Comparatively long-term exposure of guinea pigs to a mixture of ozone (O
3) and nitrogen dioxide (NO
2) has been shown to cause airway hyperresponsiveness (AHR) to infused methacholine (Mch); however, the mechanism by which this occurs is not known. In this study we examined the roles of leukotrienes (LTs) and thromboxane B
2 (TXB
2) on the AHR induced by this combination of gases. Guinea pigs were continuously exposed to either filtered air or to a combination of 2 ppm NO
2 and 0.2 ppm O
3 for 8 weeks, then divided into two groups. The first group was anesthetized and intubated, then pulmonary mechanics and airway responsiveness to infused Mch were measured. The second group underwent bronchoalveolar lavage (BAL), and levels of LTs and TXB
2 were measured.
We found that exposure to O
3 and NO
2 did not alter static respiratory compliance, or baseline measures of respiratory flow resistance (R) or dynamic compliance (Cdyn). Exposure to the combined gases decreased ED
200R (the dose of Mch necessary to cause a 2-fold increase in R over baseline) significantly from 3.24±0.16μg/kg/min, which were seen in the filtered air-exposed animals, to 2.29±0.29μg/kg/min (p<0.05). The ED
50Cdyn (the dose of Mch necessary to reduce Cdyn to 50% of its baseline value) of this group was also significantly reduced from 3.67±0.46 to 2.39±0.19μg/kg/min (p<0.05). The level of LTB
4 recovered in the BAL fluid increased significantly from 94.7±8.7 pg/m
l, in the air-exposed controls, to 139.5±8.8 pg/m
l (p<0.005). Though not statistically significant, exposure to O
3 and NO
2 also resulted in an approximately 2-fold increase in TXB
2, from 87.2±33.0 pg/m
l in the air-exposed animals, to 161.8±47.9 pg/m
l in the O
3 and NO
2. In all of the animals, the levels of LTC
4, LTD
4 and LTE
4 were below detectable limits (<60 pg/ m
l for LTC
4;<80 pg/m
l for LTD
4 and LTE
4).
After 4 weeks recovery period, airway responsiveness, as well as BAL levels of LTB
4 and TXB
2 returned to normal. These data support the hypothesis that LTB
4 and TXB
2 play a role in the AHR induced by 8 weeks exposure to O
3 and NO
2.
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