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Ratlarda bleomisin ile oluşturulan deneysel akciğer fibrozisi modelinde erdostein ve N-asetilsistein’in fibrozis üzerine etkilerinin incelenmesi

Year 2021, Volume: 2 Issue: 4, 136 - 142, 21.12.2021
https://doi.org/10.47582/jompac.1008477

Abstract

Amaç: İdiyopatik pulmoner fibrozis (İPF) etiyolojisi bilinmeyen, progresif seyirli, etkili bir tedavi seçeneği olmayan bir İnterstisyel Akciğer Hastalığı’dır. Bleomisin (BLM) ile oluşturulan akciğer fibrozis modeli, insanlardaki İPF’nin değerlendirilmesi için kullanılan en önemli modeldir. Erdostein (ERD) ve N-asetilsistein (NAC) sülfhidril içeren antioksidanlardır. Bu çalışmada bu ajanların BLM ile oluşturulan fibrozis üzerine etkinliğinin araştırılması amaçlanmıştır.
Gereç ve Yöntem: Çalışmaya alınan ratlar 5 gruba ayrıldı. Kontrol grubuna (n=7), 0. günde intratrakeal (i.t.) salin, BLM-I (n=5), BLM-II (n=6), ERD (n=6) ve NAC (n=7), gruplarına 0. günde 7.5 Ü/kg BLM i.t. verildi. 14. günden 29. güne kadar BLM-II grubuna distile su, ERD grubuna ERD (10 mg/kg/gün) ve NAC grubuna NAC (3 mmol/kg /gün) peroral verildi. BLM-I grubu için 14. günde, diğerleri için 29. günde çalışma sonlandırıldı. Bronkoalveoler lavajda (BAL) Malondialdehit (MDA), inflamatuvar hücre sayımı, serumda total antioxidant status (TAS), total oxidant status (TOS), tumor necrosis factor alfa (TNFα), transforming growth factor beta 1 (TGFβ1), makrofaj inflamatuvar protein 2 (MIP 2), matrix metalloproteinase 1 (MMP 1), MMP 7 çalışıldı. Akciğer dokusunda hidroksiprolin ölçümü ve histopatolojik inceleme yapıldı.
Bulgular: Nötrofil düzeyleri, ERD grubunda BLM I, BLM II, NAC gruplarına göre anlamlı düşük bulundu (Sırasıyla; p=0,004, p=0,015, p=0,022). Lenfosit düzeyleri, ERD, NAC gruplarında BLM I’e göre anlamlı düşük bulundu (Sırasıyla; p=0,030, p=0,010). Akciğer dokusu fibrozis derecesi, ERD grubunda BLM I, BLM II, NAC gruplarına göre anlamlı düşük bulundu (p<0,001). TAS düzeyleri, ERD grubunda BLM I-II, NAC gruplarına göre anlamlı yüksek bulundu (BLM II için p=0,002, diğerleri için p<0,001). TOS düzeyleri, ERD grubunda BLM I-II, NAC gruplarına göre anlamlı düşük bulundu (Sırasıyla; p<0,001, p=0,009, p=0,025). MİP 2 düzeyleri, ERD grubunda BLM I grubuna göre anlamlı düşük bulundu (p=0,004). MMP 1 düzeyleri, ERD grubunda BLM I-II gruplarına göre anlamlı düşük bulundu (Sırasıyla; p=0,007, p=0,022). MDA düzeyleri, ERD grubunda BLM I grubuna göre anlamlı düşük bulundu (p=0,026). Hidroksiprolin düzeyleri, ERD, NAC gruplarında BLM I grubuna göre anlamlı düşük bulundu (Sırasıyla; p=0,001, p=0,003).
Sonuç: Bu çalışmanın sonuçları ERD’in BLM ile oluşturulan fibrozis üzerine tedavi edici etkisinin olduğunu göstermektedir. Bu etkiyi akciğerde çeşitli kemokin ve kollagenaz düzeylerini ve inflamatuvar hücre birikimini azaltarak, oksidan/antioksidan dengesini düzenleyerek gösterebilir.

