İRBESARTAN LİPOPOLİSAKARİT TARAFINDAN İNDÜKLENEN KARACİĞER HASARINI, TOPLAM OKSİDAN DURUMU, İNTERLÖKİN-1B VE KASPAZ-3 SEVİYELERİNİN İNHİBİSYONU YOLUYLA AZALTIR

Abstract

Amaç Septik koşullarda hiperinflamatuar yanıta ve hepatotoksisiteye; oksidatif stres, inflamasyon ve apoptoz neden olur. Bir adrenerjik reseptör blokeri olan irbesartan (IB), antiinflamatuar ve antioksidan özelliklere sahiptir. Bu çalışmada, IB'nin lipopolisakkarit (LPS) kaynaklı akut hepatotoksisite üzerindeki koruyucu etkisinin araştırılması amaçlandı. Gereç ve Yöntem Üç grupta toplam sekiz sıçan kullanıldı; kontrol grubu, LPS grubu [5 mg/kg, intraperitoneal (IP)]; ve LPS + IB grubu [5 mg/kg LPS (IP) + 50 mg/kg IB (oral)]. Sakrifikasyondan sonra interlökin-1 beta (IL-1β), kaspaz- 3 (Cas-3) alanin aminotransferaz (ALT), aspartat aminotransferaz (AST), oksidatif stres indeksi (OSI), toplam oksidan durumu (TOS) ve toplam antioksidan durumu (TAS) gibi immünohistokimyasal ve biyokimyasal değerlendirmeler için karaciğer ve kandan dokular alındı. Bulgular Kontrol grubuyla karşılaştırıldığında kanda AST ve ALT düzeylerinde artış, biyokimyasal olarak dokuda TOS ve OSI düzeyinde artış ve TAS düzeyinde azalma, immünohistokimyasal olarak IL-1β, Cas-3 düzeyinde artış tespit edildi. Ayrıca LPS grubunda karaciğer dokusunda histopatolojik olarak hiperemi, kanama, vakuolizasyon ve belirgin nötrofil infiltrasyonu saptandı. IB tüm bu bulguları tersine çevirdi. IB uygulaması ile TAS seviyeleri yükselirken, TOS ve OSI seviyeleri azaldı (p = 0.001). IB ayrıca AST ve ALT değerlerini de düşürdü (p = 0.001). IB grubunda, Cas-3 ve IL-1β seviyeleri, IB uygulamasıyla önemli ölçüde azaldı (p = 0.001). Ek olarak, IB, artmış hiperemi, kanama, vakuolizasyon ve önemli nötrofilik lökosit infiltrasyon gibi histopatolojik bulguları iyileştirdi (p = 0.001). IB tedavisi, antioksidan, antienflamatuar ve antiapoptotik özellikleriyle LPS'nin neden olduğu hepatotoksisiteyi zayıflattı. Sonuç Karaciğer hasarını hafifletmek ve karaciğer fonksiyonunu eski haline getirmek sepsisli hastalarda morbi- dite ve mortalite oranlarını düşürür. IB, antioksidan, antiinflamatuar ve antiapoptotik özellikleri sayesinde karaciğer dokusunu LPS'nin neden olduğu hepatotoksisiteden korur. Karaciğerin sepsisteki rolünün daha fazla araştırılması, yeni terapötik hedeflerin ve stratejilerin geliştirilmesine yol açabilir. IB, sepsis sırasında akut hepatotoksisitenin önlenmesi için alternatif bir terapötik ajan olabilir.

Keywords

• Sepsis
• irbesartan
• inflamasyon
• hepatotoksisite
• oksidatif stres
• apoptoz

IRBESARTAN REDUCES LIVER DAMAGE INDUCED BY LIPOPOLYSACCHARIDE VIA INHIBITION OF TOTAL OXIDANT STATUS, INTERLEUKIN-1B AND CASPASE-3 LEVELS

