Tohda Y, Muraki M, Kubo H, Itoh M, Haraguchi R, Nakajima S, Fukuoka M
4th Department of Internal Medicine, Kinki University School of Medicine, Osaka, Japan.
Respiration. 2001;68(1):73-7. doi: 10.1159/000050466.
Airway hyperresponsiveness (AHR) is one of the characteristic features of human asthma. The presence of AHR and the precise mechanisms immediately after establishment of sensitization in guinea pigs are unclear, although there are many reports showing allergen exposure that causes an increase in bronchial responsiveness associated with eosinophil influx into the airway in sensitized guinea pigs.
We investigated the inhibitory effects on AHR to histamine of ONO-1078, a leukotriene antagonist; indomethacin, a cyclooxygenase inhibitor; S-145, a thromboxane A(2) (TXA(2)) antagonist, and Y-24180, a platelet-activating factor (PAF) antagonist, to assess the involvement of chemical mediators in AHR employing ovalbumin (OA) sensitized guinea pig models.
Male Hartley guinea pigs were used. Each group comprised 4-7 animals. The animals were sensitized to OA, injecting intraperitoneally 30 mg of cyclophosphamide and 2,000 microg of OA together with 100 mg of aluminum hydroxide as the adjuvant. The guinea pigs were artificially ventilated via a cannula using a small-animal respirator after intraperitoneal anesthesia with pentobarbital sodium for tracheotomy. The pressure at the airway opening (PAO) was measured using a differential pressure transducer, and a differential pressure of peak PAO (peak DeltaPAO) at inspiratory phase as an overall index of bronchial response to bronchoactive agents was used. While being artificially ventilated, the animals were exposed to physiological saline solution containing various concentrations of histamine (4.9, 9.8, 20, 39, 78, and 156 microg/ml) by inhalation for 30 s at 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 animals.
The airway response to histamine was significantly greater in the sensitized group than in the nonsensitized group at histamine concentrations of 36 (p < 0.05), 78, and 156 mg/ml (p < 0.01). Leukotrienes C(4) and D(4): 30 mg/kg of ONO-178 did not show any inhibitory effect on airway response to inhaled histamine. Cyclooxygenase: 5 mg/kg of indomethacin did not show any inhibitory effect on the airway response to inhaled histamine. TXA(2): the AHR to inhaled histamine at doses of 9.8, 39, 78, and 156 microg/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 microg/ml was significantly inhibited by prior administration of 1 mg/kg of Y-24180.
S-1452 (3 mg/kg) and Y-24180 (1 mg/kg) significantly inhibited AHR to histamine, while ONO-108 (30 mg/kg) and indomethacin (5 mg/kg) did not. The results suggest that TXA(2) and PAF are involved in AHR in OA-sensitized guinea pigs.
气道高反应性（AHR）是人类哮喘的特征之一。尽管有许多报道表明，变应原暴露会导致致敏豚鼠支气管反应性增加，并伴有嗜酸性粒细胞流入气道，但在豚鼠致敏后立即出现的AHR及其确切机制尚不清楚。
我们研究了白三烯拮抗剂ONO-1078、环氧化酶抑制剂吲哚美辛、血栓素A2（TXA2）拮抗剂S-145和血小板活化因子（PAF）拮抗剂Y-24180对组胺引起的AHR的抑制作用，以评估化学介质在使用卵清蛋白（OA）致敏豚鼠模型的AHR中的作用。
使用雄性Hartley豚鼠。每组包括4-7只动物。动物用30mg环磷酰胺和2000μg OA腹腔注射致敏，并加入100mg氢氧化铝作为佐剂。豚鼠在腹腔注射戊巴比妥钠麻醉后行气管切开术，通过插管使用小动物呼吸机进行人工通气。使用差压传感器测量气道开口处的压力（PAO），并将吸气相时的PAO峰值差（峰值ΔPAO）作为支气管对支气管活性剂反应的总体指标。在人工通气时，动物每隔3分钟吸入含不同浓度组胺（4.9、9.8、20、39、78和156μg/ml）的生理盐水溶液30秒。每次吸入后1分钟进行测定。将化学介质分别（30mg/kg的ONO-1078、3mg/kg的S-1452和1mg/kg的Y-24）口服给予致敏豚鼠，并评估气道对组胺的反应。每组包括4-7只动物。
在组胺浓度为36（P<0.05）、78和156mg/ml（P<0.01）时，致敏组对组胺的气道反应明显大于未致敏组。白三烯C4和D4：30mg/kg的ONO-178对吸入组胺的气道反应未显示任何抑制作用。环氧化酶：5mg/kg的吲哚美辛对吸入组胺的气道反应未显示任何抑制作用。TXA2：预先给予3mg/kg的S-1452可显著抑制9.8、39、78和156μg/ml剂量的吸入组胺引起的AHR。PAF：预先给予1mg/kg的Y-24180可显著抑制9.8、39和78μg/ml剂量的吸入组胺引起的AHR。
S-1452（3mg/kg）和Y-24180（1mg/kg）可显著抑制对组胺的AHR，而ONO-108（30mg/kg）和吲哚美辛（5mg/kg）则不能。结果表明，TXA2和PAF参与了OA致敏豚鼠的AHR。
