This proposal will establish whether hypotheses that have emerged from isolated airway smooth muscle (ASM) studies regarding airway hyperreactivity (AHR) are relevant in situ and in human asthma, emphasizing the contrast between severe versus mild-to-moderate asthmatics. Past studies have shown that periodic stretching of isolated ASM reduces the muscle's contractile response to provocation whereas lack of stretching results in a stiffer, more contractile muscle. They hypothesize that AHR in asthmatics results from abnormal chronic shortening of the ASM resulting in remodeling of its contractile apparatus. This hypothesis infers a role for inflammation but does not go so far as to require it. Such ASM abnormalities should manifest themselves via a reduced capacity to dilate airways with a deep inspiration (DI) and heterogeneous constriction inclusive of airway closures that are not resolvable with a DI. Such heterogeneities can result in marked increase in the work of breathing and in hypoxemia. While inhibiting a DI in healthy subjects seems to amplify their reactivity, our preliminary data suggest it does so by invoking additional mechanisms and in a manner that is more resolvable with a subsequent DI. Hence, we propose to test two key hypotheses: 1) Hyperreactivity in asthmatics requires that the airway smooth muscle reside in a uniquely stiff, contractile state such that deep inspirations cannot produce sustained bronchodilation nor resolution of heterogeneities. Corollary 1: Prohibiting a DI in healthy subjects does not sufficiently mimic conditions and mechanisms associated with airway hyperreactivity in asthma. 2) Inflammation amplifies airway hyperreactivity via a sustained increase in airway smooth muscle tone and in shortening, leading to increased muscle stiffness and contractility. Corollary: With increased inflammation, a DI is less able to dilate airways or reduce heterogeneity. To test these hypotheses we will synthesize three advanced technologies: 1) Tracking of airway resistance, a surrogate for airway caliber, in real time thus allowing us to assay changes in smooth muscle tone and airway wall stiffness; 2) Tracking mechanical heterogeneity via the frequency dependence of dynamic lung resistance and elastance; and 3) Applying hyperpolarized helium magnetic resonance imaging (HP 3He MRI) to create whole-lung images that reveal heterogeneity and non-ventilated alveolar regions. Our studies will confirm whether AHR requires simply reduced length stretching of airway smooth muscle, or whether inflammatory and remodeling abnormalities in the airway network as a system are also necessary to chronically sustain increased stiffness, tone, and heterogeneities that are uniquely resistant to a DI. These studies are a crucial step in translating theories and experiments at the level of isolated smooth muscle and cells to the level of the asthmatic airway system as a whole. Asthma treatment and diagnosis will be advanced by establishing whether the distinguishing feature in those subjects that respond to treatments is reinstatement and/or sustenance of the capacity to modulate airway caliber with a DI; a capacity reflecting that the treatment can restore a softer, less responsive airway system. ? ?
