Celastrol enhances Nrf2 mediated antioxidant enzymes and exhibits anti-fibrotic effect through regulation of collagen production against bleomycin-induced pulmonary fibrosis
Celastrol enhances Nrf2 mediated antioxidant enzymes and exhibits anti-fibrotic effect through regulation of collagen production against bleomycin-induced pulmonary fibrosis
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DOI：
10.1016/j.cbi.2016.01.006
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发表时间：
2016-02-25
影响因子：
5.1
通讯作者：
Sudhandiran, Ganapasam
中科院分区：
文献类型：
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作者：
Divya, Thomas;Dineshbabu, Vadivel;Sudhandiran, Ganapasam
肺纤维化（PF）的特点是肺泡区细胞外基质成分过度积累，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（一种主要存在于雷神藤根提取物中的奎宁甲基三萜类化合物）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.bw) 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又恢复了活性。与对照和雷公藤红素处理的大鼠相比，BLM 诱导的大鼠显示总细胞计数和差异细胞计数增加。组织病理学分析显示炎症和肺泡损伤增加；而羟脯氨酸和马森三色染色的测定显示，BLM 攻击的大鼠中胶原沉积增加，而雷公藤红素治疗后胶原沉积减少。雷公藤红素还可以减少 BLM 诱导的大鼠的炎症，具体表现为肥大细胞、肿瘤坏死因子-α (TNF-α) 和基质金属蛋白酶 (MMP) 2 和 9 的表达减少。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，并且可以恢复 II 期酶的活性，例如血氧合酶-1 (HO-1)、谷胱甘肽-S-转移酶 (GST) 和 NADP(H)：奎宁氧化还原酶 (NQO1) 在 BLM 给药后下降。这项研究的结果证明了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。 (C) 2016 Elsevier Ireland Ltd. 保留所有权利。
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-alpha) 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. (C) 2016 Elsevier Ireland Ltd. All rights reserved.