References

  • Antoine M, Mlika M. Interstitial Lung Disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; August 3, 2021.
  • American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161: 646-64.
  • Okutan O, Ayten Ö. Tanım ve Sınıflama In: Kartaloğlu Z, Okutan O, editörs. İdiyopatik pulmoner fibrozis güncel tanı ve tedavi rehberi. TÜSAD Eğitim kitapları serisi. İstanbul: G.M. Matbaacılık; 2013.p.2.
  • Goldstein RH, Fine A. Potential therapeutic initiatives for fibrogenic lung diseases. Chest 1995; 108: 848-55.
  • Hunninghake GW, Kalica AR. Approaches to the treatment of pulmonary fibrosis. Am J Respir Crit Care Med 1995; 15: 915-8.
  • Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev 2012; 21: 355-61.
  • Musellim B, Okumus G, Uzaslan E, et al. Epidemiology and distribution of interstitial lung diseases in Turkey. Clin Respir J 2014; 8: 55-62.
  • Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007; 176: 636-43.
  • Silva CI, Müller NL, Fujimoto K, et al. Acute exacerbation of chronic interstitial pneumonia: high-resolution computed tomography and pathologic findings. J Thorac Imaging 2007; 22: 221-9.
  • Raghu G. Idiopathic pulmonary fibrosis: guidelines for diagnosis and clinical management have advanced from consensus-based in 2000 to evidence-based in 2011. Eur Respir J 2011; 37: 743-6.
  • Erden ES, Kirkil G, Deveci F, et al. Ratlarda bleomisin ile oluşturulan akciğer fibrozisinde erdosteinin inflamasyon ve fibrozis üzerine etkileri [Effects of erdosteine on inflammation and fibrosis in rats with pulmonary fibrosis induced by bleomycin]. Tuberk Toraks 2008; 56: 127-38.
  • Yildirim Z, Kotuk M, Iraz M, et al. Attenuation of bleomycin-induced lung fibrosis by oral sulfhydryl containing antioxidants in rats: erdosteine and N-acetylcysteine. Pulm Pharmacol Ther 2005; 18: 367-73.
  • Moeller A, Ask K, Warburton D, Gauldie J, Kolb M. The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis?. Int J Biochem Cell Biol 2008; 40: 362-82.
  • Moretti M, Bottrighi P, Dallari R, et al. The effect of long-term treatment with erdosteine on chronic obstructive pulmonary disease: the EQUALIFE Study. Drugs Exp Clin Res 2004; 30: 143-52.
  • Inglesi M, Nicola M, Fregnan GB, Bradamante S, Pagani G. Synthesis and free radical scavenging properties of the enantiomers of erdosteine. Farmaco 1994; 40: 703-8.
  • Vagliasindi M, Fregnan GB. Erdosteine protection against cigarette smoking-induced functional antiprotease deficiency in human bronchiolo-alveolar structures. Int J Clin Pharmacol Ther Toxicol 1989; 27: 238-41.
  • Slama I, Dufresne C, Jourdan E, et al. Vancomycin dimerization and chiral recognition studied by high-performance liquid chromatography. Anal Chem 2002; 74: 5205-11.
  • Türker H. Kronik obstrüktif akciğer hastalığında mukolitikler ve antioksidanlar. In: Umut S ve Erdinç E; eds. Kronik Obstrüktif Akciğer Hastalığı İstanbul: 2000; 2: 124-7.
  • Erdoğan Y. İdiyopatik interstisyel pnömoniler In: Özlü T, MetintaĢ M, Karadağ M, Kaya A. editörs. Solunum Sistemi ve Hastalıkları 1 ed. İstanbul: istanbul medikal yayıncılık; 2011.p.1069.
  • Keane MP, Standiford TJ, Strieter RM. Chemokines are important cytokines in the pathogenesis of interstitial lung disease. Eur Respir J 1997; 10: 1199-202.
  • Smith RE, Strieter RM, Phan SH, Lukacs N, Kunkel SL. TNF and IL-6 mediate MIP-1alpha expression in bleomycin-induced lung injury. J Leukoc Biol 1998; 64: 528-36.
  • Zhang K, Gharaee-Kermani M, McGarry B, Phan SH. In situ hybridization analysis of rat lung alpha 1(I) and alpha 2(I) collagen gene expression in pulmonary fibrosis induced by endotracheal bleomycin injection. Lab Invest 1994; 70: 192-202.
  • Smith RE, Strieter RM, Zhang K, et al. A role for C-C chemokines in fibrotic lung disease. J Leukoc Biol 1995; 57: 782-7.
  • Keane MP, Belperio JA, Moore TA, et al. Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis. J Immunol 1999; 162: 5511-8.
  • Yara S, Kawakami K, Kudeken N, et al. FTS reduces bleomycin-induced cytokine and chemokine production and inhibits pulmonary fibrosis in mice. Clin Exp Immunol 2001; 124: 77-85.
  • Hagiwara SI, Ishii Y, Kitamura S. Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice. Am J Respir Crit Care Med 2000; 162: 225-31.
  • Verma R, Kushwah L, Gohel D, Patel M, Marvania T, Balakrishnan S. Evaluating the ameliorative potential of quercetin against the bleomycin-induced pulmonary fibrosis in wistar rats. Pulmonary Med 2013; 2013: 921724.
  • Oury TD, Thakker K, Menache M, Chang LY, Crapo JD, Day BJ. Attenuation of bleomycin-induced pulmonary fibrosis by a catalytic antioxidant metalloporphyrin. Am J Respir Cell Mol Biol 2001; 25: 164-9.
  • Piguet PF. Is “tumor necrosis factor” the major effector of pulmonary fibrosis?. Eur Cytokine Netw 1990; 1: 257-8.
  • Zhang Y, Lee TC, Guillemin B, Yu MC, Rom WN. Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. J Immunol 1993; 150: 4188-96.
  • Serrano-Mollar A, Closa D, Prats N, et al. In vivo antioxidant treatment protects against bleomycin-induced lung damage in rats. Br J Pharmacol 2003; 138: 1037-48.
  • Li S, Yang X, Li W, et al. N-acetylcysteine downregulation of lysyl oxidase activity alleviating bleomycin-induced pulmonary fibrosis in rats. Respiration 2012; 84: 509-17.
  • 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: 277-85.
  • Işık A, Koca S: Behçet hastaliğinda total antioksidan cevap ve oksidatifstres. Fırat Üniversitesi Sağlık Bilimleri Derg 2006; 20: 415-21.
  • Kilic T, Parlakpinar H, Polat A, et al. Protective and therapeutic effect of molsidomine on bleomycin-induced lung fibrosis in rats. Inflammation 2014; 37: 1167-78.
  • Koyama K, Goto H, Morizumi S, et al. The Tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-induced Lung Fibrosis in Mice. Am J Respir Cell Mol Biol 2019; 60: 478-87.
  • Henry MT, McMahon K, Mackarel AJ, et al. Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF. Eur Respir J 2002; 20: 1220-7.
  • Kamel E, Abdel Hady A, Abd-Elrahman A, Diab M. Evaluation of role of captopril and endostatin in protection of the lung against bleomycin-induced injury in rats. Egypt J Hospital Med 2019; 75: 1937-45.

