Asthma affects between 3 and 8 percent of the adult population and nearly 10 percent of children between the ages of 5 and 9 years in this country. This disease is characterized by three hallmark features: intermittent reversible airway obstruction, airway hyper-responsiveness (AHR), and airway inflammation. The AHR has been widely assumed to be due to an increased tendency of airway smooth muscle to constrict upon stimulation from a number of stimuli. The specific mechanisms underlying AHR and the reversible airway obstruction remain poorly understood. A view shared by some investigators is that AHR may be due to an absence of bronchodilation, which occurs in non-asthmatics in response to a deep inspiration the excessive bronchoconstriction, or AHR, in asthma may be principally due to the failure of reflex responses in mechanical forces that reduce obstruction during a deep breath (DB) in healthy individuals. The mechanism responsible for the differences in DB-responses between these two groups is not known. The mechanism most widely supported is that there are differences between DB-effects on the mechanical properties of airways and lung parenchyma, which influence their mechanical interaction (i.e., the loading effect of lung parenchyma on airways). Data from our preliminary studies provide evidence that another important mechanism is involved. Specifically we found that, 1) in mild asthmatics much of the bronchodilation during a DB occurs very rapidly (i.e., less than 0.5 seconds) and is triggered when the lungs are almost maximally inflated, and 2) this bronchodilation is transient and the bronchoconstriction returns to pre-DB levels in 10-15 seconds. These results are consistent with the possibility that the bronchodilation is due to airway recruitment and the subsequent bronchoconstriction is due to closure of airways. Because of the rapidity of these events, they have not been reported previously. The studies outlined in this proposal are designed to characterize more thoroughly the differences between responses to DBs in asthmatics and non-asthmatics. In these studies, we propose to measure airway obstruction using the transfer impedance technique that is able to follow rapid transients in airway caliber during and following DBs; along with simultaneous measurements that provide evidence of airway opening (lung sounds), and airway closure (gas dilution). Our current understanding of the important mechanisms underlying asthma includes hyper responsiveness of airway smooth muscle and airway inflammation but not airway closure. Thus, asthma is currently treated with bronchodilators and anti-inflammatory drugs. If we can demonstrate that asthma includes a major component of airway closure, this may very well identify a new direction for future research, which may lead to entirely new treatment approaches.
| Dybas, Joseph M; Andresen, Catharine J; Schelegle, Edward S et al. (2006) Deep-breath frequency in bronchoconstricted monkeys (Macaca fascicularis). J Appl Physiol 100:786-91 |
| Jackson, Andrew C; Murphy, Margaret M; Rassulo, John et al. (2004) Deep breath reversal and exponential return of methacholine-induced obstruction in asthmatic and nonasthmatic subjects. J Appl Physiol 96:137-42 |
