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Background Idiopathic pulmonary fibrosis is a devastating fibrotic diffuse parenchymal lung disorder that remains refractory to pharmacological therapies. Therefore, novel treatments are urgently required. CCAAT/enhancer binding protein delta (C/EBPδ) is a transcription factor that mediates critical cellular functions in pathophysiology and which was recently suggested to be a key regulatory component in IPF. The purpose of this study was to prove or refute the importance of C/EBPδ in pulmonary fibrosis. Methods Pulmonary fibrosis was induced by intranasal instillation of bleomycin into wild-type and C/EBPδ deficient mice. At different time intervals after bleomycin instillation, fibrosis was assessed by hydroxyproline analysis, histochemistry and q-PCR for fibrotic marker expression. Results C/EBPδ deficient mice developed pulmonary fibrosis to a similar degree as wildtype mice as evident from similar Ashcroft scores, hydroxyproline levels and expression levels of collagen, fibronectin and α-smooth muscle actin at both 14 and 21 days after bleomycin instillation. The resolution of fibrosis, assessed at 48 days after bleomycin instillation, was also similar in wildtype and C/EBPδ deficient mice. In line with the lack of effect of C/EBPδ on fibrosis progression/resolution, macrophage recruitment and/or differentiation were also not different in wildtype or C/EBPδ deficient mice. Conclusions Overall, C/EBPδ does not seem to affect bleomycin-induced experimental pulmonary fibrosis and we challenge the importance of C/EBPδ in pulmonary fibrosis. Relevance for patients This study shows that the transcription factor C/EBPδ does not play a major role in the development of pulmonary fibrosis. Pharmacological targeting of C/EBPδ is therefore not likely to have a beneficial effect for patients suffering from pulmonary fibrosis.

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.