Nrf2 inhibitörü Brusatol, sıçanlarda anti-inflamasyon ve anti-oksidatif stres yoluyla çekal ligasyonu ve delinmeye bağlı akciğer hasarını iyileştirir

Yıl 2020, Cilt: 77 Sayı: 4, 467 - 476, 01.12.2020

Ersen Eraslan Ayhan Tanyeli Mustafa Can Güler Fazile Nur Ekinci Akdemir Tuncer Nacar Ömer Topdağı Elif Polat

Öz

Amaç: Bu çalışmanın amacı, brusatolün sıçanlarda çekal ligasyon ve delinme CLD modelinin neden olduğu akciğer hasarı üzerine olası yararlı etkilerinin incelenmesidir.Yöntem: Bu çalışmada 32 adet Sprague Dawley erkek sıçan 4 rastgele gruba ayrıldı. Gruplar; grup 1 sham , grup 2 CLD , grup 3 DMSO ve grup 4 0.5 mg/ml brusatol olarak programlandı. Grup 1’de karın bölgesine orta hatta dikey insizyon uygulandı ve CLD modeli oluşturmadan tekrar kapatıldı. Grup 2’de 18 saat CLD yapıldı. Grup 3’e, %1 DMSO 10 gün boyunca iki günde bir periton içine 0.3 ml uygulandı. Son uygulama CLD’den 30 dakika önce yapıldı. Grup 4’e brusatol 10 gün boyunca iki günde bir periton içine 0.5 mg/ml olarak uygulandı. Son uygulama CLD’den 30 dakika önce yapıldı. CLD bittikten sonra sıçanlar sakrifiye edildi ve akciğer dokuları çıkarıldı. Bulgular: MDA, MPO, OSI, TOS, TNF-α ve IL-1β değerleri grup 2 ve 3’te, grup 1’e kıyasla anlamlı derecede yükselirken, SOD ve TAS değerleri azaldı. Antioksidan enzim aktivitesindeki artışın aksine; MDA seviyesi, MPO aktivitesi, TOS, OSI, TNF-α ve IL-1β değerleri grup 4’te grup 2 ve 3’e göre önemli ölçüde azaldı. Sonuç: Sıçanlarda CLD kaynaklı akciğer hasarına karşı brusatol etkin rol oynayabilir

Anahtar Kelimeler

Brusatol, oksidatif stres, sitokin, çekal ligasyon ve delinme, akciğer

Nrf2 Inhibitor Brusatol Ameliorates Cecal Ligation and Puncture-induced Lung Injury in Rats via Anti-inflammation and Anti-oxidative Stress

Öz

Objective: The aim of this study is to investigate the possible beneficial effects of brusatol on lung injury caused by cecal ligation and puncture CLP model in rats. Methods: In this study, 32 Sprague Dawley male rats were divided into 4 random groups. The groups were programmed as group 1 sham , group 2 CLP , group 3 DMSO , and group 4 0.5 mg/ml brusatol . In group 1, a midline vertical incision was applied to the abdominal region and closed again without forming a CLP model. Group 2 performed CLP for 18 hours. In group 3, 1% DMSO was administered intraperitoneally 0.3 ml once every two days for 10 days. The last application was made 30 minutes before CLP. In group 4, brusatol was administered intraperitoneally at 0.5 mg/ml once every two days for 10 days. The last application was made 30 minutes before CLP. After CLP was over, the rats were sacrificed and lung tissues were removed.Results: MDA, MPO, OSI, TOS, TNF-α and IL-1β values increased significantly in groups 2 and 3 compared to group 1, while SOD and TAS values decreased. Unlike the seviyesi, MPO aktivitesi, TOS, OSI, TNF-α ve IL-1β değerleri grup 4’te grup 2 ve 3’e göre önemli ölçüde azaldı. Sonuç: Sıçanlarda CLD kaynaklı akciğer hasarına karşı brusatol etkin rol oynayabilir

