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|Title:||Release and Actions of Prostaglandin E₂ From Canine Airway Epithelium|
|Keywords:||Medical Sciences;Medical Sciences|
|Abstract:||<p>Asthma is a condition of the airway characterized by 1) a reversible increase in airway resistance; 2) airway hyperresponsiveness; and 3) airway inflammation (Juniper et al., 1981; O'Byrne, 1986; Boushey and Fahy, 1995). Defects of the airway epithelium have been suggested to play a role in the pathogenesis of asthma (Goldie et al., 1986; Knight et al., 1994), and loss of the epithelium is associated with increased reactivity of the underlying smooth muscle (Jongejen et al., 1991; Candenas et al., 1992). It has been proposed that the airway epithelium releases one or more factors which inhibit smooth muscle contraction, termed the epithelial derived inhibitory factor (Tschirhart et al., 1987; Fernandes et al., 1989; Ullman et al., 1991). The inhibitory prostaglandin PGE₂ has been demonstrated to be released from the epithelium (Barrel and Bigby, 1995) and to modulate airway smooth muscle contraction (Braunstein et al., 1988; Abela and Daniel, 1995). In patients with asthma, inhalation of an allergen may result in a biphasic response consisting of an early asthmatic response and a late asthmatic response (Dolovich et al., 1989; Sterk et al., 1993). The late asthmatic response is an indirect measure of allergen-induced airway inflammation (Dolovich et al., 1989; Sterk et al., 1993) and an animal model of the late asthmatic response is produced by inhalation of the allergen Ascaris suum by dogs (Sasaki et al., 1987). in the studies presented in this thesis, the release and actions of PGE₂ from canine airway epithelium, both under unstimulated conditions and following inhalation of the Ascaris suum antigen, were examined. Tracheal and bronchial tissues were excised and studied in the organ bath where contractile responses to agonists and electrical field stimulation, as well as PGE₂ release were measured. Finally, a potential mechanism by which PGE₂ may effect smooth muscle relaxation was examined. In unstimulated animals, PGE₂ was released from tracheal epithelium and inhibited smooth muscle contraction. This release of PGE₂ was dependent upon electrical field stimulation, and was not blocked by the addition of neurotoxins. In the antigen model, tracheal PGE₂ release was increased from animals that inhaled antigen but did not develop late airway hyperresponsiveness comapred to animals that inhaled vehicle or inhaled allergen and did develop a late response. The release of PGE₂ was not dependent on field stimulation. Demonstration of in vitro hyperresponsiveness of the tracheal smooth muscle was dependent on removal of the epithelium. Bronchial smooth muscle from the antigen model did not demonstrate in vitro hyperresponsiveness, even when hyperresponsiveness was observed in vivo. There was an increase in the basal release of PGE₂ from the bronchi of animals that were hyperresponsive in vivo. PGE₂ increases intracellular cAMP concentrations (Madison et al., 1989; Coleman et al., 1994). Our investigations in tracheal smooth muscle demonstrated that cAMP does not lower intracellular Ca²⁺ and cause relaxation of airway smooth muscle by stimulation of the sarcoplasmic reticulum Ca²⁺ pump. The results indicate that PGE₂ was released from airway epithelium and modulated smooth muscle contraction. Alterations in the release of PGE₂ were demonstrated in an animal model of asthma, as PGE₂ played a protective role in the development of airway hyperresponsiveness. Modulation of PGE₂ may be a possible therapy for the treatment of asthma and prevention of the late asthmatic response.</p>|
|Appears in Collections:||Open Access Dissertations and Theses|
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