Figure 7. Model depicting pathological cascade in CF based on increased furin activity and elevated TGF-β levels.

Low intra-organellar (TGN and recycling endosome) pH in CF cells increases furin activity in respiratory epithelial cells, which causes a cascade of downstream effects. Left: Increased TGF-β maturation due to its enhanced processing contributes to suppression of iNOS and increased secretion of fibrotic tissue components (collagen). Increased TGF-β further augments furin levels in a positive feedback loop. Increased TGF-β leads to tissue fibrosis contributing to bronchiectasis, and local immunosuppression. Right: Increased activation of P. aeruginosa ExoA by furin in the TGN leads to higher cytotoxicity. These defects underlie the majority of salient aspects of lung disease in CF.