Fig. 7. Epithelial defects in CF airways occur as a ‘two-hit’ event.

In healthy airway epithelial cells functional PM CFTR has a role in protecting against EMT. However, when dysfunctional CFTR is present in these cells a shift occurs towards a less differentiated state, and the cells are more susceptible to EMT upon EMT stimuli (e.g. TGF-β1). A partial EMT occurs with cells losing their normal epithelial architecture while increasing levels of both mesenchymal markers and EMTa-TFs. Upon progression of CF lung disease, the lungs of CF individuals present the perfect mixture of conditions (e.g. constant inflammatory factors, such as TGF-β1, hypoxia, aberrant myofibroblast persistence and invasion by pathogens such as Pseudomonas) for further aberrant differentiation and enhanced EMT over time. (CK cytokeratin; DSM desmosomes; IF intermediate filaments; MTs microtubules; Ncad N-cadherin).