The Leaky Lung Test

Cartoon diagram depicting how inhaled mannitol
(or other inert substances that translocate
across epithelium via paracellular permeability) can
be used to noninvasively measure epithelial
integrity in human subjects. (Enlarged image)

There are no good assays of outside/in airway epithelial permeability in clinical use, which has slowed research in this area. Current studies rely on bronchoscopy with bronchial biopsy and brushings to document structural and functional changes in airway epithelial junctions, but this is not practical for large-scale studies and introduces artifacts of in vitro cell propagation. A more specific non-invasive assay of outside/in airway permeability would be useful in clinical asthma research, and allow us to ask specific questions in a translational manner.

For example, does enhanced permeability characterize a subset of asthmatics at-risk for future exacerbation? Do respiratory viral infections induce epithelial leakiness and if so how long does this last? What is the relationship between outside/in permeability and asthma severity? We reasoned that a useful agent to study outside/in airway permeability would translocate via paracellular pathways, and not be metabolized in the airway or bloodstream. Mannitol fulfills both of these criteria and was approved by the FDA for bronchoprovocation studies. Mannitol is not significantly metabolized and is excreted unchanged almost entirely via the kidneys. Consequently, we conceived of the Leaky Lung Test (LLT) in which urinary mannitol excretion, measured following inhalation challenge, serves as a surrogate marker of outside/in airway permeability. We conducted proof-of-concept studies documenting the utility of the Leaky Lung Test in a mouse model of respiratory syncytial virus infection, and in a pilot study of human subjects. We are currently obtaining regulatory approval from the FDA before initiating a larger clinical trial in healthy and asthmatic subjects.

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