Eritropoietinin MI Sonrası Karaciğer Dokusu Üzerinde Koruyucu Etkisi

Abstract

Amaç: Kardiyak hepatopati, kalp yetmezliğine bağlı olarak ortaya çıkar ve miyokard infarktüsü (MI) sonrası kalbin iyileşmesini etkiler. kalp dokusu iyileşmesi üzerinde etkileri bulunmaktadır. Bu çalışmanın amacı, MI nedeniyle iskemiye maruz kalan karaciğer dokusu üzerinde Eritropoetinin (EPO) koruyucu etkisinin araştırılmasıdır. Gereç ve Yöntemler: Sol ön inen koroner arter ligasyonu (KAL) ile deneysel MI oluşturuldu ve Kontrol, SF (serum fizyolojik), EPO 5000, EPO 10000, KAL+1s. olmak üzere beş grup sıçana KAL'dan hemen sonra EPO veya SF enjekte edildi: KAL+1s grubu KAL'dan bir saat sonra herhangi bir tedavi uygulanmadan sakrifiye edildi. Diğer gruplar, operasyondan altı saat sonra sakrifiye edildi. Karaciğer dokuları Hematoksilen Eozin (HE) boyama ve elektron mikroskobu ile histopatolojik olarak incelendi. Bulgular: Karaciğer dokusunda vakuolizasyon, sinüzoidal dilatasyon, hepatosit piknozu, Kuppfer hücre aktivasyonu gibi dejeneratif değişiklikler gözlendi. SF grubunda vakuolizasyon ve sinüzoidal dilatasyon Kontrol grubuna göre arttı (her ikisi için p=0,010). EPO 10000 grubunda piknotik çekirdekli dejenere hepatositler SF grubuna göre azalırken (p=0,009), ve aktive Kuppfer hücreleri SF ve KAL+1s gruplarına göre azaldı (sırasıyla p=0,035 ve p=0,019). Sonuç: EPO, MI sırasında meydana gelmesinden hemen sonra verildiğinde, dozdan bağımsız olarak karaciğer dokusunu histopatolojik hasarlanmadan korumuştur. Karaciğer ve kalbin karşılıklı etkileşimi göz önüne alındığında, MI hastalarına ilk görüşte EPO uygulanması, MI sonrası karaciğer hasarını önleyebilir ve kalbin iyileşmesine katkıda bulunabilir.

Keywords

• Kardiyak hepatopati
• eritropoietin
• iskemi
• karaciğer
• miyokard infarktüsü

Protective Effect of Erythropoietin on post-MI Liver Tissue

Abstract

Aim: Cardiac hepatopathy arises due to heart failure and influences has effects on heart recovery after myocardial infarction (MI).The aim of this study was to investigate the protective effect of Erythropoietin (EPO) on liver tissue exposed to ischemia due to MI. Material and Methods: Experimental MI was established by left anterior descending coronary artery ligation (CAL) and EPO or saline was injected immediately after CAL to five groups of rats, which groups are Control, Saline, EPO 5000, EPO 10000, CAL+1h. CAL+1h group was sacrificed one hour after CAL without any treatment. Other groups were sacrificed six hours after the operation. Liver tissues were examined histopathologically by Hematoxylin Eosin (HE) staining and electron microscopy. Results: Degenerative changes in liver tissue such as vacuolization, sinusoidal dilatation, hepatocyte pyknosis, Kuppfer cell activation were observed. Vacuolization, and sinusoidal dilatation increased in the Saline group compared to the control group (p=0.010 for both). Degenerated hepatocytes with pyknotic nuclei as well as activated Kuppfer cells were decreased in the EPO 10000 group compared to the Saline group (p=0.009), and activated Kupfer cells were decreased compared to the Saline and CAL+1h groups (p=0.035 and p=0.019, respectively). Conclusion: EPO protected liver tissue from histopathological damages regardless of dose, when given at the time of MI. EPO, when given immediately after MI, protected liver tissue from histopathological damage regardless of dose. Considering the mutual interaction of liver and heart, applying EPO to MI patients at first sight may prevent post-MI liver damage and contribute to the recovery of the heart.

