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Cathepsin S (CatS) is upregulated in the lungs of patients with cystic fibrosis (CF). However, its role in CF lung disease pathogenesis remains unclear.In this study, β-epithelial Na + channel-overexpressing transgenic (βENaC-Tg) mice, a model of CF-like lung disease, were crossed with CatS null (CatS -/- ) mice or treated with the CatS inhibitor VBY-999.Levels of active CatS were elevated in the lungs of βENaC-Tg mice compared with wild-type (WT) littermates. CatS -/- βENaC-Tg mice exhibited decreased pulmonary inflammation, mucus obstruction and structural lung damage compared with βENaC-Tg mice. Pharmacological inhibition of CatS resulted in a significant decrease in pulmonary inflammation, lung damage and mucus plugging in the lungs of βENaC-Tg mice. In addition, instillation of CatS into the lungs of WT mice resulted in inflammation, lung remodelling and upregulation of mucin expression. Inhibition of the CatS target, protease-activated receptor 2 (PAR2), in βENaC-Tg mice resulted in a reduction in airway inflammation and mucin expression, indicating a role for this receptor in CatS-induced lung pathology.Our data indicate an important role for CatS in the pathogenesis of CF-like lung disease mediated in part by PAR2 and highlight CatS as a therapeutic target., Competing Interests: Conflict of interest: D.M. Small has nothing to disclose. Conflict of interest: R.R. Brown has nothing to disclose. Conflict of interest: D.F. Doherty has nothing to disclose. Conflict of interest: A. Abladey has nothing to disclose. Conflict of interest: Z. Zhou-Suckow has nothing to disclose. Conflict of interest: R.J. Delaney has nothing to disclose. Conflict of interest: L. Kerrigan has nothing to disclose. Conflict of interest: C.M. Dougan has nothing to disclose. Conflict of interest: K.S. Borensztajn has nothing to disclose. Conflict of interest: L. Holsinger is an employee of Virobay. Conflict of interest: R. Booth has a patent US 7,547,701 issued. Conflict of interest: C.J. Scott is a consultant for Fusion Antibodies PLC, outside the submitted work; and is named inventor on various patents on antibodies to cathepsin S for treatment of cancer, many of which have now lapsed as not a current research direction for the company (Fusion Antibodies PLC). Conflict of interest: G. López-Campos has nothing to disclose. Conflict of interest: J.S. Elborn reports personal fees for advisory board work from Bayer, grants and personal fees for advisory board work from Horizion, during the conduct of the study; personal fees for advisory board work from Chiesi and Polyphor, outside the submitted work. Conflict of interest: M.A. Mall reports grants from German Federal Ministry of Education and Research (contract numbers 82DZL00401 and 82DZL004A1), during the conduct of the study; personal fees for advisory board and consultancy work from Spyryx Biosciences, Boehringer Ingelheim and Polyphor, personal fees for advisory board work from ProQR, PTC Pharmaceuticals, Arrowhead and Pro Axis, personal fees for consultancy and lecturing from Bayer, personal fees for consultancy from Enterprise Therapeutics and Sterna Biologicals, personal fees for advisory board work, consultancy and lecturing from Vertex Pharmaceuticals, outside the submitted work; and has a patent on the Scnn1b-transgenic mouse with royalties paid. Conflict of interest: S. Weldon reports grants from Randox and Pfizer UK, outside the submitted work. Conflict of interest: C.C. Taggart reports personal fees for consultancy from Albumedix, and grants from Randox and Pfizer UK, outside the submitted work., (Copyright ©ERS 2019.)

Members of the whey acidic protein (WAP) or WAP four-disulfide-core (WFDC) family of proteins are a relatively under-explored family of low molecular weight proteins. The two most prominent WFDC proteins, secretory leukocyte protease inhibitor (SLPI) and elafin (or the precursor, trappin-2), have been shown to possess multiple functions including anti-protease, anti-bacterial, anti-viral and anti-inflammatory properties. It is therefore of no surprise that both SLPI and elafin/trappin-2 have been developed as potential therapeutics. Given the abundance of SLPI and elafin/trappin-2 in the human lung, most work in the area of WFDC research has focused on the role of WFDC proteins in protecting the lung from proteolytic attack. In this review, we will outline the current evidence regarding the expanding role of WFDC protein function with a focus on WFDC activity in lung disease as well as emerging data regarding the function of some of the more recently described WFDC proteins.