Investigation of the effects of erdosteine and N-acetylcysteine on fibrosis bleomycin-induced pulmonary fibrosis in rats

Year 2021, Volume: 2 Issue: 4, 136 - 142, 21.12.2021
https://doi.org/10.47582/jompac.1008477

Abstract

Aim: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease of unknown etiology, and there is no effective treatment option. Bleomycin (BLM)-induced lung fibrosis model is the most important model used for the evaluation of IPF in human. Erdosteine (ERD) and N-acetylcysteine (NAC) are sulfhydryl-containing antioxidants. The aim of this study was to investigate the efficacy of these agents on fibrosis created by BLM.
Material and Method: The rats were divided into 5 groups. Intratracheal (IT) saline was given to the control group (n=7), and 7.5 U / kg IT BLM to BLM-I (n=5), BLM-II (n=6), ERD (n=6) and NAC (n=7) groups on day 0. Distilled water to BLM -II group, ERD (10 mg / kg / day) to ERD group and NAC (3 mmol / kg / day) to NAC group was given perorally from day 14 until day 29. Study was terminated on day 14 for BLM-I group and on day 29 for other groups. Malondialdehit (MDA) measurement and inflammatory cell count in BAL fluid, total antioxidant status (TAS), total oxidant status (TOS), tumor necrosis factor alfa (TNFα), transforming growth factor beta 1 (TGFβ1), macrophage inflammatory protein 2 (MIP 2), matrix metalloproteinase 1 (MMP 1), MMP 7 measurement in serum were performed. Hydroxyproline levels were measured and histopathological examination was performed in lung tissue.
Results: Neutrophil levels were significantly lower in ERD group than BLM I, BLM II, and NAC groups (p=0,004, p=0,015, and p=0,022, respectively). Lympohcyte levels were significantly lower in ERD and NAC groups than BLM I group (p=0,030, p=0,010, respectively). The degree of fibrosis of the lung tissue was significantly lower in ERD group than in BLM I, BLM II, and NAC groups (p<0,001). TAS levels were significantly higher in ERD group than BLM I, BLM II, and NAC groups (p=0,002 for BLM II, p<0,001 for other groups). TOS levels were significantly lower in ERD group than BLM I, BLM II, and NAC groups (p<0,001, p=0,009, p=0,025, respectively). MIP 2 levels were significantly lower in ERD group than BLM I (p=0,004). MMP 1 levels were significantly lower in ERD group than BLM I and BLM II groups. (p=0,007, p=0,022, respectively). MDA levels were significantly lower in ERD group than BLM I (p=0,026). Hydroxypirolin levels were significantly lower in ERD and NAC groups than BLM I (p=0,001, p=0,003, respectively).
Conclusion: Our results showed that ERD has therapeutic effects on fibrosis induced by BLM. It can create this effect by reducing inflammatory cell accumulation, various chemokines and collagenase levels in the lung, and regulating oxidant / antioxidant balance.

