Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.
Eur J Pharmacol. 2012 Aug 15;689(1-3):186-93. doi: 10.1016/j.ejphar.2012.05.026. Epub 2012 May 30.
Idiopathic pulmonary fibrosis is the most prevalent chronic fibrosing lung disease. Peroxisome proliferator-activated receptors-gamma agonists provide potential therapy for fibrotic diseases of the lung. Peroxisome proliferator-activated receptors-alpha agonists may be helpful in the treatment of lung inflammatory diseases, however their therapeutic potential on the "fibro-proliferative" process and extracellular matrix accumulation in idiopathic pulmonary fibrosis has been less well studied. So, the present study was conducted to evaluate the anti-fibrotic effects of fenofibrate (peroxisome proliferator-activated receptors-alpha agonist) alone and in combination with rosiglitazone (peroxisome proliferator-activated receptors-gamma agonist) on lung injury induced by bleomycin administration. Oral administration of either rosiglitazone (5 mg/kg/d) or fenofibrate (100 mg/kg/d) for 14 days, attenuated the severity of bleomycin-induced lung injury and fibrosis through decreasing lung water contents, lung fibrotic grading, lung hydroxyproline contents and lung transforming growth factor-beta1 levels; with no significant difference between them. Combined low doses of rosiglitazone (1 mg/kg/d) and fenofibrate (30 mg/kg/d) provided more benefits than full separate doses of each on the deleterious effects accompanied bleomycin administration. These findings suggested the potential use of peroxisome proliferator-activated receptors-alpha ligands as anti-fibrotic agents in lung fibrosis. Additionally, the concurrent administration of fenofibrate and rosiglitazone in low doses has synergistic effect and enhanced the beneficial effects afforded by either fenofibrate or rosiglitazone.
特发性肺纤维化是最常见的慢性纤维性肺疾病。过氧化物酶体增殖物激活受体-γ激动剂为肺纤维化疾病提供了潜在的治疗方法。过氧化物酶体增殖物激活受体-α激动剂可能有助于治疗肺部炎症性疾病，但它们在特发性肺纤维化中的“纤维增生性”过程和细胞外基质积累方面的治疗潜力研究较少。因此，本研究旨在评估非诺贝特（过氧化物酶体增殖物激活受体-α激动剂）单独使用和与罗格列酮（过氧化物酶体增殖物激活受体-γ激动剂）联合使用对博来霉素诱导的肺损伤的抗纤维化作用。罗格列酮（5mg/kg/d）或非诺贝特（100mg/kg/d）连续口服 14 天，通过降低肺含水量、肺纤维化分级、肺羟脯氨酸含量和肺转化生长因子-β1 水平，减轻博来霉素诱导的肺损伤和纤维化的严重程度；它们之间没有显著差异。联合低剂量罗格列酮（1mg/kg/d）和非诺贝特（30mg/kg/d）比单独使用全剂量更能减轻博来霉素给药带来的有害影响。这些发现表明过氧化物酶体增殖物激活受体-α配体具有作为肺纤维化抗纤维化剂的潜力。此外，非诺贝特和罗格列酮联合低剂量给药具有协同作用，增强了非诺贝特或罗格列酮各自提供的有益作用。
