The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.

Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline. Some therapies exist for the treatment of these symptoms, but they are unable to halt disease progression and patients may benefit from novel adjunct therapies. In this review, we highlight how proteases act as multifunctional enzymes that are vital for normal airway homeostasis but, when their activity becomes immoderate, also directly contribute to airway dysfunction, and impair the processes that could resolve disease. We focus on how proteases regulate the state of mucus at the airway surface, impair mucociliary clearance and ultimately, promote mucostasis. We discuss how, in parallel, proteases are able to promote an inflammatory environment in the airways by mediating proinflammatory signalling, compromising host defence mechanisms and perpetuating their own proteolytic activity causing structural lung damage. Finally, we discuss some possible reasons for the clinical inefficacy of protease inhibitors to date and propose that, especially in a combination therapy approach, proteases represent attractive therapeutic targets for muco-obstructive lung diseases.

Background. Elevated levels of the cysteine protease cathepsin S (CatS) are associated with chronic mucoobstructive lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). We have previously demonstrated that prophylactic treatment with a CatS inhibitor from birth reduces inflammation, mucus plugging, and lung tissue damage in juvenile β‐epithelial Na+ channel‐overexpressing transgenic (βENaC‐Tg) mice with chronic inflammatory mucoobstructive lung disease. In this study, we build upon this work to examine the effects of therapeutic intervention with a CatS inhibitor in adult βENaC‐Tg mice with established disease. Methods. βENaC‐Tg mice and wild‐type (WT) littermates were treated with a CatS inhibitor from 4 to 6 weeks of age, and CatS^-/-βENaC‐Tg mice were analysed at 6 weeks of age. Bronchoalveolar lavage (BAL) fluid inflammatory cell counts were quantified, and lung tissue destruction and mucus obstruction were analysed histologically. Results. At 6 weeks of age, βENaC‐Tg mice developed significant airway inflammation, lung tissue damage, and mucus plugging when compared to WT mice. CatS^-/-βENaC‐Tg mice and βENaC‐Tg mice receiving inhibitor had significantly reduced airway mononuclear and polymorphonuclear (PMN) cell counts as well as mucus plugging. However, in contrast to CatS^-/-βENaC‐Tg mice, therapeutic inhibition of CatS in βENaC‐Tg mice had no effect on established emphysema‐like lung tissue damage. Conclusions. These results suggest that while early CatS targeting may be required to prevent the onset and progression of lung tissue damage, therapeutic CatS targeting effectively inhibited airway inflammation and mucus obstruction. These results indicate the important role CatS may play in the pathogenesis and progression of mucoobstructive lung disease.

Elevated levels of the cysteine protease cathepsin S (cat S) are found in cystic fibrosis (CF) lung secretions, however, the role of cat S in CF lung disease is unclear. Cat S is capable of maintaining its activity at a neutral pH allowing it to remain active outside of the cell. Consequently, cat S has the capacity to promote remodelling of the extracellular matrix via its potent elastolytic activity. In addition, cat S can cleave and inactivate key antimicrobials in the CF airways. On the basis of findings to date, we hypothesise that active cat S contributes to the pathogenesis of CF lung disease and represents a viable therapeutic target for the treatment of chronic lung disease. The βENaC transgenic mouse model recapitulates essential features of chronic CF lung disease such as airway mucus obstruction, inflammatory lung damage and increased levels of cat S activity in the lungs when compared to wild-type controls. Pharmacological knockdown of cat S activity was achieved in the βENaC mouse using the cat S inhibitor VBY-999. Findings to date suggest that inhibition of cat S reduces inflammatory cell infiltration into the lung as well as levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid in both the early and late stage lung disease in the βENaC mouse model. Furthermore, concomitant reductions in mucus plugging were also observed. Late treatment with the cat S inhibitor had no effect on lung tissue damage, however, mucus plugging was reduced. These results support the hypothesis that active cat S plays a role in the pathogenesis of chronic lung disease and may be a viable and promising target in the treatment of diseases such as CF.

Secretory leukocyte proteinase inhibitor (SLPI) is a major airways antiprotease. Its primary function is considered to be the inhibition of damaging neutrophil elastase activity, however, it also exerts antimicrobial and immunomodulatory activity. The presence of a protease/antiprotease imbalance and associated dysregulation of the levels and/or activity of host defence proteins like SLPI are features of chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. The aim of this study was to elucidate the effects of sustained SLPI inactivation on the development and progression of chronic muco-inflammatory lung disease. β-epithelial Na+ channel-overexpressing transgenic (ENaC) mice, a model of chronic lung disease, were crossed with SLPI null (SLPI^-/-) mice to generate four genotypes; WT, SLPI^-/-, ENaC and ENaC/SLPI^-/-. Juvenile (2-3 wk old) and adult (8-14 wk old) mice were assessed for inflammatory markers, lung damage and mucus plugging. Levels of SLPI were elevated in the ENaC mice. Genetic deletion of SLPI resulted in increased protease activity and immune cell infiltration in both WT and ENaC mice. However, there was no significant effect on lung damage, airway mucus plugging or lung function in these mice. These data suggest that, while SLPI may ameliorate the recruitment of inflammatory cells in chronic lung disease, it does not limit the development of lung damage or airway mucus plugging in this model during the timeframe analysed. Further work to examine the mechanisms by which SLPI specifically regulates inflammatory cell recruitment in this model of muco-inflammatory lung disease is ongoing.