Endocannabinoid signalling/cannabinoid receptor 2 is involved in icariin-mediated protective effects against bleomycin-induced pulmonary fibrosis
Endocannabinoid signalling/cannabinoid receptor 2 is involved in icariin-mediated protective effects against bleomycin-induced pulmonary fibrosis
复制标题
内源性大麻素信号传导/大麻素受体2参与淫羊藿苷介导的抗博莱霉素诱导的肺纤维化保护作用
DOI：
10.1016/j.phymed.2022.154187
复制
发表时间：
2022-06-03
期刊：
影响因子：
7.9
通讯作者：
Dong, Jingcheng
中科院分区：
文献类型：
--
作者：
Du, Wenjing;Zhang, Ting;Dong, Jingcheng
背景：特发性肺纤维化（IPF）是一种病因不明的进行性纤维化疾病，有效治疗方案有限。探索新的治疗靶点和开发潜在的IPF药物具有重要意义。目的：本研究旨在分析IPF患者的非靶向血浆代谢物，并探讨大麻素受体（CB2）激活是否介导淫羊藿苷（ICA）的抗纤维化作用。方法：采用非靶向代谢组学方法检测稳定型IPF患者、稳定型慢性阻塞性肺疾病（COPD）患者以及健康受试者血浆中的整体代谢谱。非靶向液相色谱-质谱（LC-MS）分析显示，IPF具有差异代谢物和紊乱的信号通路。ICA具有药理生物活性，具有广泛的治疗能力，如骨保护、神经保护、心血管保护、抗癌、抗炎症和生殖功能。因此，将ICA给予肺纤维化大鼠模型4周，然后通过解剖和组织学检查ICA对肺纤维化的影响。结果：采用非靶向LC-MS法测定血浆中代谢物。采用无监督主成分分析（PCA）观察各样本的分布，有监督偏最小二乘判别分析（PLS-DA）和正交偏最小二乘判别分析（OPLS-DA）结果显示，两组之间均存在显著差异。ROC曲线分析显示，三组血浆样品中有8种代谢物auc值均在0.7以上。途径富集分析显示，3种代谢物参与逆行内源性大麻素信号传导。同时，通过京都基因与基因组百科全书（KEGG）通路分析发现IPF组逆行内源性大麻素信号传导与其他组有显著差异，然后我们通过检测博莱霉素诱导的肺纤维化、COPD大鼠模型和正常大鼠主要受体的表达进一步证实内源性大麻素信号传导。与以往的研究一致，我们发现肺组织中CB1和CB2的升高可能是肺纤维化大鼠模型的一个特征。重要的是，ICA可能通过降低博来霉素诱导的大鼠模型中CB1和CB2的表达来减轻博来霉素诱导的肺损伤。综上所述，我们测量了IPF患者的整体代谢谱，并确定CB2是一个新的潜在靶点。ICA治疗对博来霉素诱导的肺纤维化表现出显著的治疗效果，靶向CB2可能是主要的潜在机制。ICA是一种治疗肺纤维化和介导CB2受体拮抗剂的有前途的候选药物。
Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of unknown aetiology with limited effective treatment options. It is important to explore novel therapeutic targets and develop potential drugs for IPF.Purpose: The aim of the present study was to analyse nontargeted plasma metabolites in patients with IPF and investigate whether cannabinoid receptor (CB2) activation mediates the antifibrotic effect of icariin (ICA).Methods: We used an untargeted metabolomics method to detect the global metabolic profiles in the plasma of stable IPF patients and patients with stable chronic obstructive pulmonary disease (COPD), as well as healthy subjects. The untargeted liquid chromatography-mass spectrometry (LC-MS) analysis revealed that IPF showed differential metabolites and perturbed signalling pathways. ICA is pharmacologically bioactive and possesses extensive therapeutic capacities such as osteoprotective, neuroprotective, cardiovascular protective, anti-cancer, anti-inflammation and reproductive function. Therefore, ICA was administered to a pulmonary fibrosis rat model for 4 weeks and then the effect of ICA on pulmonary fibrosis was examined by dissection and histology.Results: The metabolites in the plasma were determined by untargeted LC-MS. An unsupervised principal component analysis (PCA) was used to observe the distribution of each sample, and a supervised partial least squares-discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) results showed that there was significant separation between any two groups. ROC curve analyses revealed that 8 metabolites with high AUCs above 0.7 between the three groups of plasma samples. Pathway enrichment analysis revealed that 3 metabolites are involved in retrograde endocannabinoid signalling. Meanwhile, Retrograde endocannabinoid signalling was identified significantly different in IPF group from other groups by Kyoto encyclopedia of Genes and Genomes (KEGG) pathway analysis, and then we further confirmed the endocannabinoid signalling by detecting the expression of the main receptors in bleomycin-induced pulmonary fibrosis, COPD rat model and normal rats. Consistent with previous studies, we found that the elevation of CB1 and CB2 in the lung tissues could be a signature of the pulmonary fibrosis rat model. Importantly, ICA may alleviate bleomycin-induced lung injury by decreasing CB1 and CB2 expression in the bleomycin-induced rat model.Conclusion: Taken together, we measured the global metabolic profile of IPF patients and identified CB2 as a novel potential target. ICA treatment demonstrated outstanding therapeutic effects on bleomycin-induced pulmonary fibrosis and targeting on CB2 may be the main underlying mechanism. ICA is a promising drug candidate to cure pulmonary fibrosis and mediate antagonists of the CB2 receptor.