The primary pathologic defect in obstructive sleep apnea is increased upper airway collapsibility leading to obstruction and apneic episodes. The mechanism of this defect remains unknown; however, it is likely that alterations in both mechanical and neural reflex control mechanisms lead to collapse during sleep. We hypothesize that obesity, genetic and neurohumoral factors modulate upper airway properties. We have developed a novel isolated murine upper airway preparation that can be characterized by the Starling resistor model. Using this model, we can define the critical pressure (Pcrit) at which the airway collapses and separately determine the mechanical and neural contributions to airway activity through characterization of hypotonic and dynamic pressure-flow relationships. We will delineate these relationships in the isolated upper airway of an inbred mouse strain.
In Specific Aim 1, we will characterize the passive mechanical and active neurally modulated pressure-flow relationships of the isolated murine upper airway preparation.
In Specific Aims 2 and 3, we will determine the effects of obesity and leptin on these relationships. The model will serve as a paradigm for characterizing upper airway collapse, complement ongoing human studies, and provide a foundation for future studies targeting more basic mechanisms of disease through the use of knock-out mice and neurohumoral manipulation. ? ?
