Panthotenic Acid Derrivate Dexpanthenol Mitigates the Effects of Lung Ischemia-Reperfusion Induced Cardiac Damage by its Anti-Inflammatory Action

Year 2025, Volume: 32 Issue: 1, 73 - 80, 27.03.2025

Mehtap Savran , Melih Arlıoğlu , Özlem Özmen

Abstract

Objective: Pulmonary ischemia-reperfusion (IR) injury causes cardiac damage through inflammation related to hypoxic conditions. Dexpanthenol (DEX) has an anti-inflammatory action in various tissues such as lung, liver, and kidney. This study aimed to show the effects of DEX on myocardial damage secondary to pulmonary IR injury.
Material and Method: Thirty two rats were randomly divided into four groups as sham, IR, DEX (500 mg/kg, intraperitoneally, single dose), and IR+DEX. After left thoracotomy, non-traumatic vascular clamping was applied for 60 minutes, followed by 60 minutes of reperfusion to create a lung IR model. After sacrification, heart tissues were collected and placed in formaldehyde solution for histopathological and immunohistochemical analyses. Hyperemia, hemorrhage, and degeneration were examined, Immunostainings of cyclooxygenase-1 (COX-1), hypoxia-inducible factor 2 alpha (HIF-2α), and interferon alpha (IFα) were performed.
Results: Cardiomyocytes in the sham group appeared elongated, branching, and of normal size with well-defined intercalated discs. Delicate endomysium sheaths surrounding the cardiac cells were observed, along with a dense capillary network surrounding the cells. In contrast, the IR group exhibited alterations in cardiac tissue, including hyperemia, hemorrhage, and disruption of the cross-striated banding pattern of the cardiac cells. Also; COX-1, EPAS-1/HIF-2α, and IFα expressions were elevated in the IR group. Treatment with DEX resulted in a reduction of these pathological outcomes.
Conclusions: In the context of pulmonary IR, damage is likely to occur not only in lung tissue but also in other organs. This is attributed to the dissemination of immunomodulatory cytokines developed within the tissue to other organs through the bloodstream. DEX is a derivative of pantothenic acid, recognized for its tissue-protective effects. In this study, it was histopathologically and immunohistochemically shown that DEX could be protective against lung IR-induced cardiac damage.

Keywords

Cardiac damage, Dexpanthenol, Ischemia-reperfusion, Lung ischemia

Ethical Statement

The experimental design adhered to the guidelines for animal research set forth by the National Institutes of Health, and received approval from the Committee on Animal Research at Suleyman Demirel University prior to commencement of the study (approval no: 11.07.2024/08-309).

Supporting Institution

This study was supported by the Scientific Research Projects Coordination Unit of Suleyman Demirel University with project code TSG- 2023-9010.

Project Number

TSG- 2023-9010

Thanks

This study was supported by the Scientific Research Projects Coordination Unit of Suleyman Demirel University with project code TSG- 2023-9010.

