Asthma and its associated airway hyper-reactivity is the most common respiratory disorder of childhood. The long-term goal of this project is to determine the mechanisms for the heightened airway reactivity in healthy infants and the decline in airway reactivity with lung growth and maturation. The response of a healthy infant to bronchoconstriction is more similar to an adult asthmatic than a healthy adult. The effects of lung volume maneuvers, such as deep breaths, upon airway reactivity may be an important protective mechanism that limits airway narrowing in healthy adults but not infants or asthmatics; the absence of this important protective mechanism may contribute to airway hyper reactivity. Airway narrowing during bronchoconstriction results from a balance between the mechanical loads within the lung that resist airway smooth muscle shortening and the force generated by the muscle during contraction. A lower mechanical load by the lung, greater muscle force generation, or both can contribute to greater airway narrowing in infants than adults. We hypothesize that airway reactivity declines with lung growth secondary to an increase in the mechanical loads that limit airway smooth muscle shortening. This maturational difference in the mechanics of airway narrowing is related to the cellular and the extra-cellular composition of the airway and the lung parenchyma, which also respond to the changing mechanical loads with lung growth.
The Specific Aims (SA) of this project are: SA #1: Characterize differences between human adults and infants in the effects of lung inflation on airway reactivity. SA #2: Using a rabbit model of lung development, evaluate how the mechanical properties of different tissue components of the lung change during maturation, and assess how these differences contribute to maturational differences in lung mechanical properties and airway narrowing. SA #3: Determine whether alterations in the lung structure that accompany lung growth are correlated with corresponding changes in airway responsiveness and lung mechanical properties.
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