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

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.

Anahtar Kelimeler:

Akciğer fibrozisi, Bleomisin, Erdostein, N-asetilsistein, Rat.

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

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.

Keywords:

Bleomycin, Erdosteine, N-acetylcysteine, Pulmonary Fibrosis, Rats.,

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