Huang Chengliang, Wu Xu, Wang Shengpeng, Wang Wenjun, Guo Fang, Chen Yuanyuan, Pan Bi, Zhang Ming, Fan Xianming
1Department of Respiratory Medicine II, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan China.
Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan China.
Chin Med. 2018 Jul 4;13:36. doi: 10.1186/s13020-018-0194-9. eCollection 2018.
Idiopathic pulmonary fibrosis (IPF), a chronic, progressive, fibrosing interstitial lung disease, is associated with extremely poor prognosis, and lacks effective treatment. The frequently used immunosuppressive therapies such as dexamethasone (DEX) are often associated with side effects. Recently, combination of two Chinese herbal medicine preparations, and ligustrazine (SML), serves as an alternative medicine for treatment of IPF in clinical practices in China. The aim of this study is to compare the anti-fibrotic effect of SML with that of DEX and to investigate the underlying mechanisms.
A rat model of bleomycin (BLM) induced pulmonary fibrosis was used in this study. Ninety rats were assigned to six groups: control group; BLM-group; BLM and dexamethasone group (BLM + DEX); BLM + low-dose SML; BLM + medium-dose SML and BLM + high-dose SML. Rats were sacrificed on day 7, 14 and 28 after treatment. The extent of alveolitis and fibrosis was observed by H&E and Masson's trichrome staining. The expressions of TNF-α, TGF-β1 and SMAD4 were determined and quantified by immunohistochemical analysis. The serum levels of TNF-α and TGF-β1 were further quantified by ELISA kits.
Both DEX and SML treatment attenuated BLM-induced lung injury and pathological collagen deposition in rats, showing improved alveolitis and fibrosis scores on day 7, 14, 28, compared to the BLM group (< 0.05). The anti-fibrotic effect of SML was in a dose-dependent manner, and the medium- and high-dose SML showed comparable effect with DEX on day 14 and 28. Expressions of TNF-α, TGF-β1 and SMAD4 were significantly decreased in the DEX- and SML-treated groups compared with BLM groups (< 0.05). Medium- and high-dose SML showed better repression of TNF-α, TGF-β1 and SMAD4 expression compared to DEX at all time points (< 0.05). Notably, SML at different dosages did not affect serum levels of alanine aminotransferase, aspartate aminotransferase and creatinine.
SML is safe and effective in repressing BLM-induced pulmonary fibrosis, which might be through modulating the expression of TNF-α and TGF-β1. Our findings advocate the use of SML for IPF, which might serve as a better treatment option over DEX.
特发性肺纤维化（IPF）是一种慢性、进行性、纤维化间质性肺疾病，预后极差，且缺乏有效治疗方法。常用的免疫抑制疗法如地塞米松（DEX）常伴有副作用。最近，两种中药制剂和川芎嗪（SML）的组合在中国临床实践中作为治疗IPF的替代药物。本研究的目的是比较SML与DEX的抗纤维化作用，并探讨其潜在机制。
本研究采用博来霉素（BLM）诱导的大鼠肺纤维化模型。将90只大鼠分为六组：对照组；BLM组；BLM和地塞米松组（BLM + DEX）；BLM + 低剂量SML组；BLM + 中剂量SML组和BLM + 高剂量SML组。在治疗后第7、14和28天处死大鼠。通过苏木精-伊红（H&E）和Masson三色染色观察肺泡炎和纤维化程度。通过免疫组织化学分析测定并定量肿瘤坏死因子-α（TNF-α）、转化生长因子-β1（TGF-β1）和SMAD4的表达。通过酶联免疫吸附测定试剂盒进一步定量血清中TNF-α和TGF-β1的水平。
与BLM组相比，DEX和SML治疗均减轻了BLM诱导的大鼠肺损伤和病理性胶原沉积，在第7、14、28天肺泡炎和纤维化评分有所改善（<0.05）。SML的抗纤维化作用呈剂量依赖性，中、高剂量SML在第14天和28天显示出与DEX相当的效果。与BLM组相比，DEX和SML治疗组中TNF-α、TGF-β1和SMAD4的表达显著降低（<0.05）。在所有时间点，中、高剂量SML对TNF-α、TGF-β1和SMAD4表达的抑制作用均优于DEX（<0.05）。值得注意的是，不同剂量的SML均未影响血清丙氨酸氨基转移酶、天冬氨酸氨基转移酶和肌酐水平。
SML在抑制BLM诱导的肺纤维化方面安全有效，其机制可能是通过调节TNF-α和TGF-β1的表达。我们的研究结果支持将SML用于IPF，它可能是比DEX更好的治疗选择。
