., 312, 159-163 (1985).
• Al-Mehdi AB, Shuman H, and Fisher AB.: Intracellular generation of reactive oxygen species during nonhypoxic lung ischemia. Am J Physiol 272, L294-300 (1997).
• Kelly RF.: Current strategies in lung preservation. J Lab Clin Med., 136, 427-440 (2000).
• Zhao, G., Al-Mehdi, A.B., Fisher, A.B.: Anoxia-reoxygenation versus ischemia in iso- lated rat lungs. Am. J. Physiol., 273, L1112-1117 (1997).
• Date H, Matsumura A, Manchester JK, Obo H, Lima O, Cooper JM, Sundaresan S, Lowry OH, and Cooper JD.: Evaluation of lung metabolism during successful twenty- four-hour canine lung preservation. J Thorac Cardiovasc Surg., 105, 480-491 (1993).
• Fisher AB, Dodia C, Tan ZT, Ayene I, and Eckenhoff RG.: Oxygen-dependent lipid per- oxidation during lung ischemia. J Clin Invest., 88, 674-679 (1991).
• Eckenhoff RG, Dodia C, Tan Z, and Fisher AB.: Oxygen-dependent reperfusion injury in the isolated rat lung. J Appl Physiol., 72, 1454-1460 (1992).
• Fisher AB, Dodia C, Tan ZT, Ayene I, and Eckenhoff RG.: Oxygen-dependent lipid per- oxidation during lung ischemia. J Clin Invest., 88: 674-679 (1991).
• Eckenhoff RG, Dodia C, Tan Z, and Fisher AB.: Oxygen-dependent reperfusion injury in the isolated rat lung. J Appl Physiol., 72, 1454-1460 (1992).
• Ware LB, Golden JA, Finkbeiner WE, and Matthay MA.: Alveolar epithelial fluid trans- port capacity in reperfusion lung injury after lung transplantation. Am J Respir Crit Care Med., 159, 980-988 (1999).
• Sugita M, Suzuki S, Kondo T, Noda M, and Fujimura S.: Transalveolar fluid absorption ability in rat lungs preserved with Euro-Collins solution and EP4 solution. Transplan- tation, 67, 349-354 (1999).
• t3. Zhao G, Ayene IS, Fisher AB.: Role of iron in ischemia-reperfusion oxidative injury of rat lungs. Am J Respir Cell Mol Biol., 16, 293-299 (1997).
• Huang YT, Ghio AJ, Nozik-Grayck E, Piantadosi CA.: Vascular release of nonheme iron in perfused rabbit lungs. Am J Physiol Lung Cell Mol Physiol., 280, L474-L481 (2001).
• Bysani GK, Kennedy TP, Ky N, Rao NV, Blaze CA, Hoidal JR.: Role of cytochrome P-450 in reperfusion injury of the rabbit lung. J Clin Invest., 86, 1434-1441 (1990).
• Fischer S, Cassivi SD, Xavier AM, Cardella JA, Cutz E, Edwards V, Liu M, Keshavjee S.: Cell death in human lung transplantation: apoptosis induction in human lungs during ischemia and after tranplantation. Ann Surg., 231, 424-431 (2000).
• Murry, C.E., Jennings, R.B., Reimer, K.A.: Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium. Circulation., 74, 1124-1136 (1986).
• Chen, J., Graham, S.H., Zhu, R.L., Simon, R.P.: Stress proteins and tolerance to focal cerebral ischemia. J. Cereb. Blood. Flow. Metab., 16, 566-577 (1996).
• Gürke, L., Marx, A., Sutter, P.-M., Frentzel, A., Salm, T., Harder, F., Seeling, J., He- berer, M.: Ischemic preconditioning improves post-ischemic skeletal muscle function. Am. Surg., 62, 391-394 (1996).
• Hardy, K.J., McClure, D.N., Subwongcharoen, S.: Ischemic preconditioning of the liv- er:a preliminary study. Aust. N. Z. J. Surg., 66, 707-710 (1996).
