肺成纤维细胞p53-miR-34a反馈调节CSP7、尼达尼布和吡非尼酮的抗纤维化作用。

IF 3.5 2区 医学 Q1 PHYSIOLOGY
Liang Fan, Rashmi S Shetty, Huy Minh Dao, Akarsha Balnadupete, Bharath Somasundram, Ashoka Kumar Bhagavath, Akhila Kongara, Hua Tang, Deborah E Citrin, Robert O Williams, Jay I Peters, Sreerama Shetty
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引用次数: 0

摘要

特发性肺纤维化(IPF)是一种以肺功能进行性和不可逆丧失为特征的致命性疾病。CSP7通过恢复p53- microrna -34a反馈诱导,对纤维化肺(myo)成纤维细胞发挥抗纤维化作用,而成纤维细胞是进行性肺纤维化(PF)的主要效应细胞。然而,p53-microRNA-34a在尼达尼布和吡非尼酮抗纤维化作用中的作用尚未探讨。我们使用肺成纤维细胞中缺乏p53 (p53ko)或microRNA-34a (microRNA-34afl/fl)和他莫昔芬诱导的条件敲除小鼠,比较了口服灌胃标准护理抗纤维化药物尼达尼布或吡非尼酮与CSP7腹腔注射或经气道干粉吸入对博来霉素诱导的PF的影响。与野生型、p53fl/fl或microRNA-34afl/fl小鼠相比,p53cKO和miR-34acKO小鼠在博来霉素作用后表现出更严重的体重和肺功能损失、更低的存活率和更多的细胞外基质沉积。尽管在博莱霉素治疗后的第14-21天,每天用CSP7或尼达尼布或吡非尼酮治疗野生型小鼠可改善生存、体重和肺功能,但CSP7与尼达尼布或吡非尼酮联合使用比任何一种药物更有效。有趣的是,p53- miR-34acKO-PF小鼠抵抗这些治疗,支持恢复肺(肌)成纤维细胞中p53- mir -34a反馈诱导的抗纤维化作用的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
p53-miR-34a Feedback in Lung Fibroblasts Regulates Antifibrotic Effects of CSP7, Nintedanib and Pirfenidone.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by progressive and irreversible loss of lung function. CSP7 exerts anti-fibrotic effects on fibrotic lung (myo)fibroblasts, which are the primary effector cells in progressive pulmonary fibrosis (PF) via restoring p53-microRNA-34a-feedback induction. However, p53-microRNA-34a's role in the anti-fibrotic effects of Nintedanib and Pirfenidone have not been explored. We compared the effects of oral-gavage-fed standard-of-care anti-fibrotic drugs, Nintedanib or Pirfenidone with CSP7 administered by intraperitoneal injection or via airway by dry powder inhalation against bleomycin induced PF using wild-type, p53 flox (p53fl/fl), microRNA-34a flox (microRNA-34afl/fl) and tamoxifen inducible conditional knockout mice lacking p53 (p53cKO) or microRNA-34a (miR-34acKO) expression in lung fibroblasts. Compared to wild-type or p53fl/fl or microRNA-34afl/fl mice, p53cKO and miR-34acKO mice exhibited more severe post-bleomycin body weight and lung function loss, lower survival, and more extracellular matrix deposition. Although daily treatment of wild-type mice with CSP7 or with Nintedanib or Pirfenidone between day 14-21 post-bleomycin improved survival, body weight and lung function, combination of CSP7 with Nintedanib or Pirfenidone was more effective than either drug. Interestingly, p53cKO- and miR-34acKO-PF mice resisted these treatments, supporting the importance of restoration of p53-miR-34a-feedback induction in lung (myo)fibroblasts for the anti-fibrotic effects.

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来源期刊
CiteScore
9.20
自引率
4.10%
发文量
146
审稿时长
2 months
期刊介绍: The American Journal of Physiology-Lung Cellular and Molecular Physiology publishes original research covering the broad scope of molecular, cellular, and integrative aspects of normal and abnormal function of cells and components of the respiratory system. Areas of interest include conducting airways, pulmonary circulation, lung endothelial and epithelial cells, the pleura, neuroendocrine and immunologic cells in the lung, neural cells involved in control of breathing, and cells of the diaphragm and thoracic muscles. The processes to be covered in the Journal include gas-exchange, metabolic control at the cellular level, intracellular signaling, gene expression, genomics, macromolecules and their turnover, cell-cell and cell-matrix interactions, cell motility, secretory mechanisms, membrane function, surfactant, matrix components, mucus and lining materials, lung defenses, macrophage function, transport of salt, water and protein, development and differentiation of the respiratory system, and response to the environment.
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