Gwen S. Skloot

Research

Airway Responsiveness in Asthma

Our laboratory focuses on clinical asthma studies. We hypothesize that hyperresponsiveness is caused by impairment in the ability of inspiration to stretch airway smooth muscle (ASM) -- i.e. impaired bronchodilation. This hypothesis is supported by our finding that sensitivity to the constrictor agent Methacholine is the same in normals and asthmatics when challenge is conducted without deep breaths. It is also known that deep inspiration (DI) prior to a constrictor agent is bronchoprotective in normal subjects. We have shown that this effect relates to inspiratory velocity, i.e. a fast DI is more bronchoprotective than a slow DI. We speculate that in healthy subjects, DI stretches ASM and breaks cross bridges and that cross bridge breakage is enhanced with increased inspiratory velocity. In asthmatics, inflammation may impair this ability. Further protocols will focus on the mechanism of the impaired response to DI in asthma in order to ultimately develop interventions to treat this aspect of hyperresponsiveness.

We have developed an in vitro model to test similar ideas. We hypothesize that stretching guinea pig (GP) tracheal smooth muscle releases a humoral "relaxant" factor [i.e. stretch-induced relaxation (SIR) involves a receptor-mediated mechanism]. The analogous in vivo situation may be the release of a "bronchodilating" substance when a normal subject takes a deep breath. This bronchodilating substance may be decreased in asthma. We have demonstrated that GP tracheal smooth muscle does relax when stretched; this relaxation is enhanced post-carbachol. We have characterized this relaxation response by pharmacokinetic studies. Additional characterization studies are focused on inhibiting the SIR response with agents such as beta-blockers, indomethacin, etc. We have shown that after induction of airway inflammation, the SIR response is reduced. Future protocols will address the mechanism of this reduced response and the relevance to human asthma.