Role of chemical mediators in airway hyperresponsiveness in an asthmatic model

Background: Airway hyperresponsiveness (AHR) is one of the characteristic f eatures of hu man asthma. The presence of AHR and the precise mechanisms im mediately after establishment of sensitization in guinea pigs are unclear, although there are many reports showing allergen exposure that causes an in crease in bronchial responsiveness associated with eosinophil influx into t he airway in sensitized guinea pigs. Objective: We investigated the inhibit ory effects on AHR to histamine of ONO-1078, a leukotriene antagonist; indo methacin, a cyclooxygenase inhibitor; S-145, a thromboxane A(2) (TXA(2)) an tagonist, and Y-24180, a platelet-activating factor (PAF) antagonist, to as sess the involvement of chemical mediators in AHR employing ovalbumin (OA) sensitized guinea pig models. Methods: Male Hartley guinea pigs were used. Each group comprised 4-7 animals. The animals were sensitized to OA, inject ing intraperitoneally 30 mg of cyclophosphamide and 2,000 mug of OA togethe r with 100 mg of aluminum hydroxide as the adjuvant. The guinea pigs were a rtificially ventilated via a cannula using a smalt-animal respirator after intraperitoneal anesthesia with pentobarbital sodium for tracheotomy. The p ressure at the airway opening (PAO) was measured using a differential press ure transducer, and a differential pressure of peak PAO (peak Delta PAO) at inspiratory phase as an overall index of bronchial response to bronchoacti ve agents was used. While being artificially ventilated, the animals were e xposed to physiological saline solution containing various concentrations o f histamine (4.9, 9.8, 20, 39, 78, and 156 mug/ml) by inhalation for 30 s a t 3-min intervals. Determinations were made at 1 min after each inhalation. The chemical mediators were each (30 mg/kg of ONO-1078, 3 mg/kg of S-1452, and 1 mg/kg of Y-24180) administered orally to sensitized guinea pigs, and the airway response to histamine was assessed. Each group comprised 4-7 an imals. Results: The airway response to histamine was significantly greater in the sensitized group than in the nonsensitized group at histamine concen trations of 36 (p < 0.05), 78, and 156 mg/ml (p < 0.01). Leukotrienes C-4 a nd D-4: 30 mg/kg of ONO-178 did not show any inhibitory effect on airway re sponse to inhaled histamine. Cyclooxygenase: 5 mg/kg of indomethacin did no t show any inhibitory effect on the airway response to inhaled histamine. T XA(2): the AHR to inhaled histamine at doses of 9.8, 39, 78, and 156 mug/ml was significantly inhibited by prior administration of 3 mg/kg of S-1452. PAF: the AHR to inhaled histamine at doses of 9.8, 39, and 78 mug/ml was si gnificantly inhibited by prior administration of 1 mg/kg of Y-24180. Conclu sions: S-1452 (3 mg/kg) and V-24180 (1 mg/kg) significantly inhibited AHR t o histamine, while ONO-108 (30 mg/kg) and indomethacin (5 mg/kg) did not. T he results suggest that TXA(2) and PAF are involved in AHR in OA-sensitized guinea pigs. Copyright(C)2001 S. Karger AG, Basel.