Tripathi Lokesh P, Itoh Mari N, Takeda Yoshito, Tsujino Kazuyuki, Kondo Yasushi, Kumanogoh Atsushi, Mizuguchi Kenji
National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
Artificial Intelligence Center for Health and Biomedical Research (ArCHER), National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
Front Genet. 2020 Dec 10;11:585998. doi: 10.3389/fgene.2020.585998. eCollection 2020.
While both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are multifactorial disorders characterized by distinct clinical and pathological features, their commonalities and differences have not been fully elucidated. We sought to investigate the preventive roles of tetraspanins Cd151 and Cd9 -that are involved in diverse cellular processes in lung pathophysiology- in pulmonary fibrosis and emphysema, respectively, and to obtain a deeper understanding of their underlying molecular mechanisms toward facilitating improved therapeutic outcomes. Using an integrative approach, we examined the transcriptomic changes in the lungs of Cd151- and Cd9-deficient mice using functional-enrichment-analysis, pathway-perturbation-analysis and protein-protein-interaction (PPI) network analysis. Circadian-rhythm, extracellular-matrix (ECM), cell-adhesion and inflammatory responses and associated factors were prominently influenced by Cd151-deletion. Conversely, cellular-junctions, focal-adhesion, vascular-remodeling, and TNF-signaling were deeply impacted by Cd9-deletion. We also highlighted a "common core" of factors and signaling cascades that underlie the functions of both Cd151 and Cd9 in lung pathology. Circadian dysregulation following Cd151-deletion seemingly facilitated progressive fibrotic lung phenotype. Conversely, TGF-β signaling attenuation and TNF-signaling activation emerged as potentially novel functionaries of Cd9-deletion-induced emphysema. Our findings offer promising avenues for developing novel therapeutic treatments for pulmonary fibrosis and emphysema.
虽然慢性阻塞性肺疾病（COPD）和特发性肺纤维化（IPF）都是具有独特临床和病理特征的多因素疾病，但其共性和差异尚未完全阐明。我们试图研究四跨膜蛋白Cd151和Cd9（它们参与肺病理生理学中的多种细胞过程）分别在肺纤维化和肺气肿中的预防作用，并更深入地了解其潜在分子机制，以促进改善治疗效果。我们采用综合方法，通过功能富集分析、通路扰动分析和蛋白质-蛋白质相互作用（PPI）网络分析，研究了Cd151和Cd9基因缺陷小鼠肺组织中的转录组变化。昼夜节律、细胞外基质（ECM）、细胞黏附、炎症反应及相关因子受Cd151缺失的影响显著。相反，细胞连接、粘着斑、血管重塑和TNF信号通路受Cd9缺失的影响较大。我们还强调了在肺病理学中Cd151和Cd9功能基础的因子和信号级联的“共同核心”。Cd151缺失后的昼夜节律失调似乎促进了进行性肺纤维化表型。相反，TGF-β信号通路减弱和TNF信号通路激活成为Cd9缺失诱导肺气肿的潜在新作用机制。我们的研究结果为开发肺纤维化和肺气肿的新型治疗方法提供了有前景的途径。
