67* Preclinical evaluation of preventive hypertonic saline therapy for cystic fibrosis-like lung disease in mice

Dehydration of airway surfaces and reduced mucus clearance due to ENaC-mediated increased airway Na+ absorption plays an important role in the pathogenesis of cystic fibrosis (CF) lung disease in patients and causes CF-like lung disease in bENaC-transgenic (bENaC-Tg) mice. Previous clinic trials demonstrated that inhalation of hypertonic saline (HS, NaCl 7%) improved mucus clearance and lung function in CF patients (Donaldson SH et al., 2006), and pilot studies demonstrated that inhalation of HS is well tolerated in young children with CF (Dellon EP et al., 2008). However, effects of HS therapy on airway mucus obstruction and airway inflammation, and the benefits of preventive HS treatment have not been studied. To determine the effects of preventive and late HS therapy on these characteristic features of CF-like lung disease in vivo, we used newborn or 4-week old bENaCTg mice and wild-type littermates and applied intrapulmonary instillation of HS or vehicle alone for 2 weeks. Subsequently, mice were euthanized, bronchoalveolar lavage performed, and lungs processed for histology. We demonstrate that both preventive and late HS treatment provide an effective mucolytic therapy for CF-like lung disease. However, HS promoted airway inflammation in neonates and had no therapeutic effect on airway inflammation in adult bENaC-Tg mice with established CF-like lung disease. These results suggest that potential proinflammatory side effects of early HS treatment should be evaluated before using HS as treatment for CF infants, and that combined mucolytic and anti-inflammatory therapies may be necessary for the treatment of CF lung disease. Supported by EC (MEXT-2004–013666).