• Matsuyama, K., Chiba, Y., Ihaya, A., Kimura, T., Tanigawa, N., Muraoka, R.: Effect of spinal cord preconditioning on paraplegia during cross-clamping of the thoracic aorta. Ann. Thorac. Surg., 63, 1315-1320 (1997).
• Neely, C.F., Keith, I.M.: A1 adenosine receptor antagonists block ischemia-reperfusion injury of the lung. Am. J. Physiol., 268, L1036-46 (1995).
• Du, Z.Y., Hicks, M., Winlaw, D., Spratt, P., MacDonald, P.: Ischemic preconditioning enhances donor lung preservation in the rat. J. Heart Lung Transplant., 15, 1258-67 (1996).
• Featherstone, R.L., Chambers, D.J., Kelly, F.J.: Ischemic Preconditioning Enhances Recovery of Isolated Rat Lugs After Hypothermic Preservation. Ann. Thorac. Surg., 69, 237-242 (2000).
• Hawaleshka, A., Jacobsohn, E.: Ischemic preconditioning:mechanisms and potential clinical applications. Can. J. Anaesth., 45, 670-682 (1998).
• Cohen, M.V., Liu, G.S., Downey, J.M.: Preconditioning causes improved wall motion as well as smaller infarcts after transient coronary occlusion in rabbits. Circulation., 84, 341-349, (1991).
• Liu, Y., Downey, J.M.: Ischemic preconditioning protects against infarction in rat heart. Am. J. Physiol., 263, H1107-1112 (1992).
• Van Winkle, D.R., Thornton, J.D., Downey, D.M., Downey J.M.: The natural history of preconditioning:cardioprotection depends on duration of transistent ischemia and time to subsequent ischemia. Coron. Artery Dis., 2, 613-619 (1991).
• Li, Y., Whittaker, P., Kloner, R.A.: The transient nature of the effect of ischemic pre- conditioning on myocardial infarct size and ventricular arrhythmia. Am. Heart. J., 123, 346-353 (1992).
• Murry, C.E., Richard, V.J., Jennings, R.B., Reimer, K.A.: Myocardial protection is lost before contractile function recovers from ischemic preconditioning. Am. J. Physiol., 260, H796-H804 (1991).
• Marber, M.S., Latchman, D.S., Walker, J.M., Yellon, D.M.: Cardiac stress protein el- evation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation., 88, 1264-1272 (1993).
• Chen, J., Graham, S.H., Zhu, R.L., Simon, R.P.: Stress proteins and tolerance to focal cerebral ischemia. J. Cereb. Blood. Flow. Metab., 16, 566-577 (1996)
• Pagliaro, P., Gattullo, D., Rastaldo, R., Losano, G.: Ischemic preconditioning from the first to the second window of protection. Life Sciences., 69, 1-15 (2001)
• Lawson CS and Downey JM.: Preconditioning: state of the art myocardial protection. Cardiovasc Res., 27, 542-550 (1993)
• Liu GS, Thornton J, Van Winkle DM, Stanley AW, Olsson RA, and Downey JM.: Protec- tion against infarction afforded by preconditioning is mediated by A1 adenosine recep- tors in rabbit heart. Circulation, 84, 350-356 (1991).
• Auchampach JA and Gross GJ.: Adenosine A1 receptors, KATP channels, and ischemic preconditioning in dogs. Am J Physiol., 264: H1327-1336 (1993).
• Dana A, Baxter GF, Walker JM, and Yellon DM.: Prolonging the delayed phase of myo- cardial protection: repetitive adenosine A1 receptor activation maintains rabbit myo- cardium in a preconditioned state. J Am Coll Cardiol., 31: 1142-1149 (1998).
• Zweier, J.L., Wang, P., Kuppusamy, P.: Direct measurement of nitric oxide generation in the ischemic heart using electron paramagnetic resonance spectroscopy. J. Biol. Chem., 270, 304-307 (1995).
• Nakanishi, K., Vinten-Johansen, J., Lefer, D.J., Zhao, Z., Fowler III, W.C., McGee, D.S., Johnston, W.E.: Intracoronary L-arginine during reperfusion improves endothe- lial function and reduces infarct size. Am. J. Physiology., 263, H1650-1658 (1992).
