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    Anti-inflammatory and anti-fibrotic effects of sirolimus on bleomycin-induced pulmonary fibrosis in rats
    (CANADIAN SOC CLINICAL INVESTIGATION, 2011) Tulek, Baykal; Kiyan, Esen; Toy, Hatice; Kiyici, Aysel; Narin, Cuneyt; Suerdem, Mecit
    Purpose: Pulmonary fibrosis is a devastating disease with a poor prognosis. Although the diagnosis and pathophysiology of this disease have been better characterized over the past few years, there is no effective therapy for the disease. The aim of this study was to evaluate the anti-inflammatory and anti-fibrotic effects of sirolimus (SRL), which is a potential anti-fibrotic agent, by using bleomycin (BLM)-induced pulmonary fibrosis model in rats. Methods: A single intra-tracheal injection of BLM (2.5 U/kg) was administered and sirolimus (2.5 mg/kg/day) was given orally, beginning either one day before (early SRL) or nine days after (late SRL) the BLM administration. The effect of SRL on fibrosis was studied by analysis of cytokine levels in BAL fluid, measurement of lung tissue hydroxyproline (HPL) content and histopathological examination. Results: Both early and late SRL administrations caused a decrease in the levels of IL-13, PDGF-A and TGF-beta 1 (p=0.001) and an increase in IFN-beta levels (p=0.001) in BAL fluid. Early and late SRL also caused a decrease in HPL content (p=0.001). Early sirolimus caused a significant decrease in fibrosis score (p=0.001), while late SRL did not. Conclusion: Sirolimus was effective in BLM-induced pulmonary fibrosis model, especially in the early phases of the disease.
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    Effects of simvastatin on bleomycin-induced pulmonary fibrosis in female rats
    (SOC BIOLGIA CHILE, 2012) Tulek, Baykal; Kiyan, Esen; Kiyici, Aysel; Toy, Hatice; Bariskaner, Hulagu; Suerdem, Mecit
    Statins reduce cholesterol levels by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase and have a major place in the treatment of atherosclerotic disease. Recent studies have shown anti-inflammatory properties of statins. The purpose of this study was to evaluate the anti-inflammatory effect of simvastatin on bleomycin (BLM)-induced pulmonary fibrosis in rats. A total of 31 female Sprague-Dawley rats were divided into four groups: (1) intratracheal (IT) phosphate-buffered saline (PBS) + intraperitoneal (IP) PBS (n=7); (2) IT BLM + IP PBS (n=8); (3) IT BLM + low dose (LD) simvastatin (1 mg/kg daily, n=8); (4) IT BLM + high dose (HD) simvastatin (5 mg/kg daily, n=8). Simvastatin was administered IP for 15 days, beginning 1 day prior to IT BLM. The effect of simvastatin on pulmonary fibrosis was studied by measurements of IL-13, PDGF, IFN-gamma, TGF-beta 1 levels in bronchoalveolar lavage (BAL) fluid and lung tissue hydroxyproline (HPL) content and by histopathological examination (Ashcroft score). BLM caused significant change in BAL fluid cytokine levels and increased both HPL content and histopathological score (p<0.001 for all). While LD simvastatin had no effect on cytokine levels, HD significantly reduced IL-13 (15.12 +/- 7.08 pg /ml vs. 4.43 +/- 2.34 pg/mL; p<0.05) and TGF-beta 1 levels (269.25 +/- 65.42 pg/mL vs. 131.75 +/- 32.65 pg/mL; p<0.05). Neither HD nor LD simvastatin attenuated HPL content or Ashcroft score. In conclusion, this study showed that LD simvastatin had no effect on a BLM-induced pulmonary fibrosis model, while the high dose caused partial improvement in profibrotic cytolcine levels.