Role of arachidonate metabolites in C5a-induced bronchoconstriction

The complement cleavage product, C5a, causes a bronchoconstriction in the guinea pig as evidenced by a decrease in dynamic lung compliance and an increase in pulmonary resistance. Previous studies had demonstrated that the antihistamine pyrilamine and the cyclooxygenase inhibitor indomethacin inhibited the C5a-induced bronchoconstriction but the leukotriene (LT)D₄ antagonist L-649,923 did not. As an extension of those studies, the purpose of the present study was to determine the contribution of specific cyclooxygenase products and/or LTB₄ in mediating C5a-induced bronchoconstriction. To assess the role of the various potential mediators, plasma levels of thromboxane (TX)B₂, prostaglandin (PG)D₂ and PGF(2alpha) were monitored. In addition, guinea pigs were treated either with the TX synthetase inhibitor U-63557A, treated with the TX receptor antagonist SQ 29,548 or made tachyphylactic to the bronchoconstrictor actions of LTB₄. C5a challenge caused an increase in plasma concentrations of TXB₂, which peaked before the maximum of the bronchoconstriction. However, no significant increase in plasma concentrations of PGD₂ or PGF(2alpha) was seen. Both U-63557A at 80 mg/kg and SQ 29,548 significantly inhibited the C5a-induced bronchoconstriction, whereas 10 mg/kg of U-63557A did not. The inability of 10 mg/kg of U-63557A to inhibit the response could be explained by both incomplete inhibition of TX synthesis as well as possible by the increased plasma concentrations of the potent bronchoconstrictor PGD₂, which occurred with C5a challenge in the presence of U-63557A. In animals tachyphylactic to LTB₄, the maximum of the C5a-induced bronchoconstriction was no different from control. Thus, the results of these studies indicate that the C5a-induced decrease in dynamic lung compliance and increase in pulmonary resistance is due primarily to TX generation wtihout a major contribution by LTB₄.