Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India.
Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India.
Int Immunopharmacol. 2018 Sep;62:191-202. doi: 10.1016/j.intimp.2018.07.012. Epub 2018 Jul 20.
The purpose of this study was to investigate the protective effect of andrographolide in silica-induced pulmonary fibrosis (PF) in mice and its underlying mechanisms. Male Swiss albino mice were divided into five groups: Normal control group, disease control group (1.5 mg silica/60 μL/mice) via oropharyngeal route, low dose (LD) group received silica + andrographolide (3 mg/kg), high dose (HD) group received silica + andrographolide (10 mg/kg), andrographolide per se group received 10 mg/kg andrographolide. Various bronchoalveolar lavage fluid (BALF) and biochemical parameters, inflammatory cytokines, histology and protein expression studies were carried out. Andrographolide significantly reduced total protein concentration, albumin, accumulation of inflammatory cells and lactate dehydrogenase (LDH) level in BALF. We found that andrographolide intervention led to decreased levels of the inflammatory cells including neutrophils, macrophages and lymphocytes in the BALF of the treated animals. In addition, andrographolide significantly reduced nitrite (p < 0.01 at HD), malondialdehyde (p < 0.01 at HD) and upregulated glutathione (p < 0.01 at HD) in silica challenged animals. Andrographolide showed anti-fibrotic activity by reducing collagen deposition and inflammation in lung. Histopathology revealed that andrographolide decreased irregular cellular nodules, inflammatory infiltration and fibrosis. Andrographolide intervention significantly reduced the expression of N-cadherin, α-SMA and vimentin (mesenchymal markers) and upregulated the expression of E-cadherin (an epithelial marker). Hence, andrographolide elicits its anti-pulmonary fibrotic effect by halting the progression of epithelial-to-mesenchymal transition (EMT) via affecting fibroblasts. We, to the best of our knowledge prove for the first time that andrographolide possesses potent antifibrotic activity by targeting inflammatory cells and EMT associated fibroblasts.
本研究旨在探讨穿心莲内酯在二氧化硅诱导的肺纤维化（PF）小鼠模型中的保护作用及其机制。雄性瑞士白化小鼠分为五组：正常对照组、疾病对照组（经口给予 1.5mg 二氧化硅/60μL/只）、低剂量（LD）组给予二氧化硅+穿心莲内酯（3mg/kg）、高剂量（HD）组给予二氧化硅+穿心莲内酯（10mg/kg）、穿心莲内酯组给予 10mg/kg 穿心莲内酯。进行了各种支气管肺泡灌洗液（BALF）和生化参数、炎症细胞因子、组织学和蛋白质表达研究。穿心莲内酯显著降低了 BALF 中的总蛋白浓度、白蛋白、炎症细胞和乳酸脱氢酶（LDH）水平。我们发现，穿心莲内酯干预导致治疗动物 BALF 中炎症细胞包括中性粒细胞、巨噬细胞和淋巴细胞水平降低。此外，穿心莲内酯显著降低了二氧化硅刺激动物 BALF 中的亚硝酸盐（HD 组 p<0.01）、丙二醛（HD 组 p<0.01）和上调谷胱甘肽（HD 组 p<0.01）。穿心莲内酯通过减少胶原沉积和肺部炎症表现出抗纤维化活性。组织病理学显示，穿心莲内酯减少了不规则细胞结节、炎症浸润和纤维化。穿心莲内酯干预显著降低了 N-钙粘蛋白、α-SMA 和波形蛋白（间充质标志物）的表达，并上调了 E-钙粘蛋白（上皮标志物）的表达。因此，穿心莲内酯通过影响成纤维细胞，阻止上皮-间质转化（EMT）的进展，发挥其抗肺纤维化作用。据我们所知，我们首次证明穿心莲内酯通过靶向炎症细胞和 EMT 相关成纤维细胞发挥强大的抗纤维化活性。
