Investigators were able to distinguish current smokers from ex-smokers with severe asthma based on the patient’s sputum proteomic level of colony stimulating factor (CSF) 2, according to an article published in the European Respiratory Journal.

Smokers with asthma may have poorly controlled asthma and a poor response to corticosteroid therapy. Their lung function may decline in an accelerated manner, and they often use more healthcare resources. Researchers from the United Kingdom and Japan set out to describe the differences in protein and gene expression among patients with severe asthma who still smoked, those with asthma who had quit smoking, and those with asthma who had never smoked.

The investigators analyzed data from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) project on blood and sputum cell counts, fractional exhaled nitric oxide, and spirometry. 

U-BIOPRED recruited patients with severe asthma, including both active/current smokers and ex-smokers, as well as nonsmokers and healthy nonsmokers. The investigators performed exploratory proteomic analysis of sputum supernatants and transcriptomic analysis of bronchial brushing, biopsies, and sputum cells.


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CSF2 protein levels were increased in current smokers’ sputum supernatants, and azurocidin 1, neutrophil elastase, and CXCL8 were upregulated in ex-smokers. In ex-smokers, phagocytosis and innate immune pathways were associated with neutrophilic inflammation. Gene Set Variation Analysis of bronchial epithelial cell transcriptome from current smokers demonstrated an enrichment of xenobiotic metabolism, oxidative stress, and endoplasmic reticulum stress, but there were no significant differences between ex-smoker and nonsmoker patients for these pathways. CXCL5 and matrix metallopeptidase 12 genes were upregulated in ex-smokers and the epithelial protective genes, mucin 2, and cystatin SN, were downregulated.

The authors noted that distinct pathways were activated in current smokers and nonsmoker sputum, and sputum protein data suggested that being an ex-smoker with asthma was associated with airway epithelial cell damage. Overall, although current smokers could be differentiated from nonsmokers using proteomics and transcriptomics, ex-smokers and nonsmokers could only be distinguished using sputum proteomics.

The authors suggested that increased activation of the xenobiotic response and oxidative and endoplasmic reticulum stress pathways influence innate immunity in patients who are current smokers. 

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The authors concluded that current smokers with severe asthma are characterized by increased sputum CFS2 and anterior gradient protein 2 expression, indicating enhanced macrophage recruitment and mucus production as well as airway tissue genes associated with increased xenobiotic metabolism and responses to oxidative and endoplasmic reticulum stress. However, airway gene expression analysis demonstrated few differences between patients with severe asthma who were ex-smokers and patients who had never smoked.

Reference

Takahashi K, Pavlidis S, Ng Kee Kwong K, et al. Sputum proteomics and airway cell transcripts of current and ex-smokers with severe asthma in U-BIOPRED: an exploratory analysis [published online April 12, 2018]. Eur Respir J. doi:10.1183/13993003.02173-2017