To determine whether thromboxane A2 may be involved in ozone (O3)-induced airway hyperresponsiveness, we studied the effect of a thromboxane synthase inhibitor (OKY-046, 100 micrograms X kg-1 X min-1 iv) in five dogs exposed to O3. Airway responsiveness was assessed by determining the provocative concentration of acetylcholine aerosol that increased total pulmonary resistance by 5 cmH2O X l-1 X s. O3 (3 ppm) increased airway responsiveness as demonstrated by a decrease in acetylcholine provocative concentration from 2.42 (geometric SEM = 1.64) to 0.14 mg/ml (geometric SEM = 1.30). OKY-046 significantly inhibited this effect without altering pre-O3 responsiveness or the O3-induced increase in neutrophils and airway epithelial cells in bronchoalveolar lavage fluid. To further examine the role of thromboxane A2, we studied the effect of a thromboxane A2 mimetic, U-46619, on airway responsiveness in five additional dogs. U-46619 in subthreshold doses (i.e., insufficient to increase base-line pulmonary resistance) caused a fourfold increase in airway responsiveness to acetylcholine. Subthreshold doses of histamine had no effect. These results suggest that thromboxane A2 may be an important mediator of O3-induced airway hyperresponsiveness.
The aim of the present study was to examine whether endogenous neuropeptides released from sensory nerves can potentiate airway responsiveness to histamine. Total pulmonary resistance (RL) was measured to assess the bronchial responsiveness to increasing doses of histamine (1.25, 2.5, 5, and 10 micrograms/kg) administered intravenously in 29 anesthetized and artificially ventilated guinea pigs. Pretreatment with aerosolized capsaicin (3 micrograms/ml for 15 to 60 s) 30 min before obtaining the dose-response to histamine significantly potentiated percent increase in RL caused by each dose of intravenously administered histamine. Pretreatment with substance P (0.5 ml/kg of 10(-5) M) administered intravenously also potentiated the airway responsiveness to histamine. As assessed by the amount of extravasation of Monastral blue pigments, both capsaicin aerosol and substance P injected intravenously induced increased vascular permeability in the tracheal mucosa. These findings suggest that endogenous neuropeptides, especially tachykinin such as substance P, can induce airway hyperresponsiveness to nonspecific stimuli and play a possible role in producing airway hyperresponsiveness in bronchial asthma.
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