Bob Lubamba

Cystic fibrosis: insight into CFTR pathophysiology and pharmacotherapy

Cystic fibrosis is the most common life-threatening recessively inherited disease in Caucasians. Due to early provision of care in specialized reference centers and more comprehensive care, survival has improved over time. Despite great advances in supportive care and in our understanding of its pathophysiology, there is still no cure for the disease. Therapeutic strategies aimed at rescuing the abnormal protein are either being sought after or under investigation. This review highlights salient insights into pathophysiology and candidate molecules suitable for CFTR pharmacotherapy. Clinical trials using Ataluren, VX-809 and ivacaftor have provided encouraging data. Preclinical data with inhibitors of phosphodiesterase type 5, such as sildenafil and analogs, have highlighted their potential for CFTR pharmacotherapy. Because sildenafil and analogs are in clinical use for other clinical applications, research on this class of drugs might speed up the development of new therapies for CF.

Inhaled phosphodiesterase type 5 inhibitors restore chloride transport in cystic fibrosis mice

Sildenafil and vardenafil, two selective inhibitors of phosphodiesterase type 5 (PDE5) are able, when applied by intraperitoneal injection, to activate chloride transport in cystic fibrosis (CF) mice homozygous for the F508del mutation. Oral treatment with the drugs may be associated with adverse haemodynamic effects. We hypothesised that inhaled PDE5 inhibitors are able to restore ion transport in F508del CF airway epithelium. We developed a restraint-free mouse chamber for inhalation studies. PDE5 inhibitors were nebulised for 15 min at concentrations adjusted from recommended therapeutic oral doses for male erectile dysfunction. We measured in vivo nasal transepithelial potential difference 1 h after a single inhalation of sildenafil, vardenafil or tadalafil in F508del CF and normal homozygous mice. After nebulisation with the drugs in F508del mice, chloride transport, evaluated by perfusing the nasal mucosa with chloride-free buffer containing amiloride followed by forskolin, was normalised; the forskolin response was increased, with the largest values being observed with tadalafil and intermediate values with vardenafil. No detectable effect was observed on sodium conductance. Our results confirm the role of PDE5 inhibitors in restoring chloride transport function of F508del CF transmembrane conductance regulator protein and highlight the potential of inhaled sildenafil, vardenafil and tadalafil as a therapy for CF.

Immunomodulatory activity of vardenafil on induced lung inflammation in cystic fibrosis mice

BACKGROUND We tested the hypothesis that vardenafil, a common drug used for improving erectile dysfunction and able to partially normalize transepithelial chloride transport in cystic fibrosis (CF), modulates CF lung inflammation. METHODS Inflammatory markers in lungs of F508del-CF and wild-type mice were monitored in response to lipopolysaccharide from Pseudomonas aeruginosa (LPS). The effect of pretreatment with vardenafil (0.14 mg/kg) was evaluated. RESULTS A latent inflammatory status, characterized by neutrophil infiltrate, mouse macrophage inflammatory protein (MIP)-2 and tumor necrosis factor (TNF)-α, was found in baseline conditions in F508del-CF mice. Inflammatory markers were increased after LPS with higher responses in CF. Vardenafil globally attenuated inflammatory responses in both genotypes however reduction of macrophage infiltration, macrophage chemoattractant chemokine and interleukin-1β was observed in the CF group only. CONCLUSION Vardenafil reduces lung inflammation with a more pronounced effect in F508del-CF mice, particularly on macrophage cell markers.

Pharmacological Potential of PDE5 Inhibitors for the Treatment of Cystic Fibrosis

Recent basic research has aroused great interest in the therapeutic potential of phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, vardenafil and taladafil, for the treatment of cystic fibrosis (CF). CF is the most common, life-threatening, recessively inherited disease in Caucasian populations. An estimated 1 in 2,500 Caucasian live births are affected and approximately 80,000 people in the world are diagnosed with CF. Due to mutation in the CF transmembrane conductance regulator (CFTR) gene [1,2], which encodes the main chloride channel expressed in epithelia, CF causes abnormal mucociliary clearance mainly in the lungs, leading to a vicious cycle of obstruction/infection/inflammation that progressively and irreversibly damages the lung tissue and architecture. Although many organs are affected in CF, pulmonary disease is the major cause of morbidity and mortality [3,4]. Despite more than two decades of intensive investigation of the genetics [1,2], pathophysiology and clinical phenotypes of CF [3,4], there is still no cure for CF. As a matter of fact, therapies have been limited to alleviating clinical manifestations. Although life expectancy and quality of life have progressively improved, CF continues to inflict major burdens and to shorten lives.

27 Comparative variability of nasal potential difference measurements in human and mice, healthy or carrying two severe CFTR mutations

Comparative variability of nasal potential difference measurements in human and mice, healthy or carrying two severe CFTR mutations

63 Resveratrol improves chloride secretion in cystic fibrosis mice homozygous for the F508del mutation

63 Resveratrol improves chloride secretion in cystic fibrosis mice homozygous for the F508del mutation A. Palem1, C. Bouckaert1, B. Dhooghe1, A. Leonard2, B. Lubamba1, P. Wallemacq1, P. Lebecque2, T. Leal1. 1Universite Catholique de Louvain, Centre for Toxicology and Applied Pharmacology, Brussels, Belgium; 2Universite Catholique de Louvain, Pediatric Pulmonology & Cystic Fibrosis Unit, Cliniques Saint Luc, Brussels, Belgium