Abstract

Objective In septic conditions, hyperinflammatory response and hepatotoxicity are caused by oxidative stress, inflammation, and apoptosis. Irbesartan (IB), an adrenergic receptor blocker, has anti-inflammatory and antioxidant properties. This study aimed to investigate the protective effect of IB on lipopolysaccharide (LPS)- induced acute hepatotoxicity. Material and Method A total of eight rats were used in three groups; a control group; LPS group [5 mg/kg, intraperitoneally (IP)]; and LPS + IB group [5 mg/kg LPS (IP) + 50 mg/kg IB (orally)]. After sacrification, tissues from the liver and blood were obtained for immunohistochemical and biochemical evaluations, such as interleukin-1 beta (IL-1β), caspase-3 (Cas-3) alanine aminotransferase (ALT), aspartate aminotransferase (AST), oxidative stress index (OSI), total oxidant status (TOS), and total antioxidant status (TAS). Results Compared with the control group, increased AST and ALT levels in the blood, biochemically increased TOS and OSI and decreased TAS levels in the tissue, immunohistochemically increased IL-1β, Cas- 3, detected. Also, in liver tissue, histopathologically hyperemia, hemorrhage, vacuolization, and significant neutrophilia infiltration were found in the LPS group. IB administration significantly reversed all these parameters. TAS levels were increased by IB administration, whereas TOS and OSI levels were decreased (p = 0.001). IB also decreased AST and ALT values (p = 0.001). In the IB group, Cas-3 and IL-1β levels were significantly decreased by IB administration (p = 0.001). In addition, the IB ameliorated histopathological findings showed enhanced hyperaemia, haemorrhages, vacuolisation and significant neutrophilic leukocyte infiltration (p = 0.001). IB treatment attenuated LPS-induced hepatotoxicity by its antioxidant, anti-inflammatory and antiapoptotic properties. Conclusion Attenuating liver injury and restoring liver function lowers morbidity and mortality rates in patients with sepsis. IB protects liver tissue from hepatotoxicity caused by LPS thanks to its antioxidant, anti-inflammatory, and anti-apoptotic properties. Further investigation of the liver’s role in sepsis may lead to the development of new therapeutic targets and strategies. IB may be an alternative therapeutic agent for the prevention of acute hepatotoxicity during sepsis.

Keywords

• Apoptosis
• Hepatotoxicity
• Irbesartan
• Inflammation
• Oxidative stress
• Sepsis

References

1. 1. de Pádua Lúcio K, Rabelo ACS, Araújo CM, Brandão GC, de Souza GHB, da Silva RG, et al. Anti-Inflammatory and Antioxidant Properties of Black Mulberry (Morus nigra L.) in a Model of LPSS-Induced Sepsis. Oxid Med Cell Longev 2018;2018:5048031.
2. 2. Pool R, Gomez H, Kellum JA. Mechanisms of Organ Dysfunction in Sepsis. Crit Care Clin 2018;34(1):63-80.
3. 3. Usmani J, Khan T, Ahmad R, Sharma M. Potential role of herbal medicines as a novel approach in sepsis treatment. Biomed Pharmacother 2021;144:112337.
4. 4. Al-Tawfiq JA, Alhumaid S, Alshukairi AN, Temsah MH, Barry M, Al Mutair A et al. COVID-19 and mucormycosis superinfection: the perfect storm. Infection 2021;49(5):833-53.
5. 5. Berton AM, Prencipe N, Giordano R, Ghigo E, Grottoli S. Systemic steroids in patients with COVID-19: pros and contras, an endocrinological point of view. J Endocrinol Invest 2021;44(4):873-75.
6. 6. Brenner C, Galluzzi L, Kepp O, Kroemer G. Decoding cell death signals in liver inflammation. J Hepatol. 2013;59(3):583-94.
7. 7. Savran M, Aslankoc R, Ozmen O, Erzurumlu Y, Savas HB, Temel EN et al. Agomelatine could prevent brain and cerebellum injury against LPSS-induced neuroinflammation in rats. Cytokine 2020;127:154957.
8. 8. Nemzek JA, Hugunin KM, Opp MR. Modeling sepsis in the laboratory: merging sound science with animal well-being. Comp Med 2008;58(2):120-28.