• Hartman, J.C., Kurc, G.M., Hullinger, T.G., Wall, T.M., Sheehy, R.M., Shebuski, R.J.: Inhibition of nitric oxide synthase prevents myocardial protection by ramiprilat. J. Pharmacol. Exp. Ther., 270, 1071-1076 (1994).
• Williams, M.W., Taft, C.S., Ramnauth, S., Zhao, Z.Q., Vinten-Johansen, J.: Endog- enous nitric oxide protects against ischemia-reperfusion injury in the rabbit. Cardio- vasc. Res., 30, 79-86 (1995).
• Bolli, R., Manchikalapudi, S., Tang, X.L., Takano, H., Qiu, Y., Guo, Y.,Zhang, Q., Jadoon, A.K.: The protective effect of late preconditioning against myocardial stunning in conscious rabbits is mediated by nitric oxide synthase: evidence that nitric oxide acts both as a trigger and as a mediator of the late phase of ischemic preconditioning. Circ. Res., 81, 1094-1107 (1997).
• Takano, H., Tang, X.L., Qui, Y., Guo, Y., French, B.A., Bolli, R.: Nitric oxide donors induce late preconditioning against myocardial stunning and infarction in conscious rabbits via an antioxidant-sensitive mechanism. Circ. Res., 83, 73-84 (1998).
• Bolli, R., Dawn, B., Tang, X.L., Qiu, Y., Ping, P., Xuan, X.T., Jones, W.K., Takano, H., Guo, Y., Zhang, J.: The nitric oxide hypothesis of late preconditioning. Basic. Res. Car- diol., 93, 325-338 (1998).
• Vegh, A., Szekeres, L., Parrat, J.R.: Preconditioning of the ischemic myocardium; invol- ment of the L-arginine nitric oxide pathway. Br. J. Pharmacol., 107, 648-652 (1992).
• Williams MW, Taft CS, Ramnauth S, Zhao ZQ, and Vinten-Johansen J.: Endogenous nitric oxide (NO) protects against ischaemia-reperfusion injury in the rabbit. Cardio- vasc Res., 30, 79-86 (1995).
• Banerjee S, Tang XL, Qiu Y, Takano H, Manchikalapudi S, Dawn B, Shirk G, and Bolli R.: Nitroglycerin induces late preconditioning against myocardial stunning via a PKC- dependent pathway. Am J Physiol., 277, H2488-2494 (1999).
• Ping P, Takano H, Zhang J, Tang XL, Qiu Y, Li RC, Banerjee S, Dawn B, Balafonova Z, and Bolli R.: Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits: a signaling mechanism for both nitric oxide-induced and ischemia-induced preconditioning. Circ Res., 84, 587-604 (1999).
• Miyoshi H, Nakaya Y, and Moritoki H.: Nonendothelial-derived nitric oxide activates the ATP-sensitive K+ channel of vascular smooth muscle cells. FEBS Lett., 345, 47-49 (1994).
• Downey JM and Cohen MV.: Signal transduction in ischemic preconditioning. Adv Exp Med Biol., 430, 39-55 (1997).
• Sasaki N, Sato T, Ohler A, O’Rourke B, and Marban E.: Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation, 101, 439-445 (2000)
• Gross GJ and Fryer RM.: Sarcolemmal versus mitochondrial ATP-sensitive K+ channels and myocardial preconditioning. Circ Res., 84, 973-979 (1999).
• Gross, G.J., Fryer, R.M.: Sarcolemmal versus mitokondrial ATP-sensitive K+ channels and myocardial preconditioning. Circ. Res., 84, 973-979 (1999).
• Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D’Alonzo AJ, Lodge NJ, Smith MA, and Grover GJ.: Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res., 81: 1072-1082 (1997).
• Baines CP, Liu GS, Birincioglu M, Critz SD, Cohen MV, and Downey JM.: Ischemic pre- conditioning depends on interaction between mitochondrial K+ATP channels and actin cytoskeleton. Am J Physiol., 276, H1361-1368 (1999).