Keywords

• Cardiac hepatopathy
• erythropoietin
• ischemia
• liver
• myocardial infarction

References

1. Correale M, Tarantino N, Petrucci R, Tricarico L, Laonigro I, Di Biase M, et al. Liver disease and heart failure: Back and forth. Eur J Intern Med. 2018; 48: 25-34.
2. Moller S, Bernardi M. Interactions of the heart and the liver. Eur Heart J. 2013; 34(36): 2804-11.
3. Hasanzadeh-Moghadam M, Khadem-Ansari MH, Farjah GH, Rasmi Y. Hepatoprotective effects of betaine on liver damages followed by myocardial infarction. Vet Res Forum. 2018; 9(2): 129-35.
4. Tang TT, Li YY, Li JJ, Wang K, Han Y, Dong WY, et al. Liver-heart crosstalk controls IL-22 activity in cardiac protection after myocardial infarction. Theranostics. 2018; 8(16): 4552-62.
5. Rahmathulla SBM, Maruthi E, Bheemewsaraiah K, Manjunatha S, Devi KL. Effect of Tribulus terrestris (L.) on liver in Isoproterenol-Induced Myocardial Infarction. Int J Res Biochem Biophy. 2012; 2(4): 10-2.
6. Sepodes B, Maio R, Pinto R, Sharples E, Oliveira P, McDonald M, et al. Recombinant human erythropoietin protects the liver from hepatic ischemia-reperfusion injury in the rat. Transpl Int. 2006; 19(11): 919-26.
7. Luo YH, Li ZD, Liu LX, Dong GH. Pretreatment with erythropoietin reduces hepatic ischemia-reperfusion injury. Hepatobiliary Pancreat Dis Int. 2009; 8(3): 294-9.
8. Shawky HM, Younan SM, Rashed LA, Shoukry H. Effect of recombinant erythropoietin on ischemia-reperfusion-induced apoptosis in rat liver. J Physiol Biochem. 2012; 68(1): 19-28.

