UC San Diego

Asthma is defined by its intermittence. Periods of normal function are interrupted by intermittent bouts of airflow obstruction, and the severity and frequency of these bouts define the severity of the disease. Asthma also varies in space just as it does in time. Patches of the lung become compromised during an asthma attack, while the rest of the lung continues to function normally. This dissertation explores the intersection of these two modes of variation – what causes bronchoconstriction to occur in patches, and will it cause the same patches to emerge time after time?

A seminal modeling study predicted that lung units under smooth muscle stress exhibit a type of emergent behavior; self-organized patches of constriction can arise from the small airways because of the interdependence of airflow through the airway tree. In a sense, airways “communicate” with each other through flow patterns in a way that allows large-scale patterns to emerge.

One goal of this dissertation work was to empirically verify the findings of this model. We chose to perform studies in healthy normal subjects to ensure that the patterns of constriction we observed were due to interdependence and not to underlying inflammation or remodeling. The results of our first study (Chapter 2) found that bronchoconstriction – provoked with methacholine – in healthy subjects did indeed occur in a spatially patchy pattern.

Further, we found that this patchy pattern was recurrent in challenges weeks to months apart. We showed that, although subjects each had a characteristic pattern of constriction, there was an overall tendency for the dependent lung to constrict when supine. Our second study (Chapter 3) showed that this was due to the interaction between gravitational compression of tissue and the underlying topography of the airway tree structure.

Our final study (Chapter 4) showed that healthy subjects did not recover from constriction immediately after albuterol inhalation, even though traditional metrics of lung function indicated that they had. We interpreted this as evidence for the power and utility of functional imaging in detecting and characterizing pathologic function.