• Takashi E, Wang Y, and Ashraf M.: Activation of mitochondrial K+ATP channel elicits late preconditioning against myocardial infarction via protein kinase C signaling pathway. Circ Res., 85, 1146-1153 (1999).
• Fryer RM, Hsu AK, Eells JT, Nagase H, and Gross GJ.: Opioid-induced second window of cardioprotection: potential role of mitochondrial K+ATP channels. Circ Res., 84, 846- 851 (1999).
• Duncker DJ and Verdouw PD.: Role of K+ATP channels in ischemic preconditioning and cardioprotection. Cardiovasc Drugs Ther., 14, 7-16 (2000).
• Qiu Y, Rizvi A, Tang XL, Manchikalapudi S, Takano H, Jadoon AK, Wu WJ, and Bolli R.: Nitric oxide triggers late preconditioning against myocardial infarction in conscious rabbits. Am J Physiol., 273, H2931-2936 (1997).
• Potoka DA, Nadler EP, Zhou X, Zhang XR, Upperman JS, and Ford HR.: Inhibition of NF-kappaB by IkappaB prevents cytokine-induced NO production and promotes en- terocyte apoptosis in vitro. Shock, 14, 366-373 (2000).
• Parratt J and Vegh A.: Pronounced antiarrhythmic effects of ischemic preconditioning. Cardioscience, 5, 9-18 (1994).
• Vegh A, Papp JG, and Parratt JR.: Prevention by dexamethasone of the marked an- tiarrhythmic effects of preconditioning induced 20 h after rapid cardiac pacing. Br J Pharmacol., 113, 1081-1082 (1994).
• Vegh A, Gyorgy K, Rastegar MA, Papp JG, and Parratt JR. Delayed protection against ventricular arrhythmias by monophosphoryl lipid-A in a canine model of ischaemia and reperfusion. Eur J Pharmacol., 382: 81-90 (1999).
• Kaszala K, Vegh A, Papp JG, Parratt JR. Modification by bradykinin B2 receptor block- ade of protection by pacing againts ischemia-induced arrhythmias. Eur J Pharmacol., 328:51-60, (1997).
• Bouchard JF, Chouinard J, and Lamontagne D.: Role of kinins in the endothelial pro- tective effect of ischaemic preconditioning. Br J Pharmacol., 123, 413-420 (1998).
• Bugge E and Ytrehus K.: Endothelin-1 can reduce infarct size through protein kinase C and KATP channels in the isolated rat heart. Cardiovasc Res., 32, 920-929 (1996).
• Brown JM, Grosso MA, Terada LS, Whitman GJ, Banerjee A, White CW, Harken AH, and Repine JE.: Endotoxin pretreatment increases endogenous myocardial catalase ac- tivity and decreases ischemia-reperfusion injury of isolated rat hearts. Proc Natl Acad Sci U S A, 86, 2516-2520 (1989).
• Brown JM, White CW, Terada LS, Grosso MA, Shanley PF, Mulvin DW, Banerjee A, Whitman GJ, Harken AH, and Repine JE.: Interleukin-1 pretreatment decreases isch- emia/reperfusion injury. Proc Natl Acad Sci U S A., 87, 5026-5030 (1990).
• Hutter MM, Sievers RE, Barbosa V, and Wolfe CL.: Heat-shock protein induction in rat hearts. A direct correlation between the amount of heat-shock protein induced and the degree of myocardial protection. Circulation, 89, 355-360 (1994).
• Friedrich, I., Spiller, J., Lu, E., Bartling, B., Barnscheid, M., Sablotzki, A., Schade, U., Reidemeister, J.C., Silber, R.E., Gunther, A., Borgermann, J.: Ischemic pre-condition- ing of 5 minutes but not of 10 minutes improves lung function after warm ischemia in a canine model. J. Heart. Lung. Transplant, 20, 985-995 (2001).
• Soncul, H.,Öz, E., Kalaycıoğlu, S.: Role of ischemic preconditioning on ischemia-reper- fusion injury of the lung. Chest, 115, 1672-1677 (1999).