9. Riehle KJ, Hoagland V, Benz W, Campbell JS, Liggitt DH, Langdale LA. Hepatocellular heme oxygenase-1: a potential mechanism of erythropoietin-mediated protection after liver ischemia-reperfusion injury. Shock. 2014; 42(5): 424-31.
10. Liu QS, Cheng ZW, Xiong JG, Cheng S, He XF, Li XC. Erythropoietin pretreatment exerts anti-inflammatory effects in hepatic ischemia/reperfusion-injured rats via suppression of the TLR2/NF-κB pathway. Transplant Proc. 2015; 47(2): 283-9.
11. Yilmaz S, Ates E, Tokyol C, Pehlivan T, Erkasap S, Koken T. The protective effect of erythropoietin on ischaemia/reperfusion injury of liver. HPB (Oxford). 2004; 6(3): 169-73.
12. Algin MC, Hacioglu A, Yaylak F, Gulcan E, Aydin T, Hacioglu BA, et al. The role of erythropoietin in hemorrhagic shock-induced liver and renal injury in rats. Adv Ther. 2008; 25(12): 1353-74.
13. Nandra KK, Collino M, Rogazzo M, Fantozzi R, Patel NS, Thiemermann C. Pharmacological preconditioning with erythropoietin attenuates the organ injury and dysfunction induced in a rat model of hemorrhagic shock. Dis Model Mech. 2013; 6(3): 701-9.
14. Liu FC, Chaudry IH, Yu HP. Hepatoprotective effects of corilagin following hemorrhagic shock are through Akt-dependent pathway. Shock. 2017; 47(3): 346-51.
15. Lombardero M, Kovacs K, Scheithauer BW. Erythropoietin: a hormone with multiple functions. Pathobiology. 2011; 78(1): 41-53.
16. Parsa CJ, Matsumoto A, Kim J, Riel RU, Pascal LS, Walton GB, et al. A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest. 2003; 112(7): 999-1007.
17. Lipsic E, Schoemaker RG, van der Meer P, Voors AA, van Veldhuisen DJ, van Gilst WH. Protective effects of erythropoietin in cardiac ischemia: from bench to bedside. J Am Coll Cardiol. 2006; 48(11): 2161-7.
18. Patel NS, Sharples EJ, Cuzzocrea S, Chatterjee PK, Britti D, Yaqoob MM, et al. Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo. Kidney Int. 2004; 66(3): 983-9.
19. Sharples EJ, Patel N, Brown P, Stewart K, Mota-Philipe H, Sheaff M, et al. Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol. 2004; 15(8): 2115-24.
20. Vesey DA, Cheung C, Pat B, Endre Z, Gobe G, Johnson DW. Erythropoietin protects against ischaemic acute renal injury. Nephrol Dial Transplant. 2004; 19(2): 348-55.
21. Guven Bagla A, Ercan E, Asgun HF, Ickin M, Ercan F, Yavuz O, et al. Experimental acute myocardial infarction in rats: HIF-1α, caspase-3, erythropoietin and erythropoietin receptor expression and the cardioprotective effects of two different erythropoietin doses. Acta Histochem. 2013; 115(7): 658-68.
22. Güven Bağla A, Içkin Gülen M, Ercan F, Aşgün F, Ercan E, Bakar C. Changes in kidney tissue and effects of erythropoietin after acute heart failure. Biotech Histochem. 2018; 93(5): 340-53.
23. Lambers Heerspink HJ, de Zeeuw D. Novel drugs and intervention strategies for the treatment of chronic kidney disease. Br J Clin Pharmacol. 2013; 76(4): 536-50.
24. Schmeding M, Hunold G, Ariyakhagorn V, Rademacher S, Boas-Knoop S, Lippert S, et al. Erythropoietin reduces ischemia-reperfusion injury after liver transplantation in rats. Transpl Int. 2009; 22(7): 738-46.
25. Ben-Dor I, Hardy B, Fuchs S, Kaganovsky E, Kadmon E, Sagie A, et al.Repeated low-dose of erythropoietin is associated with improved left ventricular function in rat acute myocardial infarction model. Cardiovasc Drugs Ther. 2007; 21(5): 339-46.
26. Fang H, Liu A, Sun J, Kitz A, Dirsch O, Dahmen U. Granulocyte colony stimulating factor induces lipopolysaccharide (LPS) sensitization via upregulation of LPS binding protein in rat. PLoS One. 2013; 8(2): e56654.
27. Matheson PJ, Fernandez-Botran R, Smith JW, Matheson SA, Downard CD, McClain CJ, et al. Association between MC-2 peptide and hepatic perfusion and liver injury following resuscitated hemorrhagic shock. JAMA Surg. 2016; 151(3): 265-72.
28. Zhang Y, Yi W, Yao J, Yu X, Qian C, Hu Z. Hypoxia serves a key function in the upregulated expression of vascular adhesion protein 1 in vitro and in a rat model of hemorrhagic shock. Mol Med Rep. 2017; 16(2): 1189-99.
29. Aydın B, Eren Z. The effects of Aspirin and vitamin E on blood antioxidant enzymes of rats during experimental liver ischemia-reperfusion. J.appl.biol.sci. 2007; 1(1): 51-6.
30. Shaqura M, Mohamed DM, Aboryag NB, Bedewi L, Dehe L, Treskatsch S, et al. Pathological alterations in liver injury following congestive heart failure induced by volume overload in rats. PLoS One. 2017; 12(9): e0184161.
31. Akıncı O, Durgun V, Kepil N, Ergun S, Tosun Y, Goksoy E. The role of genistein in experimental hepatic ischemia‒ reperfusion model in rats, Bratisl Med J 2019; 120(8): 558-62.
32. Deng WS, Xu Q, Liu YE, Jiang CH, Zhou H, Gu L. Effects of melatonin on liver function and lipid peroxidation in a rat model of hepatic ischemia/reperfusion injury. Exp Ther Med. 2016; 11(5): 1955-60.
33. Zhang Y, Fang XM. Hepatocardiac or cardiohepatic interaction: from traditional Chinese medicine to western medicine. Evid Based Complement Alternat Med. 2021; 2021: 6655335.
34. Liu Y, Verma VK, Malhi H, Gores GJ, Kamath PS, Sanyal A, et al. Lipopolysaccharide downregulates macrophage-derived IL-22 to modulate alcohol-induced hepatocyte cell death. Am J Physiol Cell Physiol. 2017; 313(3): C305-13.