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A3946 - The Leaky Lung Test: A Novel Non-Invasive Way to Study Airway Permeability in Asthma Using Inhaled Mannitol
Author Block: S. N. Georas1, S. Eliseeva1, K. Le2, T. Smyth1, J. Veazey1, S. Khurana1, J. Meddings2; 1Univ of RochesterMed Ctr, Rochester, NY, United States, 2Univ of Calgary, Calgary, AB, Canada.
Epithelial barrier dysfunction is increasingly associated with asthma, and can be caused by inhaled viruses, allergens, and pollution particles. There are currently no non-invasive ways to study airway barrier function in humans. We reasoned that measuring the absorption of an inert inhaled molecule would provide one way to study airway leakiness in humans. Here we report that dry powder mannitol can be used in this context since it fulfills three key criteria. First, mannitol moves across airway epithelial monolayers in vitro in a non-saturable manner, indicating translocation via paracellular routes (and not receptor mediated uptake). Second, after inhalation or ingestion, mannitol is absorbed into the blood stream and excreted in urine almost entirely unchanged. Third, inhaled mannitol is safe and well tolerated in human subjects, when used in a dose-escalating manner (Aridol® Bronchoprovocation Kits, Pharmaxis Ltd, Australia). We conducted an RSRB-approved phase I dose escalation study in 10 healthy controls and 10 mild asthmatic subjects, each administered either 155 mg or 315 mg mannitol separated by at least four weeks. Inclusion criteria included doctor diagnosis of asthma, bronchodilator reversibility by spirometry, and no exacerbation within 6 months. Subjects were asked to withhold medications prior to challenge according to current guidelines. Mannitol inhalation was performed using an FDA-approved protocol, and challenges were stopped if FEV1 decreased by ≥15% from baseline. Serum was collected at time 0, 60, 90, and 150 minutes after challenge, and urine was collected over 18 hours. Serum mannitol concentrations, which were measured using HPLC, increased in a time-dependent manner in all subjects. In 10 healthy subjects challenged with 155 mg mannitol, serum concentrations at 30, 90, and 150 mins were 1.1±0.5, 1.4±0.4, and 1.3±0.4 µg/ml (mean±SD), whereas after challenge with 315 mg, corresponding values were 1.7±0.6, 2.5±0.8, and 2.2±0.5 µg/ml. In 10 mild asthmatics, serum mannitol concentrations were 1.0±0.6, 1.3±0.5, and 1.3±0.5 at the 155 mg dose, and 1.8±0.7, 2.8±1.0, and 2.7±0.9 µg/ml (mean±SD) at the 315 mg dose. There were no significant differences between healthy controls and asthmatics at either dose level, although there was more variability in the asthmatic subjects. Urinary mannitol excretion was also unchanged between groups. We conclude that measuring the absorption and excretion of inhaled mannitol, which we call The Leaky Lung Test, can potentially be used in clinical research studies to identify asthma subjects with increased airway permeability.