ROLE OF ARACHIDONIC-ACID METABOLITES IN AIRWAY RESPONSES INDUCED BY TRIMELLITIC ANHYDRIDE IN ACTIVELY SENSITIZED GUINEA-PIGS

We studied the role of arachidonic acid metabolites, histamine, and 5-HT in airway responses to trimellitic anhydride (TMA) in actively sensitized guinea pigs. Sensitization was produced by two intradermal injections of free TMA (0.1 ml of 0.3% TMA in corn oil). After 21 to 28 days, guinea pigs were anesthetized and challenged with intratracheal instillation of 0.5% TMA conjugated to guinea pig serum albumin (TMA-GPSA; 50 mul). Lung resistance (RL) was measured to assess airflow obstruction, and the tissue content of Evans blue dye was measured to assess airway plasma exudation. Before challenge, sensitized animals were pretreated intravenously with inhibitors of different mediators: pyrilamine (antihistamine: 2 mg/kg, indomethacin (cyclooxygenase inhibitor: 10 mg/kg), OKY-046 (thromboxane synthetase inhibitor: 30 mg/kg), ICI-198,615 (leukotriene receptor antagonist: 10(-6) mol/kg), ketanserin (5-HT2 receptor antagonist: 1 mg/kg), or azelastine (antiallergic agent'': 1 mg/kg). Intratracheal instillation of TMA-GPSA induced a slowly progressing increase in RL and produced extravasation of Evans blue dye at all airway levels in sensitized animals. Pyrilamine and azelastine abolished the increase in RL induced by TMA-GPSA until 2.5 min after the challenge. Indomethacin and OKY-046 significantly attenuated the increase in RL 3 min after the challenge. ICI-198,615 and ketanserin did not significantly affect the increase in RL. Extravasation of Evans blue dye induced by TMA-GPSA was decreased by pyrilamine, azelastine and ICI-198,615 in main bronchi and intrapulmonary airways. Indomethacin, OKY-046 and ketanserin did not significantly affect the extravasation of dye into the airway tissue. We conclude that the early bronchoconstrictor response to TMA-GPSA in actively sensitized guinea pigs is mediated mainly by histamine. Thromboxane A2 is partly involved in the delayed bronchoconstrictor response to TMA-GPSA. Leukotrienes and histamine, but not thromboxane A2, participate in TMA-induced airway plasma exudation in actively sensitized guinea pigs.