Mediators of C5a-induced bronchoconstriction.

Previous studies had suggested that histamine and products of arachidonate metabolism were mediators of the bronchoconstriction induced in guinea pigs by the complement cleavage product C5a. The present study was conducted to further define the arachidonate metabolite(s) involved. Tracheal airflow and transpulmonary pressure were measured in anesthetized and artificially ventilated guinea pigs and pulmonary resistance and dynamic lung compliance were calculated as a measure of bronchoconstriction. The effect of the peptido-leukotriene antagonist L-649,923 and the thromboxane synthetase inhibitor U-63557A on the C5a-induced bronchoconstriction was determined. Also, the response to C5a was evaluated in animals made tachyphylactic to the bronchoconstrictor actions of LTB4. C5a-induced bronchoconstriction was not altered in animals treated with L-649,923 or made tachyphylactic to LTB4 suggesting that LTB4 and peptido-leukotrienes are not major mediators of the response. C5a challenge caused a significant increase in plasma thromboxane B2 levels which was prevented in part by the thromboxane synthetase inhibitor U-63557A. In addition, C5a-induced bronchoconstriction was significantly inhibited by U-63557A. Thus, these studies suggest that thromboxane is the arachidonate metabolite at least in part responsible for C5a-induced bronchoconstriction.