Epithelial-to-mesenchymal transition (EMT) is a reversible process, in which epithelial cells lose their epithelial traits and acquire a mesenchymal phenotype. This transformation has been described in different lung diseases, such as lung cancer, interstitial lung diseases, asthma, chronic obstructive pulmonary disease and other muco-obstructive lung diseases, such as cystic fibrosis and non-cystic fibrosis bronchiectasis. The exaggerated chronic inflammation typical of these pulmonary diseases can induce molecular reprogramming with subsequent self-sustaining aberrant and excessive profibrotic tissue repair. Over time this process leads to structural changes with progressive organ dysfunction and lung function impairment. Although having common signalling pathways, specific triggers and regulation mechanisms might be present in each disease. This review aims to describe the various mechanisms associated with fibrotic changes and airway remodelling involved in chronic airway diseases. Having better knowledge of the mechanisms underlying the EMT process may help us to identify specific targets and thus lead to the development of novel therapeutic strategies to prevent or limit the onset of irreversible structural changes.

Aerosol lung gene therapy using non-viral delivery systems represents a credible therapeutic strategy for chronic respiratory diseases, such as cystic fibrosis (CF). Progress in CF clinical setting using the lipidic formulation GL67A has demonstrated the relevance of such a strategy while emphasizing the need for more potent gene transfer agents. In recent years, many novel non-viral gene delivery vehicles were proposed as potential alternatives to GL67 cationic lipid. However, they were usually evaluated using procedures difficult or even impossible to implement in clinical practice. In this study, a clinically-relevant administration protocol via aerosol in murine lungs was used to conduct a comparative study with GL67A. Diverse lipidic compounds were used to prepare a series of formulations inspired by the composition of GL67A. While some of these formulations were ineffective at transfecting murine lungs, others demonstrated modest-to-very-efficient activities and a series of structure-activity relationships were unveiled. Lipidic aminoglycoside derivative-based formulations were found to be at least as efficient as GL67A following aerosol delivery of a luciferase-encoding plasmid DNA. A single aerosol treatment with one such formulation was found to mediate long-term lung transgene expression, exceeding half the animal’s lifetime. This study clearly supports the potential of aminoglycoside-based cationic lipids as potent GL67-alternative scaffolds for further enhanced aerosol non-viral lung gene therapy for diseases such as CF.

Background: In the era of highly effective modulator therapies, pulmonary function, the number and severity of exacerbations and the quality of life of people with cystic fibrosis (CF) are improving significantly. The polymeric immunoglobulin receptor (pIgR)/IgA system, which is impaired in CF, protects the respiratory epithelium against harmful inhaled pathogens. The aims of this interventional prospective study were 1) to assess IgA mucosal immunity in bodily fluids from people with CF before and after elexacaftor/tezacaftor/ivacaftor (ETI) initiation, and 2) to investigate the mucosal IgA response in urine from people with CF compared with healthy controls. Methods: We quantified by ELISA the different agents comprising the pIgR/IgA system (total IgA, IgA1, IgA2, secretory IgA (S-IgA), secretory component of pIgR, and specific IgA against Pseudomonas aeruginosa or against staphylococcal enterotoxin B in sputum, serum, and urine from 57 people with CF and 30 healthy controls. Results: Hyperactivation of the pIgR/IgA system was maintained under ETI, with no significant differences between total IgA, IgA1, IgA2, S-IgA nor secretory component levels in sputum, serum and urine from people with CF before and after ETI initiation, except for an increase in urine S-IgA after treatment. We demonstrate an activation of the mucosal immune system in the urinary tract of people with CF, with a higher level of total IgA (p=0.0141) compared with healthy controls. Conclusion: Even with highly effective modulator therapy, the pIgR/IgA system remains hyperactivated after ≥3 months of treatment, suggesting that at this time the local IgA immunity is always impaired.

Cystic fibrosis (CF) is a genetic disease characterized by progressive lung and chronic digestive manifestations. We have shown that therapeutic doses of vardenafil, a phosphodiesterase type 5 (PDE5) inhibitor, corrects CF Transmembrane conductance Regulator (CFTR)-dependent chloride transport in respiratory and intestinal tissues of F508del homozygous mice. Here, we studied the effect of vardenafil on CFTR in 16HBE14o^– and CFBE41o⁻ cell lines. First, the expression levels of PDE5 mRNA in these cell lines were monitored. The two cell lines were exposed to different drugs (dimethyl sulfoxide, 8-Br-cGMP, forskolin or vardenafil). The cAMP and cGMP intracellular concentrations were measured. Finally, we localised the CFTR by immunolabelling. PDE5 was similarly expressed in both wild-type and in CF cells. A fast and transient rise in cGMP intracellular contents followed treatment with vardenafil, confirming its PDE5 inhibitory effect. We showed that vardenafil promoted both the early steps of the cellular processing and the trafficking of F508del without fully addressing the protein to the plasma membrane. The effect was not reproduced by the brominated cGMP analogue and it was not prevented by the combination of a protein kinase G (PKG) inhibitor and vardenafil. These findings support the view that vardenafil partially rescues F508del through cGMP/PKG-independent mechanisms.