ANTIGEN-INDUCED MEDIATOR RELEASE IN PRIMATES

We examined the release of bronchoactive mediators into the airways of allergic primates during the acute response to specific antigen inhalation. Twelve adult male cynomolgus monkeys (Macaca fascicularis) with a naturally occurring respiratory sensitivity to inhaled Ascaris suum extract were anesthetized and intubated for each study. Respiratory system resistance (Rrs) and dynamic lung compliance (CLdyn) were measured before and after antigen inhalation, and the release of mediators into the airways was assessed by bronchoalveolar lavage (BAL). BAL samples were concentrated approximately 5-fold before quantitation of LTC4 and PGD2 by RP-HPLC and radio-immunoassay and histamine by a fluorometric assay. Antigen inhalation resulted in a 40-fold increase in BAL levels of i-LTC4 (1.5 +/- 0.7 to 41.6 +/- 12.7 ng, p < 0.01), a 10-fold increase in i-PGD2 (2.4 +/- 0.9 to 25.9 +/- 5.5 ng, p < 0.01), and a 20-fold increase in BAL histamine (1.0 +/- 1.5 to 21.4 +/- 2.3-mu-g, p < 0.01). Dexamethasone (n = 7) inhibited the antigen-induced increase in BAL i-LTC4 (71 +/- 6%, p < 0.01) and i-PGD2 (52 +/- 8%, p < 0.05) while weakly inhibiting histamine release (43 +/- 10%). Indomethacin (n = 7) had a variable effect on i-LTC4 levels (6 +/- 51%), strongly inhibited i-PGD2 (88 +/- 9%, p < 0.01), and had no effect on histamine release (25 +/- 8%). Pretreatment with lodoxamide tromethamine significantly blocked the release of each mediator, but mepyramine, an H-1 antagonist, had no effect on mediator release. This study indicates that specific antigen inhalation results in the production and release of lipid mediators and histamine into the airways, which are recoverable and quantifiable in BAL. Pulmonary function data from this study suggest that the rapid developing bronchoconstriction after antigen challenge is mediated by the release of histamine and the duration of the response may be mediated by lipid mediator generation and release.