References

• 1. Wu NC, Chen TH, Yang YC, et al. N-acetylcysteine improves cardiac contractility and ameliorates myocardial injury in a rat model of lung ischemia and reperfusion injury. Transplant Proc 2013;45(10):3550–4.
• 2. Ye X, Pei F, Li W, Xue J, Huang X, Huang J, Zhang L. Fibroblast growth factor 21 attenuates pulmonary ischemia/reperfusion injury via inhibiting endoplasmic reticulum stress-induced ferroptosis though FGFR1/PPARδ signaling pathway. Int Immunopharmacol 2024;25;143(Pt 1):113307. doi: 10.1016/j.intimp.2024.113307. Epub 2024 Oct 3. PMID: 39366074.
• 3. den Hengst WA, Gielis JF, Lin JY, Van Schil PE, De Windt LJ, Moens AL. Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process. Am J Physiol Heart Circ Physiol 2010;299(5):H1283-99. doi: 10.1152/ajpheart.00251.2010. Epub 2010 Sep 10. PMID: 20833966.
• 4. Laubach VE, Sharma AK. Mechanisms of lung ischemia-reperfusion injury. Curr Opin Organ Transplant 2016;21(3):246-52. doi: 10.1097/MOT.0000000000000304. PMID: 26945320; PMCID: PMC4861054.
• 5. Dutta T, Frishman WH, Aronow WS. Echocardiography in the evaluation of pulmonary embolism. Cardiol Rev 2017;25(6):309–14.
• 6. Chen-Yoshikawa TF. Ischemia-reperfusion ınjury in lung transplantation. Cells 2021;10(6).
• 7. McDonough A, Lee RV, Noor S, et al. Ischemia/reperfusion ınduces ınterferon-stimulated gene expression in microglia. J Neurosci 2017;37(34):8292–308.
• 8. Kubes P, Jutila M, Payne D. Therapeutic potential of inhibiting leukocyte rolling in ischemia/reperfusion. J Clin Invest 1995;95(6):2510–9.
• 9. Pillai R, Bando K, Schueler S, et al. Leukocyte depletion results in excellent heart-lung function after 12 hours of storage. Ann Thorac Surg 1990;50(2):211–4.
• 10. Asimakopoulos G, Smith PL, Ratnatunga CP, et al. Lung injury and acute respiratory distress syndrome after cardiopulmonary bypass. Ann Thorac Surg 1999;68(3):1107–15.
• 11. Ullah K, Ai L, Humayun Z, Wu R. Targeting endothelial HIF2α/ARNT expression for ıschemic heart disease therapy. Biology 2023;12(7).
• 12. Yu T, Lao X, Zheng H. Influencing COX-2 Activity by COX related pathways in ınflammation and cancer. Mini Rev Med Chem 2016;16(15):1230–43.
• 13. Bilister Egilmez C, Azak Pazarlar B, Erdogan MA, Erbas O. Neuroprotective effect of dexpanthenol on rotenone-induced Parkinson's disease model in rats. Neurosci Lett 2024;818:137575. doi: 10.1016/j.neulet.2023.137575. Epub 2023 Nov 29. PMID: 38040406.
• 14. Gürler M, Selçuk EB, Özerol BG, Tanbek K, Taşlıdere E, Yıldız A, Yağın FH, Gürel E. Protective effect of dexpanthenol against methotrexate-induced liver oxidative toxicity in rats. Drug Chem Toxicol 2023;46(4):708-716. doi: 10.1080/01480545.2022.2084103. Epub 2022 Jun 2. PMID: 35655424.
• 15. Erdogan MA, Yigitturk G, Erbas O, et al. Neuroprotective effects of dexpanthenol on streptozotocin-induced neuronal damage in rats. Drug Chem Toxicol 2022;45(5):2160–8.
• 16. Ucar M, Aydogan MS, Vardı N, et al. Protective effect of dexpanthenol on ischemia-reperfusion-induced liver injury. Transplant Proc. 2018;50(10):3135–43.
• 17. Tepebaşı MY, Büyükbayram Hİ, Özmen Ö, et al. Dexpanthenol ameliorates doxorubicin-induced lung injury by regulating endoplasmic reticulum stress and apoptosis. Naunyn Schmiedebergs Arch Pharmacol 2023;396(8):1837–45.
• 18. Zhao X, Zhang S, Shao H. Dexpanthenol attenuates inflammatory damage and apoptosis in kidney and liver tissues of septic mice. Bioengineered 2022;13(5):11625–35.