Anahtar Kelimeler

Brusatol, oxidative stress, cytokine, cecal ligation and puncture, lung

Kaynakça

• 1. Russell JA. Management of sepsis. N Engl J Med. 2006;355(16):1699-713.
• 2. Nemzek JA, Hugunin KM, Opp MR. Modeling sepsis in the laboratory: merging sound science with animal well-being. Comp Med. 2008;58(2):120-8.
• 3. Babayigit H, Kucuk C, Sozuer E, Yazici C, Kose K, Akgun H. Protective effect of beta-glucan on lung injury after cecal ligation and puncture in rats. Intensive Care Med. 2005;31(6):865-70.
• 4. Yang L, Li D, Zhuo Y, Zhang S, Wang X, Gao H. Protective Role of Liriodendrin in Sepsis-Induced Acute Lung Injury. Inflammation. 2016;39(5):1805- 13.
• 5. Zhai Y, Zhou X, Dai Q, Fan Y, Huang X. Hydrogenrich saline ameliorates lung injury associated with cecal ligation and puncture-induced sepsis in rats. Exp Mol Pathol. 2015;98(2):268-76.
• 6. Abraham E. Neutrophils and acute lung injury. Critical care medicine. 2003;31(4 Suppl):S195-9.
• 7. Ayhan Tanyeli DGE. The Antioxidant and Antiinflammatory Effects of Alliin on Cecal Ligation and Puncture (CLP)-Induced Lung Injury. TJOS Science. 2019;4(2):46-59.
• 8. Suliman HB, Carraway MS, Piantadosi CA. Postlipopolysaccharide oxidative damage of mitochondrial DNA. Am J Respir Crit Care Med. 2003;167(4):570-9.
• 9. Tang W, Xie J, Xu S, Lv H, Lin M, Yuan S, et al. Novel nitric oxide-releasing derivatives of brusatol as anti-inflammatory agents: design, synthesis, biological evaluation, and nitric oxide release studies. J Med Chem. 2014;57(18):7600-12.
• 10. Zhu S, Liu S, Wang L, Ding W, Sha J, Qian H, et al. Brusatol Protects HepG2 Cells against OxygenGlucose Deprivation-Induced Injury via Inhibiting Mitochondrial Reactive Oxygen Species-Induced Oxidative Stress. Pharmacology. 2019:1-8.
• 11. Bu T, Wang C, Meng Q, Huo X, Sun H, Sun P, et al. Hepatoprotective effect of rhein against methotrexate-induced liver toxicity. Eur J Pharmacol. 2018;834:266-73.
• 12. Ren D, Villeneuve NF, Jiang T, Wu T, Lau A, Toppin HA, et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci U S A. 2011;108(4):1433-8.
• 13. Xiang Y, Ye W, Huang C, Yu D, Chen H, Deng T, et al. Brusatol Enhances the Chemotherapy Efficacy of Gemcitabine in Pancreatic Cancer via the Nrf2 Signalling Pathway. Oxid Med Cell Longev. 2018;2018:2360427.
• 14. Park SH, Kim JH, Ko E, Kim JY, Park MJ, Kim MJ, et al. Resistance to gefitinib and cross-resistance to irreversible EGFR-TKIs mediated by disruption of the Keap1-Nrf2 pathway in human lung cancer cells. Faseb J. 2018:fj201800011R.
• 15. Xiang Y, Ye W, Huang C, Lou B, Zhang J, Yu D, et al. Brusatol inhibits growth and induces apoptosis in pancreatic cancer cells via JNK/p38 MAPK/NFkappab/Stat3/Bcl-2 signaling pathway. Biochem Biophys Res Commun. 2017;487(4):820-6.
• 16. Meng QT, Chen R, Chen C, Su K, Li W, Tang LH, et al. Transcription factors Nrf2 and NF-kappaB contribute to inflammation and apoptosis induced by intestinal ischemia-reperfusion in mice. Int J Mol Med. 2017;40(6):1731-40.
• 17. Ohkawa H, Ohishi N, Yagi K. Assay for Lipid Peroxides in Animal-Tissues by Thiobarbituric Acid Reaction. Anal Biochem. 1979;95(2):351-8.
• 18. Harma M, Harma M, Kocyigit A, Erel O. Increased DNA damage in patients with complete hydatidiform mole. Mutat Res-Gen Tox En. 2005;583(1):49-54.
• 19. Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol. 1982;78(3):206-9.
• 20. Sun Y, Oberley LW, Li Y. A Simple Method for Clinical Assay of Superoxide-Dismutase. Clin Chem. 1988;34(3):497-500.
• 21. Singer M, Deutschman CS, Seymour CW, ShankarHari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10.
• 22. Sadowitz B, Roy S, Gatto LA, Habashi N, Nieman G. Lung injury induced by sepsis: lessons learned from large animal models and future directions for treatment. Expert Rev Anti Infect Ther. 2011;9(12):1169-78.
• 23. Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353(16):1685- 93.
• 24. Maybauer MO, Maybauer DM, Herndon DN. Incidence and outcomes of acute lung injury. N Engl J Med. 2006;354(4):416-7.
• 25. Husak L, Marcuzzi A, Herring J, Wen E, Yin L, Capan DD, et al. National analysis of sepsis hospitalizations and factors contributing to sepsis in-hospital mortality in Canada. Healthcare quarterly (Toronto, Ont). 2010;13:35-41.
• 26. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Critical care medicine. 2001;29(7):1303-10.