• Li, G., Chen, S., Lou, W., Lu, E.: Protective effects of ischemic preconditioning on donor lung in canine lung transplantation. Chest, 113, 1356-1359 (1998).
• McCormick PH, Chen G, Tlerney S, Kelly CJ, and Bouchier-Hayes DJ.: Clinically rel- evant thermal preconditioning attenuates ischemia-reperfusion injury. J Surg Res., 109, 24-30 (2003).
• Sartori C and Scherrer U.: Turning up the heat in the lungs. A key mechanism to pre- serve their function. Adv Exp Med Biol., 543, 263-275 (2003).
• Waldow T, Alexiou K, Witt W, Wagner FM, Gulielmos V, Matschke K, and Knaut M.: At- tenuation of reperfusion-induced systemic inflammation by preconditioning with nitric oxide in an in situ porcine model of normothermic lung ischemia. Chest, 125, 2253- 2259, (2004).
• Waldow T, Alexiou K, Witt W, Wagner FM, Kappert U, Knaut M, and Matschke K.: Protection of lung tissue against ischemia/reperfusion injury by preconditioning with inhaled nitric oxide in an in situ pig model of normothermic pulmonary ischemia. Nitric Oxide, 10, 195-201 (2004).
• Das KC and Misra HP.: Prevention of reperfusion lung injury by lidocaine in isolated rat lung ventilated with higher oxygen levels. J Postgrad Med., 49, 17-20 (2003).
• Bernardo, N.L., D’Angelo, M., Okubo, S., Joy, A., Kukreja, R.C.: Delayed ischemic pre- conditioning is mediated by opening of ATP-sensitive potassium channels in the rabbit heart. Am. J. Physiol., 276, H1323-H1330 (1999).
• Schulz, R., Rose, J., Heusch, G.: Involvement of activation of ATP-dependent potassium channels in ischemic preconditioning in swine. Am. J. Physiol., 267, H1341-H1352 (1994).
• Khimenko PL, Moore TM, and Taylor AE. ATP-sensitive K+ channels are not involved in ischemia-reperfusion lung endothelial injury. J Appl Physiol., 79, 554-559, (1995).
• Yamashita M, Schmid RA, Fujino S, Cooper JD, and Patterson GA. Nicorandil, a po- tent adenosine triphosphate-sensitive potassium-channel opener, ameliorates lung al- lograft reperfusion injury. J Thorac Cardiovasc Surg., 112, 1307-1314 (1996).
• Fukuse T, Hirata T, Omasa M, and Wada H.: Effect of adenosine triphosphate-sensitive potassium channel openers on lung preservation. Am J Respir Crit Care Med., 165, 1511-1515 (2002).
• Tang DG, Pavot DR, Mouria MM, Holwitt DM, and Cohen NM.: Warm ischemia lung protection with pinacidil: an ATP regulated potassium channel opener. Ann Thorac Surg., 76, 385-389; discussion, 389-390 (2003).
• Asemu G., Papoušek, F., Oštádal, B., Kolár, F.: Adaptation to altitude hypoxia protects the rat heart against ischemia-induced arrhythmias.Involment of mitochondrial KATP channel. J. Mol. Cell. Cardiol., 31, 1821-1831 (1999).
• Armstrong, S., Downey, J.M., Ganote, C.E.: Preconditioning of isolated rabbit cardio- myocytes:induction by metabolic stress and blockade by the adenosine antagonist SPT and calphostin C,a protein kinase C inhibitor. Cardiovasc. Res., 28, 72-77 (1994).
• de Perrot M, Liu M, Waddell TK, and Keshavjee S.: Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med., 167, 490-511 (2003).
• Clavien PA YS, Sindram D, Bentley RC.: Protective effects of ischemic preconditioning for liver resection performed under inflow occlusion in humans. Ann Surg., 232, 155- 162, (2000).
• Wu ZK, Tarkka MR, Eloranta J, Pehkonen E, Kaukinen L, Ehonkonen EL, Kaukinen S.: Effect of ischemic preconditioning on myocardial protection in coronery artery bypass graft patients: can the free radicals act as a trigger for ischemic preconditioning? Chest, 119,1061-1068 (2001).