Massachusetts General Hospital, Boston, Massachusetts, United States of America.
PLoS One. 2013 May 13;8(5):e62910. doi: 10.1371/journal.pone.0062910. Print 2013.
Endotoxin is a near ubiquitous environmental exposure that that has been associated with both asthma and chronic obstructive pulmonary disease (COPD). These obstructive lung diseases have a complex pathophysiology, making them difficult to study comprehensively in the context of endotoxin. Genome-wide gene expression studies have been used to identify a molecular snapshot of the response to environmental exposures. Identification of differentially expressed genes shared across all published murine models of chronic inhaled endotoxin will provide insight into the biology underlying endotoxin-associated lung disease.
We identified three published murine models with gene expression profiling after repeated low-dose inhaled endotoxin. All array data from these experiments were re-analyzed, annotated consistently, and tested for shared genes found to be differentially expressed. Additional functional comparison was conducted by testing for significant enrichment of differentially expressed genes in known pathways. The importance of this gene signature in smoking-related lung disease was assessed using hierarchical clustering in an independent experiment where mice were exposed to endotoxin, smoke, and endotoxin plus smoke.
A 101-gene signature was detected in three murine models, more than expected by chance. The three model systems exhibit additional similarity beyond shared genes when compared at the pathway level, with increasing enrichment of inflammatory pathways associated with longer duration of endotoxin exposure. Genes and pathways important in both asthma and COPD were shared across all endotoxin models. Mice exposed to endotoxin, smoke, and smoke plus endotoxin were accurately classified with the endotoxin gene signature.
Despite the differences in laboratory, duration of exposure, and strain of mouse used in three experimental models of chronic inhaled endotoxin, surprising similarities in gene expression were observed. The endotoxin component of tobacco smoke may play an important role in disease development.
内毒素是一种普遍存在的环境暴露物，与哮喘和慢性阻塞性肺疾病（COPD）都有关联。这些阻塞性肺部疾病的病理生理学较为复杂，因此很难在涉及内毒素的情况下对其进行全面研究。全基因组基因表达研究已被用于确定对环境暴露的分子反应快照。确定所有已发表的慢性吸入内毒素的小鼠模型中共享的差异表达基因，将有助于深入了解内毒素相关肺部疾病的生物学基础。
我们鉴定了三个具有重复低剂量吸入内毒素后进行基因表达谱分析的已发表小鼠模型。对这些实验的所有阵列数据进行了重新分析、一致注释，并对差异表达的共享基因进行了测试。通过测试差异表达基因在已知途径中的显著富集，进行了额外的功能比较。使用在暴露于内毒素、烟雾和内毒素加烟雾的独立实验中进行的分层聚类，评估了该基因特征在与吸烟相关的肺部疾病中的重要性。
在三个小鼠模型中检测到了一个 101 个基因的特征，其数量超过了随机预期。与共享基因相比，这三个模型系统在途径水平上还表现出了更多的相似性，随着内毒素暴露时间的延长，炎症途径的富集程度也随之增加。在所有内毒素模型中都存在与哮喘和 COPD 都相关的重要基因和途径。用内毒素基因特征可以准确地对暴露于内毒素、烟雾和内毒素加烟雾的小鼠进行分类。
尽管在三个慢性吸入内毒素的实验模型中存在实验室、暴露时间和小鼠品系的差异，但观察到的基因表达惊人地相似。烟草烟雾中的内毒素成分可能在疾病发展中起着重要作用。
