ROLE OF EICOSANOIDS IN AIR-FLOW OBSTRUCTION AND AIRWAY PLASMA EXUDATION INDUCED BY TRIMELLITIC ANHYDRIDE-CONJUGATE IN GUINEA-PIGS 3 AND 8 WEEKS AFTER SENSITIZATION

Trimellitic anhydride (TMA) is a low molecular weight chemical which can cause occupational asthma. We studied the role of eicosanoids in airway responses to TMA at different times after sensitization in actively sensitized guinea-pigs. Sensitization was performed by two intradermal injections of free TMA (0.1 ml of 0.3% TMA in corn oil). At 3 and 8 weeks after sensitization, the guinea-pigs were anaesthetized and challenged with intratracheal instillation of 0.5% TMA conjugated to guinea-pig serum albumin (TMA-GPSA; 50 mu l). Lung resistance (R(L)) was measured to assess airflow obstruction, and the tissue content of Evans Blue dye was measured to assess airway plasma exudation. Intratracheal instillation of TMA-GPSA induced a slowly progressing increase in R(L), reaching a peak at approximately 35 min after the challenge (6.0 +/- 2.0 cm H2O/ml/s in the 3-week group and 3.8 +/- 0.6 in the 8-week group). Pretreatment before challenge with pyrilamine (anti-histamine: 2 mg/kg, intravenously) slowed the onset of the increase in R(L) following challenge with TMA-GPSA, and significantly attenuated the peak response. A combination of pyrilamine and ICI-192,605 (thromboxane receptor antagonist; 0.5 mg/kg, intravenously) completely abolished the increase in R(L) in both week groups. A combination of pyrilamine and ICI-198,615 (leukotriene C-4/D-4/E(4) receptor antagonist: 0.5 mg/kg, intravenously) did not further attenuate the increase in R(L) compared with pretreatment with pyrilamine alone, but the induced Evans Blue dye extravasation was completely inhibited in the 3-week group, whereas a remaining extravasation was observed in the 8-week group. We conclude that the bronchoconstrictor response to TMA-GPSA in actively sensitized guinea-pigs is mediated by histamine and thromboxane A(2) both early and late after sensitization, whereas leukotrienes and histamine partially mediate TMA-induced airway plasma exudation.