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

Interleukin-8 (IL-8) has been shown to be a chemotactic factor for neu trophils, T-lymphocytes and eosinophils, but it is unknown whether the IL-8-induced inflammatory cell accumulation into the airways can caus e the bronchial hyperresponsiveness (BHR) characteristic of asthma. IL -8 at a dose of 0.5 or 5 mu g/kg was administered intranasally to guin ea-pigs twice a week for 3 weeks. One day after the last administratio n, animals were anesthetized and artificially ventilated through trach eal cannula and lateral pressure at the cannula (Pao) was measured as an overall index of airway responses to increasing concentrations of i nhaled histamine (25, 50, 100, and 200 mu g/ml). The IL-8 treatment si gnificantly enhanced bronchial responsiveness to histamine in a dose-d ependent manner (ANOVA P < 0.01). The provocative concentration of his tamine causing a 100% increase in Pao (PC100) at a dose of 0.5 and 5 m u g/kg of IL-8 was 68.1 (GSEM 1.12) and 35.6 (GSEM 1.25) mu g/ml, resp ectively. The latter was significantly (P < 0.01) lower than that in c ontrol 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 eo sinophils, 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 anima ls). Furthermore, we examined the effect of the thromboxane receptor a ntagonist 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 dos e-dependently (ANOVA P < 0.001). PC100 was 94.0 (GSEM 1.19), 137.4 (GS EM 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 impor tant in the development of BHR induced by IL-8.