Date of Award
Doctor of Philosophy (PhD)
Physiology and Pharmacology
Paul M O'Byrne
Exercise has long been recognized to be an important natural stimulus causing bronchoconstriction in most patients with symptomatic asthma, particularly in children and young adults. In the laboratory, bronchoconstriction caused by exercise is documented by examining a reduction in airway calibre after exercise which is measured as a fall in the forced expired volume in one second (FEV₁). Exercise bronchoconstriction is generally short lived, wearing off within 60 minutes.
More than 50% of asthmatic subjects, experience progressively less and less airway narrowing with repeated exercise challenges on the same day. This progressive decrease in exercise bronchoconstriction is considered to be a potentially important airway inhibitory protective effect and is termed exercise refractoriness. O'Byrne and Jones (O'Byrne and Jones, 1986), first demonstrated the likely involvement of inhibitory prostaglandins in exercise refractoriness, when they demonstrated that indomethacin inhibited the effect in asthmatic subjects.
The precise mechanism underlying exercise bronchoconstriction is unclear. However, the initiating stimulus may involve either alterations in osmolarity of the epithelial-lining fluid or changes in airway temperature resulting from the inhalation of inadequately conditioned air during exercise or both. These changes cause the release of bronchoconstrictor mediators and the development of bronchoconstriction. The work described in this thesis was undertaken to establish the role of leukotriene (LT) D₄ in the pathogenesis of exercise bronchoconstriction and of histamine-, and LTD₄ induced, inhibitory prostaglandin release in causing exercise refractoriness. The body of research described in this thesis details new findings in relation to LTD₄ and exercise responses in asthmatic subjects. It shows that tachyphylaxis, a potential airway protective mechanism, occurs to repeated challenges with LTD₄ inhalations in asthmatic subjects and that flurbiprofen, a cyclooxygenase inhibitor, blocks this effect implicating inhibitory prostaglandin release in the mechanism. Using a specific LTD₄ receptor antagonist, it shows for the first time, that LTD₄, an important mediator in asthma, is involved in exercise bronchoconstriction in asthmatic subjects. In addition, it demonstrates also that complete cross refractoriness/tachyphylaxis occurs following exercise and LTD₄ stimulation an effect which is also inhibited by flurbiprofen. However, complete cross refractoriness/tachyphylaxis does not occur following exercise and histamine.
The conclusion from the work in this thesis is that LTD₄, rather than histamine, plays the more important role in exercise bronchoconstriction and that LTD₄ induced inhibitory prostaglandin release is the cause of exercise refractoriness in asthmatic subjects.
Manning, Patrick John, "The Role of Histamine, Leukotriene D₄ and Inhibitory Prostaglandins in Exercise Bronchoconstriction and Refractoriness in Asthmatic Subjects" (1993). Open Access Dissertations and Theses. Paper 3223.