Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease

Abstract

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.

Keywords: antiproteases; chronic lung disease; inflammation; muco-obstructive lung disease; mucociliary clearance; mucosal immunity; mucus; proteases.

Figure 1

The effect of proteases on mucus and mucociliary clearance in the chronically inflamed airway. Proteases contribute to CLD pathogenesis through their impact on every step of the MCC mechanism. Elevated protease activity leads to (A) activation of ENaC and (B) loss of CFTR at the epithelial surface contributing to airway surface dehydration. (C) Protease-dependent damage to ciliated epithelial cells and cleavage of ciliary proteins leads to ineffective mucus clearance. This clearance defect is compounded by (D) protease-mediated increases in mucin expression and secretion from goblet cells and submucosal glands resulting in a highly viscous mucus layer that can no longer be cleared effectively. (E) Proteases can degrade mucins and (F) induce release of NETs, which may further alter mucus viscoelastic properties. Together, protease-dependent mucin/mucus hypersecretion and mucus dehydration produce highly viscous mucus, setting the stage for mucus plugging in the airways of patients with muco-obstructive lung disease.