9. 9. Park BS, Lee JO. Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp Mol Med 2013;45(12):e66.
10. 10. Gialama F, Maniadakis N. Comprehensive overview: efficacy, tolerability, and cost-effectiveness of irbesartan. Vasc Health Risk Manag 2013;9:575-92.
11. 11. Al-Kuraishy HM, Al-Gareeb AI, Al-Naimi MS. Renoprotective effect of irbesartan in a rat model of gentamicin-induced nephrotoxicity: Role of oxidative stress. J Lab Physicians. 2019;11(3):200-05.
12. 12. Chen C, Li L, Qin H, Huang Z, Xian J, Cai J et al. Effects of Irbesartan Pretreatment on Pancreatic β-Cell Apoptosis in STZ-Induced Acute Prediabetic Mice. Oxid Med Cell Longev. 2018;2018:8616194.
13. 13. Kumar VV, Srinivas NR. Application of allometry principles for the prediction of human pharmacokinetic parameters for irbesartan, a AT1 receptor antagonist, from animal data. Eur J Drug Metab Pharmacokinet 2008;33(4):247-52.
14. 14. Husain A, Md Mitra, S. A. M, Bhasin, P. S. A. review of pharmacological and pharmaceutical profile of irbesartan. Pharmacophore. 2011; 2(6): 276-86.
15. 15. Ilhan I, Asci H, Tepebasi MY, Imeci OB, Sevuk MA, Temel EN et al. Selenium exerts protective effects on inflammatory cardiovascular damage: molecular aspects via SIRT1/p53 and Cyt-c/Cas-3 pathways. Mol Biol Rep. 2023;50(2):1627-37.
16. 16. Fang H, Liu A, Sun J, Kitz A, Dirsch O, Dahmen U. Granulocyte colony stimulating factor induces lipopolysaccharide (LPSS) sensitization via upregulation of LPSS binding protein in rat. PLoS One. 2013;8(2):e56654.
17. 17. Ozdamar Unal G, Asci H, Erzurumlu Y, Ilhan I, Hasseyid N, Ozmen O. Dexpanthenol may protect the brain against lipopolysaccharide induced neuroinflammation via anti-oxidant action and regulating CREB/BDNF signaling. Immunopharmacol Immunotoxicol 2022;44(2):186-93.
18. 18. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193(1):265-75.
19. 19. Altindag O, Erel O, Soran N, Celik H, Selek S. Total oxidative/ anti-oxidative status and relation to bone mineral density in osteoporosis. Rheumatol Int 2008;28(4):317-21.
20. 20. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004;37(4):277-85.
21. 21. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005;38(12):1103-11.
22. 22. Strnad P, Tacke F, Koch A, Trautwein C. Liver - guardian, modifier and target of sepsis. Nat Rev Gastroenterol Hepatol. 2017;14(1):55-66.
23. 23. Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol 2017;27(21): R1147-R1151.
24. 24. Cheng ML, Nakib D, Perciani CT, MacParland SA. The immune niche of the liver. Clin Sci 2021;135(20):2445-66.
25. 25. Kim TS, Choi DH. Liver Dysfunction in Sepsis. Korean J Gastroenterol. 2020;75(4):182-87.
26. 26. Yan J, Li S, Li S. The role of the liver in sepsis. Int Rev Immunol 2014;33(6):498-510.
27. 27. Killilea M, Kerr DM, Mallard BM, Roche M, Wheatley AM. Exacerbated LPSS/GalN-Induced Liver Injury in the Stress-Sensitive Wistar Kyoto Rat Is Associated with Changes in the Endocannabinoid System. Molecules 2020;25(17):3834.
28. 28. Cichoż-Lach H, Michalak A. Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol. 2014;20(25):8082-91.
29. 29. Hsiao SY, Kung CT, Su CM, et al. Impact of oxidative stress on treatment outcomes in adult patients with sepsis: A prospective study. Medicine 2020;99(26):e20872.
30. 30. Hussain T, Tan B, Yin Y, Blachier F, Tossou MC, Rahu N. Oxidative Stress and Inflammation: What Polyphenols Can Do for Us? Oxid Med Cell Longev. 2016;2016:7432797.
31. 31. Zhang X, Wu X, Hu Q, Wu J, Wang G, Hong Z et al. Mitochondrial DNA in liver inflammation and oxidative stress. Life Sci 2019;236:116464.
32. 32. Islas MS, Luengo A, Franca CA, Merino MG, Calleros L, Rodriguez-Puyol M, et al. Experimental and DFT characterization, antioxidant and anticancer activities of a Cu(II)-irbesartan complex: structure-antihypertensive activity relationships in Cu(II)-sartan complexes. J Biol Inorg Chem 2016;21: 851e63.
33. 33. Vurmaz A, Atay E. Antioxidant effects of piperine on steroid- induced hepatotoxicity. Eur Rev Med Pharmacol Sci 2021;25(17):5500-06.
34. 34. Helal MG, Samra YA. Irbesartan mitigates acute liver injury, oxidative stress, and apoptosis induced by acetaminophen in mice (published correction appears in J Biochem Mol Toxicol. 2021 Jun;35(6):1). J Biochem Mol Toxicol 2020;34(12):e22447.
