Tadalafil ve telmisartanın bleomisine bağlı akciğer fibrozisi üzerindeki etkilerinin incelenmesi

Öz

Amaç: Farklı malignitelerin tedavisinde kullanılan bir antitümör ilaç olan bleomisin ile ilişkili pulmoner toksisite, önemli bir sorundur ve bu toksisiteyi önleyecek molekülleri bulmak için çalışmalar devam etmektedir. Bu deneysel çalışmada, ratlarda, bleomisinle indüklenen akciğer fibrozisinde telmisartan ve tadalafilin etkinliğini araştırmayı amaçladık. Yöntemler: 32 erkek rat dört gruba ayrıldı: Kontrol grubu, Bleomisin grubu, Bleomisin+Tadalafil grubu, Bleomisin+Telmisartan grubu. Akciğer fibrozisi intratrakeal bleomisin uygulaması ile oluşturulurken aynı prosedür kontrol grubunda bleomisin yerine salin kullanılarak uygulandı. Tadalafil ve telmisartan gruplara göre 14 gün boyunca orogastrik kateter vasıtasıyla verildi. Doku MDA düzeyleri kalorimetrik yöntemler kullanılarak ölçüldü. Masson trikrom boyama uygulanarak histolojik değerlendirme yapıldı. Bulgular: Bleomisin+tadalafil ve bleomisin+telmisartan gruplarının fibrozis skorları bleomisin grubuna göre daha düşüktü. Gruplar arasında MDA düzeyleri açısından farklılık görülmedi. Sonuç: Tadalafil ve telmisartanın bleomisine bağlı artan fibrozis skorlarını düşürdüğü ve pulmoner toksisitenin birden fazla süreçle ilişkili olduğu ve önlenebilir olduğu kanısındayız.

Anahtar Kelimeler

• pulmoner fibrozis
• bleomisin
• Telmisartan
• tadalafil

Investigation of the effects of tadalafil and telmisartan in bleomycin-induced pulmonary fibrosis on rats

Abstract

Aim: Pulmonary toxicity related to bleomycin, an antitumor drug used in the treatment of several malignancies, is a challenge, and studies to find out molecules to prevent it are ongoing. In this study, we aimed to investigate the effectiveness of telmisartan and tadalafil in an experimental rat model of bleomycin-induced lung fibrosis. Methods: A total of 32 male rats were divided into four groups: Control group, Bleomycin group, Bleomycin-plus-Tadalafil group and Bleomycin-plus-Telmisartan group. Lung fibrosis was achieved by intratracheal administration of bleomycin, and the same procedure was performed to the control group, but saline was substituted for bleomycin. Tadalafil and telmisartan were administered with an orogastric catheter for 14 days. Tissue malondialdehyde levels (MDA) were determined using colorimetric methods. Masson’s trichrome staining was used in the histological examination of the tissue samples. Results: The fibrosis scores of bleomycin-plus-tadalafil and bleomycin-plus-telmisartan groups were lower than that of the bleomycin group (P=0.007 and P=0.007, respectively). MDA levels did not differ among study groups. Conclusion: Tadalafil and telmisartan were found to decrease fibrosis scores, which were increased with bleomycin, concluding that pulmonary toxicity was related to multiple processes and preventable.

Keywords

• pulmonary fibrosis
• Bleomycin
• telmisartan
• Tadalafil

References

1. 1. O’Sullivan JM, Huddart RA, Norman AR, Nicholls J, Dearnaley DP, Horwich A. Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours. Ann Oncol. 2003;14:91–6.
2. 2. Sleijfer S. Bleomycin-Induced Pneumonitis. Chest. 2001;120:617–24.
3. 3. Bae EH, Kim IJ, Joo SY, Kim EY, Kim CS, Choi JS, et al. Renoprotective effects of sildenafil in DOCA-salt hypertensive rats. Kidney Blood Press Res. 2012;36:248–57.
4. 4. Ferrini MG, Kovanecz I, Sanchez S, Vernet D, Davila HH, Rajfer J, et al. Long-Term Continuous Treatment with Sildenafil Ameliorates Aging-Related Erectile Dysfunction and the Underlying Corporal Fibrosis in the Rat1. Biol Reprod. 2007;76:915–23.
5. 5. Kovanecz I, Rambhatla A, Ferrini MG, Vernet D, Sanchez S, Rajfer J, et al. Chronic daily tadalafil prevents the corporal fibrosis and veno-occlusive dysfunction that occurs after cavernosal nerve resection. BJU Int. 2008;101:203–10.
6. 6. Iacono F, Prezioso D, Somma P, Chierchia S, Galasso R, Micheli P. Histopathologically proven prevention of post-prostatectomy cavernosal fibrosis with sildenafil. Urol Int. 2008;80:249–52.
7. 7. Hao J, Wang B, Jones SC, Jassal DS, Dixon IMC. Interaction between angiotensin II and Smad proteins in fibroblasts in failing heart and in vitro. Am J Physiol-Heart Circ Physiol. 2000;279:H3020–30.
8. 8. Waseda Y, Yasui M, Nishizawa Y, Inuzuka K, Takato H, Ichikawa Y, et al. Angiotensin II type 2 receptor antagonist reduces bleomycin-induced pulmonary fibrosis in mice. Respir Res. 2008;9:43.

