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 Inflammation Pub Date : 2024-10-23 DOI:10.1007/s10753-024-02153-9
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。
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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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