Effects of anti-tuberculosis drugs on the proliferation and differentiation of alveolar stem cells

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-09-09 DOI:10.1016/j.taap.2025.117546

Xue Li , Yimeng Liu , Guiying Xu , Sisi Wang , Zhili Hou , Hongxia Shao , Junping Wu , Wanjie Yang , Huaiyong Chen

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引用次数: 0

Abstract

Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), not only inflicts damage on lung epithelium but also poses a challenge to the regenerative capacity of the lung. Using lung organoid culture techniques, we assessed the effects of anti-Mtb drugs on the proliferation and differentiation of type II alveolar (AT2) cells. We found that rifampicin, pyrazinamide, ethambutol, and levofloxacin decreased the organoid-forming efficiency (OFE) of AT2 cells. Additionally, rifampicin and levofloxacin inhibited the size of organoids derived from AT2 cells. Isoniazid, ethambutol, and levofloxacin promoted type I alveolar (AT1) cell differentiation. Moxifloxacin considerably promoted the OFE and clone diameter while exerting minimal effects on AT1 cell differentiation. Furthermore, we performed metabolomics to elucidate the molecular mechanisms underlying lung epithelial stem cell regeneration. The differentially expressed metabolites were closely associated with energy metabolism, which is essential for cell proliferation and differentiation. Altogether, our data suggest that anti-Mtb drugs exhibit diverse and specific impacts on the growth and differentiation of AT2 cells. This may be directly related to the effect of drugs on the energy metabolism of alveolar stem cells, providing new insights and tools for the evaluation of anti-Mtb drugs.

查看原文本刊更多论文

抗结核药物对肺泡干细胞增殖分化的影响。

结核病（TB）是由结核分枝杆菌（Mtb）引起的一种疾病，它不仅对肺上皮造成损伤，而且对肺的再生能力提出了挑战。利用肺类器官培养技术，我们评估了抗结核药物对II型肺泡（AT2）细胞增殖和分化的影响。我们发现利福平、吡嗪酰胺、乙胺丁醇和左氧氟沙星降低了AT2细胞的类器官形成效率（OFE）。此外，利福平和左氧氟沙星抑制来自AT2细胞的类器官的大小。异烟肼、乙胺丁醇和左氧氟沙星促进I型肺泡（AT1）细胞分化。莫西沙星对AT1细胞分化的影响很小，但对OFE和克隆直径有显著的促进作用。此外，我们通过代谢组学来阐明肺上皮干细胞再生的分子机制。差异表达的代谢物与能量代谢密切相关，而能量代谢是细胞增殖和分化所必需的。总之，我们的数据表明抗结核药物对AT2细胞的生长和分化表现出多样化和特异性的影响。这可能与药物对肺泡干细胞能量代谢的影响有直接关系，为抗结核药物的评价提供了新的见解和工具。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.