References

  • Antoine M, Mlika M. Interstitial Lung Disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; August 3, 2021.
  • American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161: 646-64.
  • Okutan O, Ayten Ö. Tanım ve Sınıflama In: Kartaloğlu Z, Okutan O, editörs. İdiyopatik pulmoner fibrozis güncel tanı ve tedavi rehberi. TÜSAD Eğitim kitapları serisi. İstanbul: G.M. Matbaacılık; 2013.p.2.
  • Goldstein RH, Fine A. Potential therapeutic initiatives for fibrogenic lung diseases. Chest 1995; 108: 848-55.
  • Hunninghake GW, Kalica AR. Approaches to the treatment of pulmonary fibrosis. Am J Respir Crit Care Med 1995; 15: 915-8.
  • Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev 2012; 21: 355-61.
  • Musellim B, Okumus G, Uzaslan E, et al. Epidemiology and distribution of interstitial lung diseases in Turkey. Clin Respir J 2014; 8: 55-62.
  • Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007; 176: 636-43.
  • Silva CI, Müller NL, Fujimoto K, et al. Acute exacerbation of chronic interstitial pneumonia: high-resolution computed tomography and pathologic findings. J Thorac Imaging 2007; 22: 221-9.
  • Raghu G. Idiopathic pulmonary fibrosis: guidelines for diagnosis and clinical management have advanced from consensus-based in 2000 to evidence-based in 2011. Eur Respir J 2011; 37: 743-6.
  • Erden ES, Kirkil G, Deveci F, et al. Ratlarda bleomisin ile oluşturulan akciğer fibrozisinde erdosteinin inflamasyon ve fibrozis üzerine etkileri [Effects of erdosteine on inflammation and fibrosis in rats with pulmonary fibrosis induced by bleomycin]. Tuberk Toraks 2008; 56: 127-38.
  • Yildirim Z, Kotuk M, Iraz M, et al. Attenuation of bleomycin-induced lung fibrosis by oral sulfhydryl containing antioxidants in rats: erdosteine and N-acetylcysteine. Pulm Pharmacol Ther 2005; 18: 367-73.
  • Moeller A, Ask K, Warburton D, Gauldie J, Kolb M. The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis?. Int J Biochem Cell Biol 2008; 40: 362-82.
  • Moretti M, Bottrighi P, Dallari R, et al. The effect of long-term treatment with erdosteine on chronic obstructive pulmonary disease: the EQUALIFE Study. Drugs Exp Clin Res 2004; 30: 143-52.
  • Inglesi M, Nicola M, Fregnan GB, Bradamante S, Pagani G. Synthesis and free radical scavenging properties of the enantiomers of erdosteine. Farmaco 1994; 40: 703-8.
  • Vagliasindi M, Fregnan GB. Erdosteine protection against cigarette smoking-induced functional antiprotease deficiency in human bronchiolo-alveolar structures. Int J Clin Pharmacol Ther Toxicol 1989; 27: 238-41.
  • Slama I, Dufresne C, Jourdan E, et al. Vancomycin dimerization and chiral recognition studied by high-performance liquid chromatography. Anal Chem 2002; 74: 5205-11.
  • Türker H. Kronik obstrüktif akciğer hastalığında mukolitikler ve antioksidanlar. In: Umut S ve Erdinç E; eds. Kronik Obstrüktif Akciğer Hastalığı İstanbul: 2000; 2: 124-7.
  • Erdoğan Y. İdiyopatik interstisyel pnömoniler In: Özlü T, MetintaĢ M, Karadağ M, Kaya A. editörs. Solunum Sistemi ve Hastalıkları 1 ed. İstanbul: istanbul medikal yayıncılık; 2011.p.1069.
  • Keane MP, Standiford TJ, Strieter RM. Chemokines are important cytokines in the pathogenesis of interstitial lung disease. Eur Respir J 1997; 10: 1199-202.
  • Smith RE, Strieter RM, Phan SH, Lukacs N, Kunkel SL. TNF and IL-6 mediate MIP-1alpha expression in bleomycin-induced lung injury. J Leukoc Biol 1998; 64: 528-36.
