ACPA Alleviates Bleomycin-Induced Pulmonary Fibrosis by Inhibiting TGF-β-Smad2/3 Signaling-Mediated Lung Fibroblast Activation.
ACPA Alleviates Bleomycin-Induced Pulmonary Fibrosis by Inhibiting TGF-β-Smad2/3 Signaling-Mediated Lung Fibroblast Activation.
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DOI：
10.3389/fphar.2022.835979
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发表时间：
2022
影响因子：
5.6
通讯作者：
Qian F
中科院分区：
文献类型：
--
作者：
Chen D;Tang H;Jiang H;Sun L;Zhao W;Qian F
肺纤维化是一组具有有限治疗选择的危及生命的疾病。大麻素1型受体（CB 1 R）的参与已表明在纤维化疾病，但是否CB 1 R的激活可以是纤维化治疗的好处是有争议的。在这项研究中，我们研究了花生四烯酰基环丙酰胺（ACPA），作为一种选择性CB 1受体激动剂，对博莱霉素（BLM）诱导的肺纤维化的影响。结果表明，ACPA能显著提高BLM处理小鼠的存活率，减轻BLM诱导的肺纤维化，抑制细胞外基质（ECM）标志物胶原、纤连蛋白和α-SMA的表达。ACPA可剂量依赖性地抑制转化生长因子-β（TGF-β）诱导的小鼠肺原代成纤维细胞ECM标志物的表达，并抑制TGF-β诱导的成纤维细胞迁移。此外，在BLM诱导的肺纤维化小鼠体内的肺成纤维细胞和TGF-β攻击的原代肺成纤维细胞中均观察到CB 1 R的mRNA水平增加。CB 1 R特异性激动剂ACPA显著降低了TGF-β-Smad 2/3信号传导的激活，即，降低TGF-β刺激的原代肺成纤维细胞中p-Smad 2和p-Smad 3的水平，并降低调节ECM产生的下游效应蛋白slug和snail的表达。总的来说，这些发现表明CB 1 R特异性激动剂ACPA在肺纤维化的体外和体内模型中都表现出抗纤维化功效，揭示了通过靶向CB 1 R选择性抑制TGF-β-Smad 2/3信号传导的成纤维细胞的新型抗纤维化方法。
Pulmonary fibrosis is a group of life-threatening diseases with limited therapeutic options. The involvement of cannabinoid type 1 receptors (CB1R) has been indicated in fibrotic diseases, but whether or not the activation of CB1R can be a benefit for fibrosis treatment is controversial. In this study, we investigated the effects of arachidonoylcyclopropylamide (ACPA), as a selective CB1R agonist, on bleomycin (BLM)-induced pulmonary fibrosis. We showed that ACPA treatment significantly improved the survival rate of BLM-treated mice, alleviated BLM-induced pulmonary fibrosis, and inhibited the expressions of extracellular matrix (ECM) markers, such as collagen, fibronectin, and α-SMA. The enhanced expressions of ECM markers in transforming growth factor-beta (TGF-β)-challenged primary lung fibroblasts isolated from mouse lung tissues were inhibited by ACPA treatment in a dose-dependent manner, and the fibroblast migration triggered by TGF-β was dose-dependently diminished after ACPA administration. Moreover, the increased mRNA levels of CB1R were observed in both lung fibroblasts of BLM-induced fibrotic mice in vivo and TGF-β-challenged primary lung fibroblasts in vitro. CB1R-specific agonist ACPA significantly diminished the activation of TGF-β–Smad2/3 signaling, i.e., the levels of p-Smad2 and p-Smad3, and decreased the expressions of downstream effector proteins including slug and snail, which regulate ECM production, in TGF-β-challenged primary lung fibroblasts. Collectively, these findings demonstrated that CB1R-specific agonist ACPA exhibited antifibrotic efficacy in both in vitro and in vivo models of pulmonary fibrosis, revealing a novel anti-fibrosis approach to fibroblast-selective inhibition of TGF-β-Smad2/3 signaling by targeting CB1R.
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影响因子：
8
作者：
Cinar, Resat;Iyer, Malliga R.;Kunos, George
通讯作者：
Kunos, George
影响因子：
3.9
作者：
Barratt SL;Creamer A;Hayton C;Chaudhuri N
通讯作者：
Chaudhuri N
影响因子：
15.9
作者：
Khalil, Hadi;Kanisicak, Onur;Molkentin, Jeffery D.
通讯作者：
Molkentin, Jeffery D.
DOI：
10.1513/pats.201203-023aw
发表时间：
2012-07-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Fernandez, Isis E;Eickelberg, Oliver
通讯作者：
Eickelberg, Oliver
影响因子：
19.6
作者：
Lecru, Lola;Desterke, Christophe;Francois, Helene
通讯作者：
Francois, Helene