The Overlap of Lung Tissue Transcriptome of Smoke Exposed Mice with Human Smoking and COPD

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.

Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking

“…Perhaps it is not surprising to see differences between our gene signatures and the gene signature reported by van den Berge et al . because the tissues are different (airway epithelium vs. whole lung tissue) and COPD genes are not necessarily the same as smoking genes as we have shown previously 17 .…”

Mouse Models and Online Resources for Functional Analysis of Osteoporosis Genome-Wide Association Studies

“…Further, co-expression of pathways associated with metabolic disease, cell adhesion, and the cell cycle are also highly conserved between the species (104), suggesting conserved mechanisms of regulation. In other diseases and tissues, strong concordance for eQTL identified in mice and humans has been observed (105, 106). Collectively, this suggests that, in bone, the examination of eQTL and gene co-expression in mice would be highly informative for human bone disease and provide valuable information toward functional validation of GWAS loci.…”

Dynamic changes in lung responses after single and repeated exposures to cigarette smoke in mice

“…These results are validated by the lack of an effect of cigarette smoke on the individual chemokines, cytokines and metalloproteases described in Tables 3 and 4. Changes in the immune system of the lung in response to chronic cigarette smoke exposure have previously been documented in humans [57], and have been found to be conserved in comparisons between human and mouse responses to chronic smoke [28, 58]. Decreases in the numbers of inflammatory cells and chemokines and immune suppression have also been well-documented as responses to smoke exposures [59–62].…”