Abstract
BackgroundSmoking represents a significant risk factor for many chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD).MethodsTo identify dysregulation of specific proteins and pathways in bronchoalveolar lavage (BAL) cells associated with smoking, isobaric tags for relative and absolute quantitation (iTRAQ)-based shotgun proteomics analyses were performed on BAL cells from healthy never-smokers and smokers with normal lung function from the Karolinska COSMIC cohort. Multivariate statistical modeling, multivariate correlations with clinical data, and pathway enrichment analysis were performed.ResultsSmoking exerted a significant impact on the BAL cell proteome, with more than 500 proteins representing 15 molecular pathways altered due to smoking. The majority of these alterations occurred in a gender-independent manner. The phagosomal- and leukocyte trans endothelial migration (LTM) pathways significantly correlated with FEV1/FVC as well as the percentage of CD8+ T-cells and CD8+CD69+ T-cells in smokers. The correlations to clinical parameters in healthy never-smokers were minor.ConclusionThe significant correlations of proteins in the phagosome- and LTM pathways with activated cytotoxic T-cells (CD69+) and the level of airway obstruction (FEV1/FVC) in smokers, both hallmarks of COPD, suggests that these two pathways may play a role in the molecular events preceding the development of COPD in susceptible smokers. Both pathways were found to be further dysregulated in COPD patients from the same cohort, thereby providing further support to this hypothesis. Given that not all smokers develop COPD in spite of decades of smoking, it is also plausible that some of the molecular pathways associated with response to smoking exert protective mechanisms to smoking-related pathologies in resilient individuals.Trial registrationClinicalTrials.gov identifier NCT02627872; Retrospectively registered on December 9, 2015.
Highlights
Smoking represents a significant risk factor for many chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD)
The direct effect of tobacco smoking was responsible for the death of 6 million people in 2015, with 27% of them resulting from COPD [2]
The results clearly show that smoking exerted a considerable impact on the bronchoalveolar lavage (BAL) cell proteome, with the abundances of half of the detected proteins being altered in long-term smokers
Summary
Smoking represents a significant risk factor for many chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). One-third of long-term smokers develop COPD [3], the molecular mechanisms by which smoking-induced inflammation triggers the development of disease remain unclear. Urine and lung tissue from smokers has improved our understanding of the molecular impact of smoking [4,5,6]. Quantitative proteomics analysis of resident immune cells in the lung, with respect to the inflammatory disorder in the response to smoking, are scarce. In order to define molecular disease mechanisms occurring prior to disease manifestations, alterations of the BAL cell proteome in response to smoking needs to be defined
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