Lung and Placenta Laboratory, Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA.
Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA.
Int J Mol Sci. 2024 Apr 30;25(9):4940. doi: 10.3390/ijms25094940.
The receptor for advanced glycation end-products (RAGE) has a central function in orchestrating inflammatory responses in multiple disease states including chronic obstructive pulmonary disease (COPD). RAGE is a transmembrane pattern recognition receptor with particular interest in lung disease due to its naturally abundant pulmonary expression. Our previous research demonstrated an inflammatory role for RAGE following acute exposure to secondhand smoke (SHS). However, chronic inflammatory mechanisms associated with RAGE remain ambiguous. In this study, we assessed transcriptional outcomes in mice exposed to chronic SHS in the context of RAGE expression. RAGE knockout (RKO) and wild-type (WT) mice were delivered nose-only SHS via an exposure system for six months and compared to control mice exposed to room air (RA). We specifically compared WT + RA, WT + SHS, RKO + RA, and RKO + SHS. Analysis of gene expression data from WT + RA vs. WT + SHS showed FEZ1, Slpi, and Msln as significant at the three-month time point; while RKO + SHS vs. WT + SHS identified cytochrome p450 1a1 and Slc26a4 as significant at multiple time points; and the RKO + SHS vs. WT + RA revealed Tmem151A as significant at the three-month time point as well as Gprc5a and Dynlt1b as significant at the three- and six-month time points. Notable gene clusters were functionally analyzed and discovered to be specific to cytoskeletal elements, inflammatory signaling, lipogenesis, and ciliogenesis. We found gene ontologies (GO) demonstrated significant biological pathways differentially impacted by the presence of RAGE. We also observed evidence that the PI3K-Akt and NF-κB signaling pathways were significantly enriched in DEGs across multiple comparisons. These data collectively identify several opportunities to further dissect RAGE signaling in the context of SHS exposure and foreshadow possible therapeutic modalities.
晚期糖基化终产物受体（RAGE）在多种疾病状态中，包括慢性阻塞性肺疾病（COPD），具有协调炎症反应的核心功能。RAGE 是一种跨膜模式识别受体，由于其在肺部的天然丰富表达，因此对肺部疾病特别感兴趣。我们之前的研究表明，RAGE 在急性接触二手烟（SHS）后会发挥炎症作用。然而，与 RAGE 相关的慢性炎症机制仍不清楚。在这项研究中，我们评估了在 RAGE 表达的情况下，慢性 SHS 暴露对小鼠的转录结果。通过暴露系统，将 RAGE 敲除（RKO）和野生型（WT）小鼠暴露于 SHS 6 个月，并与暴露于室内空气（RA）的对照小鼠进行比较。我们特别比较了 WT+RA、WT+SHS、RKO+RA 和 RKO+SHS。WT+RA 与 WT+SHS 的基因表达数据分析显示，FEZ1、Slpi 和 Msln 在三个月时具有显著差异；而 RKO+SHS 与 WT+SHS 的比较确定了细胞色素 P450 1a1 和 Slc26a4 在多个时间点具有显著差异；RKO+SHS 与 WT+RA 的比较表明，Tmem151A 在三个月时具有显著差异，Gprc5a 和 Dynlt1b 在三个月和六个月时具有显著差异。对显著的基因簇进行了功能分析，发现它们专门针对细胞骨架元件、炎症信号、脂肪生成和纤毛发生。我们发现基因本体（GO）显示出 RAGE 存在时显著受影响的重要生物学途径。我们还观察到证据表明，PI3K-Akt 和 NF-κB 信号通路在多个比较中都明显富集了差异表达基因。这些数据共同确定了几个机会，可以进一步剖析 SHS 暴露背景下的 RAGE 信号，并预示可能的治疗方式。
