奈罗多米司特通过调节 TGF-β1 通路改善博莱霉素诱导的小鼠系统性硬化相关性间质性肺病

IF 4.5 2区 医学 Q2 CELL BIOLOGY
Yuming Liu, Zhigang Liu, Xiaohe Li, Wenqi Li, Zhongyi Yang, Ran Jiao, Qing Wang, Lingxin Meng, Tiantian Zhang, Jing Liu, Dan Chai, Na Zhang, Shouchun Peng, Honggang Zhou, Cheng Yang
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引用次数: 0

摘要

系统性硬化症(SSc)是一种罕见的结缔组织疾病,临床病程多变。间质性肺病(ILD)是系统性硬化症的常见并发症,也是导致系统性硬化症相关死亡的主要原因。除了宁替达尼(nintedanib)和托西珠单抗(tocilizumab)外,目前还没有临床批准的治疗 SSc-ILD 的药物,因此迫切需要新的治疗策略。以往的研究表明,环磷酸腺苷(cAMP)在 SSc 和肺纤维化的发病机制中起着至关重要的作用。磷酸二酯酶(PDEs)是一种能特异性水解 cAMP 的酶,因此 PDE 抑制剂有望成为治疗 SSc-ILD 的候选药物。奈罗多米拉斯特是一种优先磷酸二酯酶4B(PDE4B)抑制剂,目前正在进行特发性肺纤维化和进行性纤维化间质性肺病(PF-ILD)的III期临床试验,它对PDE4B有良好的优先选择,但缺乏对SSc-ILD的研究。我们的研究表明,在博莱霉素诱导的 SSc-ILD 小鼠模型中,奈罗多米司特能有效抑制皮肤和肺纤维化。在肺纤维化方面,我们发现奈罗多米司特可以通过抑制PDE4B和TGF-β1-Smads/non-Smads信号通路改善博莱霉素诱导的SSc-ILD,这为SSc-ILD潜在治疗药物的开发提供了理论基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Nerandomilast Improves Bleomycin-Induced Systemic Sclerosis-Associated Interstitial Lung Disease in Mice by Regulating the TGF-β1 Pathway.

Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common complication of SSc and a major contributor to SSc-related deaths. Besides nintedanib and tocilizumab, there are currently no clinically approved drugs for SSc-ILD, highlighting the urgent need for new treatment strategies. Previous studies have shown that cyclic adenosine monophosphate (cAMP) plays a crucial role in the pathogenesis of SSc and lung fibrosis. Phosphodiesterases (PDEs) are enzymes that specifically hydrolyze cAMP, making PDE inhibitors promising candidates for SSc-ILD treatment. Nerandomilast, a preferential phosphodiesterase 4B (PDE4B) inhibitor currently undergoing phase III clinical trials for idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung diseases (PF-ILD), has good preference for PDE4B but lacks studies for SSc-ILD. Our research demonstrates that nerandomilast effectively inhibits skin and lung fibrosis in a bleomycin-induced mouse model of SSc-ILD. For lung fibrosis, we found that nerandomilast could improve bleomycin-induced SSc-ILD through inhibiting PDE4B and the TGF-β1-Smads/non-Smads signaling pathways, which provides a theoretical basis for potential therapeutic drug development for SSc-ILD.

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来源期刊
Inflammation
Inflammation 医学-免疫学
CiteScore
9.70
自引率
0.00%
发文量
168
审稿时长
3.0 months
期刊介绍: Inflammation publishes the latest international advances in experimental and clinical research on the physiology, biochemistry, cell biology, and pharmacology of inflammation. Contributions include full-length scientific reports, short definitive articles, and papers from meetings and symposia proceedings. The journal''s coverage includes acute and chronic inflammation; mediators of inflammation; mechanisms of tissue injury and cytotoxicity; pharmacology of inflammation; and clinical studies of inflammation and its modification.
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