Smoking induces sex-specific changes in the small airway proteome

Benjamin Georgi,Spela Kokelj,Henric K Olsson,Jörgen Östling,Anna-Carin Olin,Kristina Nilsson Ekdahl,Karin Fromell

doi:10.1186/s12931-021-01825-6

Abstract

IntroductionCigarette smoke triggers many cellular and signaling responses in the lung and the resulting inflammation plays a central role in smoke-related lung diseases, such as COPD. We explored the effects of smoking on the small airway proteome in samples obtained by collection of exhaled particles with the aim to identify specific proteins dysregulated by smoking.MethodsExhaled particles were obtained from 38 current smokers, 47 former smokers and 22 healthy controls with the PExA method. 120 ng of sample was collected from individual subjects and analyzed with the SOMAscan proteomics platform. General linear model-based statistics were performed.ResultsTwo hundred and three proteins were detected in at least half of 107 total samples. Active smoking exerted a significant impact on the protein composition of respiratory tract lining fluid (RTLF), with 81 proteins altered in current smokers compared to never smokers (p < 0.05, q < 0.124). Among the proteins most clearly discriminating between current and never smokers were sRAGE, FSTL3, SPOCK2 and protein S, all of them being less abundant in current smokers. Analysis stratified for sex unveiled sex differences with more pronounced proteomic alterations due to active smoking in females than males. Proteins whose abundance was altered by active smoking in women were to a larger extent related to the complement system. The small airway protein profile of former smokers appeared to be more similar to that observed in never smokers.ConclusionsThe study shows that smoking has a strong impact on protein expression in the small airways, and that smoking affects men and women differently, suggesting PExA sampling combined with high sensitivity protein analysis offers a promising platform for early detection of COPD and identification of novel COPD drug targets.

Highlights

Cigarette smoke triggers many cellular and signaling responses in the lung and the resulting inflam‐ mation plays a central role in smoke-related lung diseases, such as chronic obstructive pulmonary disease (COPD)
Demographic and clinical characteristics Female former smokers had significantly lower postFEV1/Forced vital capacity (FVC) and post-Maximal mid-expiratory flow (MMEF)/FVC ratio compared to never smokers, while no significant difference was observed between female current and never smokers
The results indicated that post-Forced expiratory volume in 1 s (FEV1)/FVC and postMMEF/FVC ratio was lower in male current and former smokers compared to never smokers

Summary

Introduction

Cigarette smoke triggers many cellular and signaling responses in the lung and the resulting inflam‐ mation plays a central role in smoke-related lung diseases, such as COPD. The inhalation of cigarette smoke triggers many cellular and signalling responses in the lung and the resulting inflammation plays a central role in smoke-related lung diseases [7]. Several proteomic studies applied to sputum, lung tissue and bronchoalveolar lavage (BAL) fluid from never, former and current smokers [7, 9] have identified smokeinduced alterations in proteins involved in the response to oxidative stress and inflammation as well as in extracellular matrix organization and wound healing [9, 10]. Several complement factors are synthesized locally in the lungs by the alveolar type II cells [14], providing a basis for local complement system activation and initiation of inflammation. Exposure to cigarette smoke has been reported to activate the alternative complement pathway [16], whereas inhibition of the alternative pathway is protective in preclinical models of lung injury [11]

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Results

Conclusion