RAGE is a Critical Mediator of Pulmonary Oxidative Stress, Alveolar Macrophage Activation and Emphysema in Response to Cigarette Smoke.
RAGE is a Critical Mediator of Pulmonary Oxidative Stress, Alveolar Macrophage Activation and Emphysema in Response to Cigarette Smoke.
复制标题
RAGE 是香烟烟雾引起的肺氧化应激、肺泡巨噬细胞激活和肺气肿的关键调节因子。
DOI：
10.1038/s41598-018-36163-z
复制
发表时间：
2019
影响因子：
4.6
通讯作者：
Hoidal,JohnR
中科院分区：
文献类型：
--
作者：
Sanders,KarlA;Delker,DonA;Huecksteadt,Tom;Beck,Emily;Wuren,Tanna;Chen,Yuntian;Zhang,Yuxia;Hazel,MarkW;Hoidal,JohnR
晚期糖基化终末产物受体（receptor for advanced glycation end products，简称AGEs）是一种细胞膜受体，可识别香烟烟雾产生的配体，与COPD的发病机制有关。我们证明，删除或药理学抑制的CS2可以防止CS诱导的肺气肿的发展。为了鉴定CS介导吸烟相关肺损伤的分子途径，我们对从暴露于CS一周或四个月的C57 BL/6 WT小鼠和C57 BL/6 null小鼠获得的肺泡巨噬细胞（AM）进行了无偏倚的基因表达谱分析。RNA表达的途径分析鉴定了许多与COPD发病机制相关的基因，这些基因受COPD缺乏的影响。抗氧化反应基因的表达和肺蛋白4-HNE免疫染色的改变表明，尽管CS暴露和肺白细胞负荷与WT小鼠相当，但在BMP-null小鼠中的氧化应激减弱。降低内质网应激反应CS曝光也观察到AM从numb null小鼠。这些发现提供了新的洞察来源的氧化应激，巨噬细胞活化，和肺部疾病的发病机制，由于CS暴露。
The receptor for advanced glycation end products (RAGE), a cell membrane receptor, recognizes ligands produced by cigarette smoke (CS) and has been implicated in the pathogenesis of COPD. We demonstrate that deletion or pharmacologic inhibition of RAGE prevents development of CS-induced emphysema. To identify molecular pathways by which RAGE mediates smoking related lung injury we performed unbiased gene expression profiling of alveolar macrophages (AM) obtained from RAGE null and C57BL/6 WT mice exposed to CS for one week or four months. Pathway analysis of RNA expression identified a number of genes integral to the pathogenesis of COPD impacted by the absence of RAGE. Altered expression of antioxidant response genes and lung protein 4-HNE immunostaining suggest attenuated oxidative stress in the RAGE null mice despite comparable CS exposure and lung leukocyte burden as the WT mice. Reduced endoplasmic reticulum stress in response to CS exposure also was observed in the AM from RAGE null mice. These findings provide novel insight into the sources of oxidative stress, macrophage activation, and the pathogenesis of lung disease due to CS exposure.