The Role of IL-4/IL-13 Signalling in Mucociliary Clearance in Bronchiectasis

Student thesis: Master's ThesisMaster of Science

Abstract

Bronchiectasis is a pulmonary condition defined by abnormal bronchial dilation resulting in chronic cough, inflammation, and repeated chest infections. Cilia are tiny hair-like structures in the airways which beat in a co-ordinated fashion to remove harmful pathogens trapped by mucus. Mucociliary dysfunction is a feature of inflammatory lung diseases like bronchiectasis and COPD which are believed to be primarily Th1 driven, and asthma which is believed to be predominantly Th2 driven. It is now recognised there is substantial overlap in the inflammatory pathways between different airway diseases. We hypothesised that both Th1 and Th2 inflammation may be associated with mucociliary dysfunction. To investigate the mechanisms of mucociliary dysfunction we performed inflammatory profiling in sputum from patients with bronchiectasis enrolled in a European cohort study. Principle component analysis of a panel of cytokines identified two different subgroups one defined by Th2 cytokines and another dominated by Th1 and neutrophil proteins. To investigate the Th2 subgroup, ciliated nasal epithelial cells grown at air liquid interface were treated with Th2 cytokines for 3 weeks and cilia parameters recorded using high-speed video microscopy. IL-4 significantly decreased ciliary beat frequency whereas IL-13 had no significant effect. Tiotropium (an inhibitor of mucus release) did not prevent the IL-4 induced decrease in cilia beat frequency. Finally, this project compared mucus properties in different respiratory conditions. The sputum percentage dry weight, rheology and inflammatory markers were compared between groups. Each of these parameters was different between disease and control groups, but few differences between CF, bronchiectasis, asthma and COPD were observed. Principle component analysis highlighted two sub-groups of patients defined by Th1/neutrophilic inflammation and Th2 high inflammation regardless of their condition. It can be concluded that a proportion of patients with bronchiectasis and other respiratory conditions have IL-4 associated Th2 inflammation and that IL-4 reduces cilia function thus propagating the cycle of disease.
Date of Award2022
Original languageEnglish
SupervisorAmelia Shoemark (Supervisor) & James Chalmers (Supervisor)

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