  • Zhang K, Gharaee-Kermani M, McGarry B, Phan SH. In situ hybridization analysis of rat lung alpha 1(I) and alpha 2(I) collagen gene expression in pulmonary fibrosis induced by endotracheal bleomycin injection. Lab Invest 1994; 70: 192-202.
  • Smith RE, Strieter RM, Zhang K, et al. A role for C-C chemokines in fibrotic lung disease. J Leukoc Biol 1995; 57: 782-7.
  • Keane MP, Belperio JA, Moore TA, et al. Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis. J Immunol 1999; 162: 5511-8.
  • Yara S, Kawakami K, Kudeken N, et al. FTS reduces bleomycin-induced cytokine and chemokine production and inhibits pulmonary fibrosis in mice. Clin Exp Immunol 2001; 124: 77-85.
  • Hagiwara SI, Ishii Y, Kitamura S. Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice. Am J Respir Crit Care Med 2000; 162: 225-31.
  • Verma R, Kushwah L, Gohel D, Patel M, Marvania T, Balakrishnan S. Evaluating the ameliorative potential of quercetin against the bleomycin-induced pulmonary fibrosis in wistar rats. Pulmonary Med 2013; 2013: 921724.
  • Oury TD, Thakker K, Menache M, Chang LY, Crapo JD, Day BJ. Attenuation of bleomycin-induced pulmonary fibrosis by a catalytic antioxidant metalloporphyrin. Am J Respir Cell Mol Biol 2001; 25: 164-9.
  • Piguet PF. Is “tumor necrosis factor” the major effector of pulmonary fibrosis?. Eur Cytokine Netw 1990; 1: 257-8.
  • Zhang Y, Lee TC, Guillemin B, Yu MC, Rom WN. Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. J Immunol 1993; 150: 4188-96.
  • Serrano-Mollar A, Closa D, Prats N, et al. In vivo antioxidant treatment protects against bleomycin-induced lung damage in rats. Br J Pharmacol 2003; 138: 1037-48.
  • Li S, Yang X, Li W, et al. N-acetylcysteine downregulation of lysyl oxidase activity alleviating bleomycin-induced pulmonary fibrosis in rats. Respiration 2012; 84: 509-17.
  • 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: 277-85.
  • Işık A, Koca S: Behçet hastaliğinda total antioksidan cevap ve oksidatifstres. Fırat Üniversitesi Sağlık Bilimleri Derg 2006; 20: 415-21.
  • Kilic T, Parlakpinar H, Polat A, et al. Protective and therapeutic effect of molsidomine on bleomycin-induced lung fibrosis in rats. Inflammation 2014; 37: 1167-78.
  • Koyama K, Goto H, Morizumi S, et al. The Tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-induced Lung Fibrosis in Mice. Am J Respir Cell Mol Biol 2019; 60: 478-87.
  • Henry MT, McMahon K, Mackarel AJ, et al. Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF. Eur Respir J 2002; 20: 1220-7.
  • Kamel E, Abdel Hady A, Abd-Elrahman A, Diab M. Evaluation of role of captopril and endostatin in protection of the lung against bleomycin-induced injury in rats. Egypt J Hospital Med 2019; 75: 1937-45.
There are 38 citations in total.

Details

Primary Language Turkish
Subjects Health Care Administration
Journal Section Research Articles [en] Araştırma Makaleleri [tr]
Authors

Mesut Demirköse 0000-0003-3862-4567

Ersin Erden

Publication Date December 21, 2021
Published in Issue Year 2021 Volume: 2 Issue: 4

Cite

AMA Demirköse M, Erden E. Ratlarda bleomisin ile oluşturulan deneysel akciğer fibrozisi modelinde erdostein ve N-asetilsistein’in fibrozis üzerine etkilerinin incelenmesi. J Med Palliat Care / JOMPAC / jompac. December 2021;2(4):136-142. doi:10.47582/jompac.1008477

TR DİZİN ULAKBİM and International Indexes (1d)

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