Dopamine receptor agonists ameliorate bleomycin-induced pulmonary fibrosis by repressing fibroblast differentiation and proliferation.
Dopamine receptor agonists ameliorate bleomycin-induced pulmonary fibrosis by repressing fibroblast differentiation and proliferation.
复制标题
DOI：
10.1016/j.biopha.2021.111500
复制
发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Yong Mou;Juan Liu;T. Pan;Qi Wang;K. Miao;Yong-jian Xu;W. Xiong;Jun Yu
中科院分区：
文献类型：
--
作者：
Yong Mou;Juan Liu;T. Pan;Qi Wang;K. Miao;Yong-jian Xu;W. Xiong;Jun Yu
特发性肺纤维化（IPF）是最常见的致死性间质性肺病，治疗选择有限。已证实成纤维细胞的异常和不受控制的分化和增殖在推动IPF的发病机制中起关键作用。因此，干扰成纤维细胞的有效且耐受性良好的抗纤维化剂将是理想的治疗，但没有这样的治疗可用。值得注意的是，我们发现多巴胺（DA）受体D1（D1 R）和DA受体D2（D2 R）在IPF患者肺和博莱霉素（BLM）诱导的小鼠模型中的肌成纤维细胞中均上调。然后，我们探讨了DA，fenoldopam（FNP，选择性D1 R激动剂）和sumanirole（SMR，选择性D2 R激动剂）逆转BLM诱导的肺纤维化的安全性和有效性。进一步的数据表明，DA受体激动剂通过抑制成纤维细胞的分化和增殖，在BLM诱导的肺纤维化中发挥有效的抗纤维化作用。详细的通路分析显示，DA受体激动剂降低TGF-β1诱导的原代人肺成纤维细胞（PHLF）和IMR-90细胞中Smad 2的磷酸化。总体而言，DA受体激动剂保护小鼠免受BLM诱导的肺纤维化，并且在临床环境中可能对IPF患者具有治疗益处。
Idiopathic pulmonary fibrosis (IPF) is the most common fatal interstitial lung disease, with limited therapeutic options. The abnormal and uncontrolled differentiation and proliferation of fibroblasts have been confirmed to play a crucial role in driving the pathogenesis of IPF. Therefore, effective and well-tolerated antifibrotic agents that interfere with fibroblasts would be an ideal treatment, but no such treatments are available. Remarkably, we found that dopamine (DA) receptor D1 (D1R) and DA receptor D2 (D2R) were both upregulated in myofibroblasts in lungs of IPF patients and a bleomycin (BLM)-induced mouse model. Then, we explored the safety and efficacy of DA, fenoldopam (FNP, a selective D1R agonist) and sumanirole (SMR, a selective D2R agonist) in reversing BLM-induced pulmonary fibrosis. Further data showed that DA receptor agonists exerted potent antifibrotic effects in BLM-induced pulmonary fibrosis by attenuating the differentiation and proliferation of fibroblasts. Detailed pathway analysis revealed that DA receptor agonists decreased the phosphorylation of Smad2 induced by TGF-β1 in primary human lung fibroblasts (PHLFs) and IMR-90 cells. Overall, DA receptor agonists protected mice from BLM-induced pulmonary fibrosis and may be therapeutically beneficial for IPF patients in a clinical setting.