Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, Univesity of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
Respir Res. 2019 Apr 10;20(1):70. doi: 10.1186/s12931-019-1038-6.
Cigarette smoking is one of the major risk factors for the development of chronic obstructive pulmonary disease (COPD). Evidence is accumulating that Receptor for Advanced Glycation-End products (RAGE)-signaling is a key pathway in the pathophysiology of COPD. To date, it is unknown how smoking affects RAGE expression. In the current study, we investigated the effect of smoking on AGER, the gene encoding RAGE, expression and on alternative splicing of AGER. To this end, we conducted RNA-Seq on bronchial biopsies for asymptomatic smokers (n = 36) and never smokers (n = 40). Total AGER gene expression was accessed using DESeq2, while alternative splicing was investigated by measuring the number of specific split reads spanning exon-exon junctions and the total split reads. One of the major isoforms of RAGE is endogenous soluble (es) RAGE, an anti-inflammatory decoy receptor, making up for approximately 10% of the total amount of soluble (s)RAGE. We found that smokers show decreased total gene expression of AGER in bronchial biopsies, while the relative abundance of the esRAGE isoform is increased. Furthermore, no difference in the serum levels of total sRAGE were observed between smokers and non-smokers. Our data indicates that smoking initiates a protective anti-inflammatory mechanism with decreased expression of the pro-inflammatory gene AGER and increased relative abundance of the anti-inflammatory isoform esRAGE.
吸烟是慢性阻塞性肺疾病（COPD）发展的主要危险因素之一。有证据表明，晚期糖基化终产物受体（RAGE）信号通路是 COPD 病理生理学的关键途径。迄今为止，尚不清楚吸烟如何影响 RAGE 的表达。在目前的研究中，我们调查了吸烟对 RAGE 基因编码的 AGER、表达和选择性剪接的影响。为此，我们对无症状吸烟者（n=36）和从不吸烟者（n=40）的支气管活检进行了 RNA-Seq。使用 DESeq2 来评估总 AGER 基因表达，通过测量跨越外显子-外显子接头的特定分裂读段的数量和总分裂读段来研究选择性剪接。RAGE 的主要同工型之一是内源性可溶性（es）RAGE，它是一种抗炎诱饵受体，约占总可溶性（s）RAGE 的 10%。我们发现吸烟者的支气管活检中 AGER 的总基因表达减少，而 esRAGE 同工型的相对丰度增加。此外，吸烟者和不吸烟者之间的血清总 sRAGE 水平没有差异。我们的数据表明，吸烟会引发一种保护性抗炎机制，降低促炎基因 AGER 的表达，并增加抗炎同工型 esRAGE 的相对丰度。
