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Macrophage migration inhibitory factor (MIF) is a cytokine found to be associated with chronic obstructive pulmonary disease (COPD). However, there is no consensus on how MIF levels differ in COPD compared to control conditions and there are no reports on MIF expression in lung tissue. Here we studied gene expression of members of the MIF family MIF, D-Dopachrome Tautomerase (DDT) and DDT-like (DDTL) in a lung tissue dataset with 1087 subjects and identified single nucleotide polymorphisms (SNPs) regulating their gene expression. We found higher MIF and DDT expression in COPD patients compared to non-COPD subjects and found 71 SNPs significantly influencing gene expression of MIF and DDTL. Furthermore, the platform used to measure MIF (microarray or RNAseq) was found to influence the splice variants detected and subsequently the direction of the SNP effects on MIF expression. Among the SNPs found to regulate MIF expression, the major LD block identified was linked to rs5844572, a SNP previously found to be associated with lower diffusion capacity in COPD. This suggests that MIF may be contributing to the pathogenesis of COPD, as SNPs that influence MIF expression are also associated with symptoms of COPD. Our study shows that MIF levels are affected not only by disease but also by genetic diversity (i.e. SNPs). Since none of our significant eSNPs for MIF or DDTL have been described in GWAS for COPD or lung function, MIF expression in COPD patients is more likely a consequence of disease-related factors rather than a cause of the disease.

Genome-wide association studies have linked gene variants of the receptor patched homolog 1 (PTCH1) with chronic obstructive pulmonary disease (COPD). However, its biological role in the disease is unclear. Our objective was to determine the expression pattern and biological role of PTCH1 in the lungs of patients with COPD. Airway epithelial-specific PTCH1 protein expression and epithelial morphology were assessed in lung tissues of control and COPD patients. PTCH1 mRNA expression was measured in bronchial epithelial cells obtained from individuals with and without COPD. The effects of PTCH1 siRNA knockdown on epithelial repair and mucous expression were evaluated using human epithelial cell lines. Ptch1+/− mice were used to assess the effect of decreased PTCH1 on mucous expression and airway epithelial phenotypes. Airway epithelial-specific PTCH1 protein expression was significantly increased in subjects with COPD compared to controls, and its expression was associated with total airway epithelial cell count and thickness. PTCH1 knockdown attenuated wound closure and mucous expression in airway epithelial cell lines. Ptch1+/− mice had reduced mucous expression compared to wildtype mice following mucous induction. PTCH1 protein is up-regulated in COPD airway epithelium and may upregulate mucous expression. PTCH1 provides a novel target to reduce chronic bronchitis in COPD patients.

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 −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.