Cystic fibrosis (CF) is an autosomal recessive genetic condition, predominantly of white populations, that impacts multiple organ systems. However, it is the chronic progressive lung disease of CF that causes the greatest morbidity and mortality. The disease is caused by mutations of the CFTR (cystic fibrosis transmembrane conductance regulator) gene. Consequently, the function of epithelial CFTR anion (chloride and bicarbonate) channels is compromised, leading to impaired anion and fluid secretion and airway surface dehydration, which in turn result in highly viscous airway mucus and impaired mucociliary clearance, setting the stage for mucus plugging, chronic inflammation, and polymicrobial infection (1). Such a state causes progressive and irreversible damage of the airways and lung parenchyma because recruited immune cells (predominantly neutrophils) release proteases, DNA, and reactive oxygen species and promote further immune cell recruitment by cytokine signaling. The introduction of CFTR modulators (potentiators, correctors, and amplifiers) in recent years has transformed the treatment of CF. Phase 2 trials of triple-combination therapy suggest that a CFTR modulator therapy approach may be effective in up to 90% of patients with CF (2, 3). Although the emerging therapies show immense promise, there are still patients with CF whose specific genotypes may not be amenable to these therapies. Furthermore, CFTR modulation alone may be insufficient to allow complete and lasting clearance of chronic airway infection and resolution of pulmonary inflammation, especially in the context of chronic CF lung disease with established structural lung damage (4). Importantly, it is unknown whether, or to what extent, these CFTR-directed therapies decrease protease activity. Until such a decrease has been demonstrated, novel antiprotease strategies are still highly relevant to limit tissue damage in CF lung disease.

The protease–antiprotease hypothesis is a simple paradigm that attempts to explain certain disease states as a product of an imbalance of proteases and cognate antiproteases, resulting in elevated protease activity and damaging consequences for lung homeostasis (5). It is now well established that proteases play a significant role in the pathobiology of the CF lung (6), regardless of whether they are derived from immune cells or indeed the cells of the lung itself. The perception of these enzymes’ roles has moved far beyond the terminal degradation of proteins; it is now recognized that proteases are key signaling molecules and that specific substrate cleavage can have myriad effects (7),