Exploring the composition of the small airway lining fluid using breath analysis

Abstract

The mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD), asthma and COVID-19 are not completely understood. The small airways, which are lined with the respiratory tract lining fluid (RTLF), represent the major site of inflammation in these diseases, and changes in the composition of the RTLF reflect the underlying inflammatory process. The aim of this thesis is to increase the knowledge on how smoking, asthma and SARS-CoV-2 infection affect the composition of the lining fluid in small airways, reflecting mechanisms of small airway inflammation, in samples obtained non-invasively through collection of exhaled particles. The variability and repeatability of the method used for the collection of exhaled particles in this thesis, the PExA method, was comparable with other methods used for the collection of RTLF and was not affected by the time interval between the measurements. The Surfactant protein A and albumin contents of exhaled particles were influenced by diurnal rhythm, highlighting the importance of considering the time of the day when the RTLF is sampled. Active smoking has a strong impact on the protein profile in RTLF and it appears to affect women and men differently, as more pronounced alterations were seen in women. The complement system was identified as a biological pathway strongly affected by active smoking. Local activation of the complement and coagulation systems was also observed in asthma, where it was associated with small airway dysfunction and asthma control. A mild SARS-CoV-2 infection was shown to cause alterations in the surfactant phospholipids and these changes appear to persist over time. During acute infection, increased small airway resistance was observed, which correlated with the abundance of several acute phase proteins, suggesting increased inflammation in small airways during mild COVID-19. These findings improve the understanding of the mechanisms driving these diseases and open up for new possibilities for targeted drug development and precision medicine.