• 19. Ozcan MS, Savran M, Kumbul Doguc D, Kubra Dogan H, Altintas M, Cosan S. Dexpanthenol ameliorates lipopolysaccharide-induced cardiovascular toxicity by regulating the IL-6/HIF1α/VEGF pathway. Heliyon 2024;10(1):e24007. doi: 10.1016/j.heliyon.2024.e24007. PMID: 38268590; PMCID: PMC10806266.
• 20. Kalkan F, Parlakpinar H, Disli OM, Tanriverdi LH, Ozhan O, Polat A, Cetin A, Vardi N, Otlu YO, Acet A. Protective and therapeutic effects of dexpanthenol on isoproterenol-induced cardiac damage in rats. J Cell Biochem 2018;119(9):7479-7489. doi: 10.1002/jcb.27058. Epub 2018 May 18. PMID: 29775243.
• 21. Aydın A, Sönmez MG, Ecer G, Kılınç F, Kocabaş R, Atılgan AE, Oltulu P, Balasar M. The effect of intratesticular dexpanthenol on experimentally-induced testicular ischaemia/reperfusion injury. J Pediatr Urol 2021;17(4):440.e1-440.e7. doi: 10.1016/j.jpurol.2021.03.031. Epub 2021 Apr 8. PMID: 33883095.
• 22. Zakaria MM, Hajipour B, Khodadadi A, Afshari F. Ameliorating effects of dexpanthenol in cerebral ischaemia reperfusion induced injury in rat brain. J Pak Med Assoc 2011;61(9):889-92. PMID: 22360030.
• 23. Tepebaşi MY, Aşci H, Coşan S, Sevük MA, Karakuyu NF, Özmen Ö. Irbesartan has a curative effect on lipopolysaccharide-induced cardiotoxicity by antioxidant and antiapoptotic pathways. Rev Port Cardiol 2023;42(11):895-903. English, Portuguese. doi: 10.1016/j.repc.2023.03.018. Epub 2023 Jun 27. PMID: 37385588.
• 24. Katira BH, Giesinger RE, Engelberts D, et al. Adverse Heart-lung ınteractions in ventilator-induced lung injury. Am J Respir Crit Care Med 2017;196(11):1411–21.
• 25. Herrmann J. Adverse cardiac effects of cancer therapies: Cardiotoxicity and arrhythmia. Nat Rev Cardiol 2020;17(8):474–502.
• 26. Peretto G, Sala S, Rizzo S, et al. Arrhythmias in myocarditis: State of the art. Heart Rhythm 2019;16(5):793–801.
• 27. Taylor CT, Scholz CC. The effect of HIF on metabolism and immunity. Nat Rev Nephrol 2022 Sep;18(9):573-587. doi: 10.1038/s41581-022-00587-8. Epub 2022 Jun 20. PMID: 35726016; PMCID: PMC9208707.
• 28. Kapitsinou PP, Sano H, Michael M, et al. Endothelial HIF-2 mediates protection and recovery from ischemic kidney injury. J Clin Invest 2014;124(6):2396–409.
• 29. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 2010;40(2):294-309. doi: 10.1016/j.molcel.2010.09.022. PMID: 20965423; PMCID: PMC3143508.
• 30. Simon LS. Role and regulation of cyclooxygenase-2 during inflammation. Am J Med 1999;31;106(5B):37S-42S. doi: 10.1016/s0002-9343(99)00115-1. PMID: 10390126.
• 31. Feitoza CQ, Câmara NO, Pinheiro HS, Gonçalves GM, Cenedeze MA, Pacheco-Silva A, Santos OF. Cyclooxygenase 1 and/or 2 blockade ameliorates the renal tissue damage triggered by ischemia and reperfusion injury. Int Immunopharmacol 2005;5(1):79-84. doi: 10.1016/j.intimp.2004.09.024. PMID: 15589463.
• 32. Félétou M, Huang Y, Vanhoutte PM. Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol 2011;164(3):894–912.
• 33. Vanhoutte PM. COX-1 and vascular disease. Clin Pharmacol Ther 2009;86(2):212–5.
• 34. Graupera M, García-Pagán JC, Parés M, et al. Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers. J Hepatol 2003;39(4):515–21.
• 35. Ji L, Li T, Chen H, et al. The crucial regulatory role of type I interferon in inflammatory diseases. Cell Biosci 2023;13(1):230.