Environmental, therapeutic, and occupational exposures to oxidant agents are of major concern with regard to lung disease. The long term goal of the present proposal is to understand how oxidant stress influences the physiologic and pharmacologic properties of airway smooth muscle. The immediate objective of these studies is to examine potential mechanisms by which in vivo hyperoxic exposure increases airway reactivity. Since airways isolated from various sites along the tracheobronchial tree exhibit differential responsiveness to pharmacologic stimuli, and since a paucity of studies exist where airways isolated from different levels have been examined in vitro in a model of airway inflammation, bronchi and bronchioles will be used in the in vitro portions of the present proposal. Isolated and cultured epithelial cells will be used to examine the effects of hyperoxia on the release from these cells of mediators which modulate contractile responses of airways. Bronchomotor responses elicited by pharmacologic and physiologic stimuli will be determined in the intact rat using a plethysmograph. Experiments will be conducted to address the following: 1. To examine the contribution of cholinergic mechanisms in the development of hyperoxia- induced airway hyperreactivity; 2. To examine the modulatory effects of respiratory epithelium on contractile responses in airways of control and hyperoxia-exposed rats; 3. To examine the role of PGE2 in the development of hyperoxia-induced changes in airway function; 4. To examine the role of 5-hydroxytryptamine in the development of airway hyperresponsiveness after hyperoxic exposure; and, 5. To examine the effects of scavengers of O2 metabolites on hyperoxia-induced changes in airway function. Although the present proposal is concerned with the effects of in vivo hyperoxic exposure on airways, information attained as a result of the proposed research will provide basic information regarding potential mechanisms involved in oxidant-induced changes in airway function. In light of the clinical potential for pharmacologic protection against oxidant stress, the presently proposed research will provide additional insight into the effectiveness of potential therapeutic modalities.
