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.

Helminth excretory-secretory products, including helminth defence molecules (HDMs), are potent immunomodulatory compounds released throughout the course of infection. A HDM from Fasciola hepatica (FhHDM-1) and its C-terminal derivative (FhHDM-1.C2) exhibit potent immunomodulatory properties in models of autoimmune and inflammatory disease, offering a potential avenue for the development of novel therapeutics. The aim of this study was to investigate the effects of FhHDM-1 and its derivative peptide in models of acute lung inflammation. FhHDM-1 and FhHDM-1.C2 inhibited Escherichia coli and Pseudomonas aeruginosa LPS-induced TNF-α release in murine macrophages. In vivo, prophylactic and therapeutic administration of both FhHDM-1 and FhHDM-1.C2 significantly decreased total cells and polymorphonuclear leukocytes in the bronchoalveolar lavage fluid (BALF). Levels of pro-inflammatory cytokines IL-6 and CXCL1/KC were also reduced in BALF. Current work is investigating intracellular targets of the FhHDM peptides within the lung and our research suggests a potential role for AMP-activated protein kinase (AMPK). Overall, our findings indicate that FhHDM-1 and FhHDM-1.C2 limit LPS-induced acute lung inflammation and may represent a novel biotherapeutic for neutrophil-dominated lung disease.