右美沙芬能抑制胶原蛋白和胶原蛋白样物质的分泌,从而改善肺纤维化

IF 15.8 1区 医学 Q1 CELL BIOLOGY
Muzamil M. Khan, George Galea, Juan Jung, Joanna Zukowska, David Lauer, Nadine Tuechler, Aliaksandr Halavatyi, Christian Tischer, Per Haberkant, Frank Stein, Ferris Jung, Jonathan J. M. Landry, Arif M. Khan, Viola Oorschot, Isabelle Becher, Beate Neumann, Thomas Muley, Hauke Winter, Julia Duerr, Marcus A Mall, Alessandro Grassi, Ernesto de la Cueva, Vladimir Benes, Janine Gote-Schniering, Mikhail Savitski, Rainer Pepperkok
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引用次数: 0

摘要

人体肺组织间质细胞外基质(ECM)中的纤维胶原过度沉积会导致肺纤维化,并最终导致器官衰竭。尽管我们了解这种疾病的分子机制,但至今仍未找到治疗肺纤维化的方法。我们筛选了一个药物库,发现止咳祛痰剂右美沙芬(DXM)能减少培养的原代人类肺成纤维细胞、博莱霉素小鼠模型和培养的人类肺纤维化精密切片模型中沉积在 ECM 中的过量纤维胶原的数量。DXM处理后细胞外纤维胶原减少的原因是TANGO1和HSP47阳性结构中内质网(ER)的I型胶原(COL1)的可逆贩运抑制。质谱分析表明,DXM 促进了各种胶原(COL1、COL3、COL4、COL5、COL7 和 COL12)和潜伏转化生长因子-β 结合蛋白(LTBP1 和 LTBP2)肽上脯氨酸和赖氨酸残基的过度羟化,这与它们的分泌受阻不谋而合。此外,DXM 处理细胞的蛋白质组分析表明,脯氨酰羟化酶 P3H2、P3H3、P3H4、P4HA1 和 P4HA2 的热稳定性增加,表明它们的活性发生了变化。在 DXM 处理后,对受到异型纤维化刺激的原代人类肺成纤维细胞和体外人类肺切片进行的转录组分析表明,通过调节多种途径(包括 MMP-ADAMTS 轴、WNT 信号转导和成纤维细胞向肌成纤维细胞的分化),抗纤维化程序被激活。这些从体外、体内和体外肺纤维化模型中获得的数据共同表明,DXM 有可能通过抑制 COL1 在 ER 中的膜贩运来限制纤维化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dextromethorphan inhibits collagen and collagen-like cargo secretion to ameliorate lung fibrosis
Excessive deposition of fibrillar collagen in the interstitial extracellular matrix (ECM) of human lung tissue causes fibrosis, which can ultimately lead to organ failure. Despite our understanding of the molecular mechanisms underlying the disease, no cure for pulmonary fibrosis has yet been found. We screened a drug library and found that dextromethorphan (DXM), a cough expectorant, reduced the amount of excess fibrillar collagen deposited in the ECM in cultured primary human lung fibroblasts, a bleomycin mouse model, and a cultured human precision-cut lung slice model of lung fibrosis. The reduced extracellular fibrillar collagen upon DXM treatment was due to reversible trafficking inhibition of collagen type I (COL1) in the endoplasmic reticulum (ER) in TANGO1- and HSP47-positive structures. Mass spectrometric analysis showed that DXM promoted hyperhydroxylation of proline and lysine residues on various collagens (COL1, COL3, COL4, COL5, COL7, and COL12) and latent transforming growth factor–β–binding protein (LTBP1 and LTBP2) peptides, coinciding with their secretion block. Additionally, proteome profiling of DXM-treated cells showed increased thermal stability of prolyl-hydroxylases P3H2, P3H3, P3H4, P4HA1, and P4HA2, suggesting a change in their activity. Transcriptome analysis of profibrotic stimulated primary human lung fibroblasts and human ex vivo lung slices after DXM treatment showed activation of an antifibrotic program through regulation of multiple pathways, including the MMP-ADAMTS axis, WNT signaling, and fibroblast-to-myofibroblast differentiation. Together, these data obtained from in vitro, in vivo, and ex vivo models of lung fibrogenesis show that DXM has the potential to limit fibrosis through inhibition of COL1 membrane trafficking in the ER.
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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