Mechanism of action of mucoactive drugs in a model of muco-obstructive lung disease

Abstract

Muco-obstructive lung diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and chronic bronchiectasis, represent a significant healthcare burden worldwide. These conditions are characterised by excessive mucus production and dehydration, airway obstruction, impaired mucociliary clearance, and declining pulmonary function. A primary feature of disease progression is the imbalance between proteases and anti-proteases in the airways, contributing to extracellular matrix degradation, chronic inflammation, and progressive lung damage. Despite affecting millions globally and contributing substantially to morbidity and mortality, current treatments are largely supportive and aimed at symptom management rather than addressing underlying disease mechanisms. However, as the efficacy of existing therapies tends to decline with disease progression, there is an urgent need for improved treatment strategies and approaches targeting the fundamental defects in mucus homeostasis and airway function. Therefore, this thesis investigated the role of secretory leukocyte protease inhibitor (SLPI) in muco-obstructive lung disease pathogenesis and evaluated the therapeutic potential of carbocisteine, a mucoactive therapeutic, using the βENaC-transgenic (Tg) mouse model, which mimics principal features of CF and COPD.

To investigate the role of SLPI in chronic lung disease βENaC-Tg mice were crossed with SLPI knock-out (SLPI-/-) mice, generating a βENaC-Tg/SLPI-/-colony. Results of this study have demonstrated that SLPI contributes to the modulation of airway protease activity, inflammatory cell recruitment, and immune cell activation, with distinct effects observed in juvenile and adult populations. In juvenile mice, SLPI deficiency altered airway protease activity, promoting MMP-2 and TIMP-1 degradation and MMP-9 activation, an effect attributed to increased unregulated NE activity, further promoting proteolytic activity in the early muco-obstructive phenotype. Conversely, in adult mice, SLPI ablation was observed to facilitate mononuclear cell recruitment into the airways through regulated changes in endothelial cell adhesion, potentially mediated by alterations in IL-1 signalling and increasedICAM-1 expression.

In addition, short-term administration of carbocisteine was demonstrated to effectively regulate mucus secretion and mitigate airway obstruction in a model of established muco-obstructive lung disease. Notably, therapeutic treatment with carbocisteine was observed to further modulate the inducers of mucus production, revealing a more comprehensive mechanism of action on regulatory pathways than previously understood. Carbocisteine administration was observed to induce alterations in mononuclear cell populations and modulate specific inflammatory subsets, indicating a broader impact of the treatment, either through direct mechanisms or secondary to mucoregulatory effects. However, despite an effect on immune cell populations, short-term administration failed to mitigate inflammation associated with established muco-obstructive lung disease.

These findings highlight the complex role of SLPI in maintaining airway homeostasis by modulating inflammation, protease activity, and mucus obstruction in muco-obstructive lung diseases, with effects being influenced in an age-dependent manner. Concurrently, carbocisteine exhibits potent mucoactive potential in established muco-obstructive lung disease, through a broader mechanism of action than previously understood, while holding potential in modulating inflammatory responses for preventative or long-term treatment strategies.

Thesis is embargoed until 31st July 2027.

Date of Award	Jul 2025
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Bronwen Connolly (Supervisor), Cliff Taggart (Supervisor), Danny McAuley (Supervisor) & Ryan Brown (Supervisor)