9. 9. Wamsley-Davis A, Padda R, Truong LD, Tsao CC, Zhang P, Sheikh-Hamad D. AT 1A -mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using candesartan. Am J Physiol-Ren Physiol. 2004;287:F474–80.
10. 10. Liu S-S, Wang H-Y, Tang J-M, Zhou X-M. Hypoxia-Induced Collagen Synthesis of Human Lung Fibroblasts by Activating the Angiotensin System. Int J Mol Sci. 2013;14:24029–45.
11. 11. Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol. 1988;41:467–70.
12. 12. Uchiyama M, Mihara M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem. 1978;86:271–8.
13. 13. Motzer RJ, Nichols CJ, Margolin KA, Bacik J, Richardson PG, Vogelzang NJ, et al. Phase III Randomized Trial of Conventional-Dose Chemotherapy With or Without High-Dose Chemotherapy and Autologous Hematopoietic Stem-Cell Rescue As First-Line Treatment for Patients With Poor-Prognosis Metastatic Germ Cell Tumors. J Clin Oncol. 2007;25:247–56.
14. 14. Huddart RA, Gabe R, Cafferty FH, Pollock P, White JD, Shamash J, et al. A Randomised Phase 2 Trial of Intensive Induction Chemotherapy (CBOP/BEP) and Standard BEP in Poor-prognosis Germ Cell Tumours (MRC TE23, CRUK 05/014, ISRCTN 53643604). Eur Urol. 2015;67:534–43.
15. 15. Necchi A, Miceli R, Oualla K, Sonpavde G, Giannatempo P, Raggi D, et al. Effect of Bleomycin Administration on the Development of Pulmonary Toxicity in Patients With Metastatic Germ Cell Tumors Receiving First-Line Chemotherapy: A Meta-Analysis of Randomized Studies. Clin Genitourin Cancer. 2017;15:213-220.e5.
16. 16. de Wit R, Roberts JT, Wilkinson PM, de Mulder PHM, Mead GM, Fosså SD, et al. Equivalence of Three or Four Cycles of Bleomycin, Etoposide, and Cisplatin Chemotherapy and of a 3- or 5-Day Schedule in Good-Prognosis Germ Cell Cancer: A Randomized Study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol. 2001;19:1629–40.
17. 17. Mansour HM, Salama AAA, Abdel-Salam RM, Ahmed NA, Yassen NN, Zaki HF. The anti-inflammatory and anti-fibrotic effects of tadalafil in thioacetamide-induced liver fibrosis in rats. Can J Physiol Pharmacol. 2018;96:1308–17.
18. 18. Sriram N, Kalayarasan S, Sudhandiran G. Epigallocatechin-3-gallate augments antioxidant activities and inhibits inflammation during bleomycin-induced experimental pulmonary fibrosis through Nrf2–Keap1 signaling. Pulm Pharmacol Ther. 2009;22:221–36.
19. 19. Ilg MM, Mateus M, Stebbeds WJ, Milenkovic U, Christopher N, Muneer A, et al. Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie’s Disease Models. Eur Urol. 2019;75:329–40.
20. 20. Rocha F, Silva Jr F, Leite A, Leite A, Girão V, Castro R, et al. Tadalafil analgesia in experimental arthritis involves suppression of intra‐articular TNF release. Br J Pharmacol. 2011;164:828–35.
21. 21. Varma A, Das A, Hoke NN, Durrant DE, Salloum FN, Kukreja RC. Anti-Inflammatory and Cardioprotective Effects of Tadalafil in Diabetic Mice. PLoS ONE. 2012;7:e45243.
22. 22. Dina AAL, Walaa YA, Olfat GS, Lobna OE. Evaluation of the colo-protective effects of tadalafil in an experimental model of ulcerative colitis in rats. Afr J Pharm Pharmacol. 2017;11:385–93.
23. 23. Yildirim A, Ersoy Y, Ercan F, Atukeren P, Gumustas K, Uslu U, et al. Phosphodiesterase-5 inhibition by sildenafil citrate in a rat model of bleomycin-induced lung fibrosis. Pulm Pharmacol Ther. 2010;23:215–21.
24. 24. Shang P, Liu T, Liu W, Li Y, Dou F, Zhang Y, et al. Telmisartan improves vascular remodeling through ameliorating prooxidant and profibrotic mechanisms in hypertension via the involvement of transforming growth factor-β1. Mol Med Rep. 2017;16:4537–44.