35. 35. Kabel AM, Alzahrani AA, Bawazir NM, Khawtani RO, Arab HH. Targeting the proinflammatory cytokines, oxidative stress, apoptosis and TGF-β1/STAT-3 signaling by irbesartan to ameliorate doxorubicin-induced hepatotoxicity. J Infect Chemother. 2018;24(8):623-31.
36. 36. Sookoian S, Pirola CJ. Liver enzymes, metabolomics and genome-wide association studies: from systems biology to the personalized medicine. World J Gastroenterol 2015;21(3):711-25.
37. 37. Xiong X, Ren Y, Cui Y, Li R, Wang C, Zhang Y. Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation. Biomed Pharmacother 2017;96: 1292-98.
38. 38. Hafez HM, Ibrahim MA, Ibrahim SA, Amin EF, Goma W, Abdelrahman AM. Potential protective effect of etanercept and aminoguanidine in methotrexate-induced hepatotoxicity and nephrotoxicity in rats. Eur J Pharmacol 2015;768:1-12.
39. 39. Beheshti F, Hosseini M, Taheri Sarvtin M, Kamali A, Anaeigoudari A. Protective effect of aminoguanidine against lipopolysaccharide-induced hepatotoxicity and liver dysfunction in rat. Drug Chem Toxicol 2021;44(2):215-21.
40. 40. Shih RH, Wang CY, Yang CM. NF-kappaB Signaling Pathways in Neurological Inflammation: A Mini Review. Front Mol Neurosci. 2015;8:77.
41. 41. Ding B, Geng S, Hou X, Ma X, Xu H, Yang F et al. Reduces Renal Cell Pyroptosis in Golden Hamsters with Diabetic Nephropathy through the Nrf2-NLRP3-Caspase-1-GSDMD Pathway (published correction appears in Evid Based Complement Alternat Med. 2022 May 14;2022:9828973). Evid Based Complement Alternat Med 2021;2021:5545193.
42. 42. Raheem KA, Abu-Raghif AR, Shaymaa Z. Abd-alakhwa SZ. Irbesartan Attenuates Sepsis-Induced Renal Injury In Mice Models. Journal of Pharmaceutical Negative Results 2022;13:662-69.
43. 43. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 2014;20(7):1126-67.
44. 44. Feng Y, Cui R, Li Z, Zhang X, Jia Y, Zhang X, et al. Feng Y, Cui R, Li Z et al. Methane Alleviates Acetaminophen-Induced Liver Injury by Inhibiting Inflammation, Oxidative Stress, Endoplasmic Reticulum Stress, and Apoptosis through the Nrf2/HO-1/NQO1 Signaling Pathway. Oxid Med Cell Longev 2019;2019:7067619.
45. 45. Li R, Yang W, Yin Y, Zhang P, Wang Y, Tao K. Protective Role of 4-Octyl Itaconate in Murine LPSS/D-GalN-Induced Acute Liver Failure via Inhibiting Inflammation, Oxidative Stress, and Apoptosis. Oxid Med Cell Longev 2021;2021:9932099.
46. 46. Mantzarlis K, Tsolaki V, Zakynthinos E. Role of Oxidative Stress and Mitochondrial Dysfunction in Sepsis and Potential Therapies. Oxid Med Cell Longev 2017;2017:5985209.
47. 47. Bolívar BE, Vogel TP, Bouchier-Hayes L. Inflammatory caspase regulation: maintaining balance between inflammation and cell death in health and disease. FEBS J 2019;286(14):2628-44.
48. 48. Zhao Y, Watanabe A, Zhao S, Kobayashi T, Fukao K, Tanaka Y. Suppressive effects of irbesartan on inflammation and apoptosis in atherosclerotic plaques of apoE-/- mice: molecular imaging with 14C-FDG and 99mTc-annexin A5. PLoS One. 2014;9(2):e89338
49. 49. Matsui T, Yamagishi S, Takeuchi M, Ueda S, Fukami K, Okuda S. Irbesartan inhibits advanced glycation end product (AGE)-induced proximal tubular cell injury in vitro by suppressing receptor for AGEs (RAGE) expression. Pharmacol Res 2010;61:34e9.
50. 50. Kikuchi K, Tancharoen S, Ito T, Morimoto-Yamashita Y, Miura N, Kawahara K, et al. Potential of the angiotensin receptor blockers (ARBs) telmisartan, irbesartan, and candesartan for inhibiting the HMGB1/RAGE axis in prevention and acute treatment of stroke. Int J Mol Sci 2013;14:18899e924.
51. 51. Woźnica EA, Inglot M, Woźnica RK, Łysenko L. Liver dysfunction in sepsis. Adv Clin Exp Med. 2018;27(4):547-51.
52. 52. Koskinas J, Gomatos IP, Tiniakos DG, Memos N, Boutsikou M, Garatzioti A et al. Liver histology in ICU patients dying from sepsis: a clinico-pathological study. World J Gastroenterol 2008;14(9):1389–93.
53. 53. Ibrahim MA, Amin EF, Ibrahim SA, Abdelzaher WY, Abdelrahman AM. Montelukast and irbesartan ameliorate metabolic and hepatic disorders in fructose-induced metabolic syndrome in rats. Eur J Pharmacol 2014;724:204-10.