RT Journal Article
SR Electronic
T1 Chest Vest therapy increases FENO and may lead to F508del CFTR maturation
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P1225
VO 44
IS Suppl 58
A1 Nadzeya Marozkina
A1 Laura Smith
A1 Calvin Cotton
A1 Benjamin Gaston
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P1225.abstract
AB RATIONALE. Chest Vest therapy is used for airway clearance in cystic fibrosis (CF). Endothelial nitric oxide synthase (eNOS)-mimetic compounds modestly correct F508del CFTR protein expression in primary human airway pseudostratified epithelial cells cultured at air liquid interface (ALI) (Marozkina et al., PNAS 107:11393, 2010). We have shown that cyclic compressive stress (CCS; passive airflow) on the airway side of ALI cultures activates subciliary eNOS, and clinical evidence suggests that CCS methods, including Vest, in vivo cause clinical improvement in CF. METHODS To assess eNOS activation in vivo, healthy adults had fraction of exhaled NO (FENO, MINO, Aerocrine) testing while fasting before and after airway clearance Vest treatment (10 Hz; 10 min). Primary airway epithelial cells were attached to a NEMI rodent ventilator and ventilated for 2 hr in a 37o C incubator after a 2 hr pre-incubation with either 100μM NOS inhibitor (L-NAME) or control diluent. Cells were harvested and immunostained with anti-CFTR antibody M3A7 (Millipore). RESULTS. F508del CFTR B band (partially mature protein) expression increased with CCS by 85% relative to no ventilation. C band was essentially undetectable in the control wells, but increased to a CFTR/actin ration of 0.46 +/- 0.12; this effect was partially inhibited by L-NAME (only a 1.8 +/- 0.31-fold increase relative to control, n = 6 wells, p = 0.002 by ANOVA). In vivo, Vest treatment increased FENO by 2.4 +/- 0.56 ppb from baseline (n = 9; p = 0.0031 by paired t- test). CONCLUSIONS. In addition to mechanical effects on mucous, airway clearance techniques such as use of the Vest may activate eNOS, leading to increased F508del CFTR expression and maturation.