Divya Thomas, Dineshbabu Vadivel, Soumyakrishnan Syamala, Sureshkumar Anandasadagopan, Sudhandiran Ganapasam
Cell Biology Laboratory, Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, India.
Department of Biochemistry, Central Leather Research Institute, Chennai 600 020, India.
Chem Biol Interact. 2016 Feb 25;246:52-62. doi: 10.1016/j.cbi.2016.01.006. Epub 2016 Jan 6.
Pulmonary fibrosis (PF) is characterized by excessive accumulation of extracellular matrix components in the alveolar region which distorts the normal lung architecture and impairs the respiratory function. The aim of this study is to evaluate the anti-fibrotic effect of celastrol, a quinine-methide tri-terpenoid mainly found in Thunder God Vine root extracts against bleomycin (BLM)-induced PF through the enhancement of antioxidant defense system. A single intratracheal instillation of BLM (3 U/kg.bw) was administered in rats to induce PF. Celastrol (5 mg/kg) was given intraperitoneally, twice a week for a period of 28 days. BLM-induced rats exhibits declined activities of enzymatic and non-enzymatic antioxidants which were restored upon treatment with celastrol. BLM-induced rats show increased total and differential cell counts as compared to control and celastrol treated rats. Histopathological analysis shows increased inflammation and alveolar damage; while assay of hydroxyproline and Masson's trichrome staining shows an increased collagen deposition in BLM-challenged rats that were decreased upon celastrol treatment. Celastrol also reduces inflammation in BLM-induced rats as evidenced by decrease in the expressions of mast cells, Tumor necrosis factor-alpha (TNF- α) and matrix metalloproteinases (MMPs) 2 and 9. Further, Western blot analysis shows that celastrol is a potent inducer of NF-E2-related factor 2 (Nrf2) and it restores the activities of Phase II enzymes such as hemoxygenase-1 (HO-1), glutathione-S-transferase (GSTs) and NADP(H): quinine oxidoreductase (NQO1) which were declined upon BLM administration. The results of this study show evidence on the protective effect of celastrol against BLM-induced PF through its antioxidant and anti-fibrotic effects.
肺纤维化（PF）的特征是肺泡区域细胞外基质成分过度积聚，这会扭曲正常的肺结构并损害呼吸功能。本研究的目的是评估雷公藤红素（一种主要存在于雷公藤根提取物中的奎宁亚甲基三萜类化合物）通过增强抗氧化防御系统对博来霉素（BLM）诱导的PF的抗纤维化作用。对大鼠进行单次气管内滴注BLM（3 U/kg体重）以诱导PF。雷公藤红素（5 mg/kg）腹腔注射，每周两次，持续28天。BLM诱导的大鼠表现出酶促和非酶促抗氧化剂活性下降，而用雷公藤红素治疗后这些活性得以恢复。与对照组和雷公藤红素治疗组大鼠相比，BLM诱导的大鼠总细胞计数和分类细胞计数增加。组织病理学分析显示炎症和肺泡损伤增加；而羟脯氨酸测定和Masson三色染色显示，在BLM攻击的大鼠中胶原沉积增加，雷公藤红素治疗后胶原沉积减少。雷公藤红素还可减轻BLM诱导大鼠的炎症，肥大细胞、肿瘤坏死因子-α（TNF-α）以及基质金属蛋白酶（MMP）2和9的表达降低证明了这一点。此外，蛋白质印迹分析表明，雷公藤红素是NF-E2相关因子2（Nrf2）的有效诱导剂，它可恢复II相酶的活性，如血红素加氧酶-1（HO-1）、谷胱甘肽-S-转移酶（GSTs）和NADP（H）：奎宁氧化还原酶（NQO1），这些酶的活性在给予BLM后下降。本研究结果表明，雷公藤红素通过其抗氧化和抗纤维化作用对BLM诱导的PF具有保护作用。
