Long-term upper airway patency depends on resistance to collapsing forces and the speed of re-opening of the airway after episodes of obstruction. This proposal is a continuation of the current Project 4A and will focus on the role of pharyngeal surface secretions in the determination of airway patency, Our hypothesis is that the physical characteristics of secretions in the pharynx will determine the ease with which the airway, once closed, re- opens. Secretions from the nose, mouth, tracheobronchial tree, and the pharynx itself will be examined for rheologic behavior and the ability of secretions to alter upper airway mechanical features of closing pressure, re-opening pressure, closing volume, and elastance, as measured in the isolated, sealed upper airway of an anesthetized animal. Secretions will be induced by autonomic manipulation (cholinergic, beta- and alpha-adrenergic agents) and by topical application of inflammatory mediators (substance P, PGF- 2alpha, and LTD-4). Studies in human subjects will examine whether saliva from patients with known sleep apnea syndrome have different rheologic properties from that obtained from healthy subjects. Induced and spontaneous secretions will be compared using measures of surface tension, creep, controlled stress flow mode, and controlled shear rate flow mode under static and oscillating modes to determine viscoelastic moduli (storage modulus and loss modulus), yield stress, and deformation history. Differences among secretions in terms of their physical and chemical properties and their effect on closing and re-opening pressures will be examined by analysis of electrolyte, protein, immunoglobulin, and mucin composition. Similar approaches will be used to examine the effect of topical therapeutic agents that could change upper airway mechanical properties or the rheologic features of pharyngeal secretions. Receptors implicated in secretory control (beta- and alpha1-adrenergic, muscarinic, substance P) will be characterized in pharyngeal epithelium and compared to that in the larynx and trachea. Localization of pharyngeal secretory control will be examined using videomicroscopy of the tantalum-coated, pharyngeal mucosal surface, allowing for direct examination of direct and reflex neural effects on secretory activity. A mechanical model will be used to examine how the physical characteristics of the lining fluid influence airway patency, and results will provide a conceptual framework by which airway re-opening may be better understood in the animal model and in human apnea. Results will provide new information on the role of surface liquid in long-term upper airway patency, on rheologic properties of secretions relevant to the opening of a previously closed airway, and on the control of pharyngeal secretions. This study will provide understanding of the mechanisms of airway collapse and re-opening and insight into new therapeutic interventions for obstructive apneas during sleep in adults and children.
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