BRONCHIAL HYPERRESPONSIVENESS AND AIRWAY NEUTROPHIL ACCUMULATION INDUCED BY INTERLEUKIN-8 AND THE EFFECT OF THE THROMBOXANE A(2) ANTAGONIST S-1452 IN GUINEA-PIGS

Interleukin-8 (IL-8) has been shown to be a chemotactic factor for neutrophils, T-lymphocytes and eosinophils, but it is unknown whether the IL-8-induced inflammatory cell accumulation into the airways can cause the bronchial hyperresponsiveness (BHR) characteristic of asthma. IL-8 at a dose of 0.5 or 5 mu g/kg was administered intranasally to guinea-pigs twice a week for 3 weeks. One day after the last administration, animals were anesthetized and artificially ventilated through tracheal cannula and lateral pressure at the cannula (Pao) was measured as an overall index of airway responses to increasing concentrations of inhaled histamine (25, 50, 100, and 200 mu g/ml). The IL-8 treatment significantly enhanced bronchial responsiveness to histamine in a dose-dependent manner (ANOVA P < 0.01). The provocative concentration of histamine causing a 100% increase in Pao (PC100) at a dose of 0.5 and 5 mu g/kg of IL-8 was 68.1 (GSEM 1.12) and 35.6 (GSEM 1.25) mu g/ml, respectively. The latter was significantly (P < 0.01) lower than that in control animals treated with PBS (93.3 [GSEM, 1.14] mu g/ml). The IL-8 treatment also induced a significant influx of neutrophils, but not eosinophils, in bronchoalveolar lavage (BAL) fluid (18.3 +/- 8.8 and 30.6 +/- 8.3% in animals treated with 0.5 and 5 mu g/kg, respectively, of IL-8 vs 3.6 +/- 0.7% in phosphate buffered saline-(PBS)-treated animals). Furthermore, we examined the effect of the thromboxane receptor antagonist S-1452 (0.01 or 0.1 mg/kg, i.p. 24 and 1 h before anesthesia) on this IL-8 induced BHR. S-1452 significantly inhibited the BHR dose-dependently (ANOVA P < 0.001). PC100 was 94.0 (GSEM 1.19), 137.4 (GSEM 1.17) and 43.0 (GSEM 1.24) mu g/ml with S-1452 at doses of 0.01 and 0.1 mg/ml and saline, respectively. We conclude that IL-8 causes BHR and airway neutrophil inflammation, and that thromboxane A(2) is important in the development of BHR induced by IL-8.