Abstract
Genome-wide mRNA profiling in lung tissue from human and animal models can provide novel insights into the pathogenesis of chronic obstructive pulmonary disease (COPD). While 6 months of smoke exposure are widely used, shorter durations were also reported. The overlap of short term and long-term smoke exposure in mice is currently not well understood, and their representation of the human condition is uncertain. Lung tissue gene expression profiles of six murine smoking experiments (n = 48) were obtained from the Gene Expression Omnibus (GEO) and analyzed to identify the murine smoking signature. The “human smoking” gene signature containing 386 genes was previously published in the lung eQTL study (n = 1,111). A signature of mild COPD containing 7 genes was also identified in the same study. The lung tissue gene signature of “severe COPD” (n = 70) contained 4,071 genes and was previously published. We detected 3,723 differentially expressed genes in the 6 month-exposure mice datasets (FDR <0.1). Of those, 184 genes (representing 48% of human smoking) and 1,003 (representing 27% of human COPD) were shared with the human smoking-related genes and the COPD severity-related genes, respectively. There was 4-fold over-representation of human and murine smoking-related genes (P = 6.7 × 10−26) and a 1.4 fold in the severe COPD -related genes (P = 2.3 × 10−12). There was no significant enrichment of the mice and human smoking-related genes in mild COPD signature. These data suggest that murine smoke models are strongly representative of molecular processes of human smoking but less of COPD.
Highlights
Cigarette 2R4F 1R3F 3R4F NA 3R4F* 2R4F 3R4F NA in vitro and in vivo studies are required to disentangle mechanism and establish causality
Pre-clinical animal models represent a valuable tool for understanding the pathogenesis of chronic obstructive pulmonary disease (COPD) and identifying novel therapeutics and biomarkers
To date, there has been a scarcity of data that have directly compared molecular profiles in the lungs of smoke-exposed mice that have been used to model COPD against those of human lungs in order to determine how ‘disease’ in these animals is representative of the human condition
Summary
Cigarette 2R4F 1R3F 3R4F NA 3R4F* 2R4F 3R4F NA in vitro and in vivo studies are required to disentangle mechanism and establish causality. 6 months of smoke exposure is used to induce histological and functional abnormalities in murine lungs that mimic those of human disease including emphysema, airway remodeling and pulmonary hypertension, though the changes are relatively mild compared with those observed in long-term human smokers[16]. How gene expression profiles compare between short term and long term smoke exposure is currently not well understood. The availability of genome-wide transcriptomic signatures in lung tissue enables comparisons between human and murine models following short- and long-term cigarette smoke exposures. The aims of this study were to compare and contrast the molecular changes in murine models following short and long term exposures with the molecular changes in human lungs induced by cigarette smoke. We sought to determine, if the human “COPD” lung tissue gene expression signature is captured in murine lungs exposed to cigarette smoke
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