Two different mechanisms for modulation of bronchoconstriction in guinea-pigs by cyclooxygenase metabolites

Leukotriene D 4 (LTD 4)-induced bronchoconstriction in guinea-pig airways has a cyclooxygenase (COX)-dependent component. The main objective of this study was to establish if prostaglandin (PG) D 2-induced bronchoconstriction also was modulated by COX products. The effects of non-selective and selective COX-1 and COX-2 inhibitors on bronchoconstriction induced by LTD 4 and PGD 2 were investigated in the perfused and ventilated guinea-pig lung (IPL). Both LTD 4-induced bronchoconstriction and thromboxane (TX) A 2 release was suppressed by COX inhibitors or by TX synthesis inhibition. The release of additional COX products following CysLT 1 receptor activation by LTD 4 was established by measurements of immunoreactive 6-keto PGF 1α (a stable metabolite of PGI 2) and PGE 2. In contrast, TP receptor-mediated bronchoconstriction by PGD 2 was somewhat enhanced by COX inhibitors, and there was no measurable release of COX products after TP receptor activation with U-46619. PGE 2 was bronchoprotective in IPL as it inhibited the histamine-induced bronchoconstriction. In the isolated guinea-pig trachea, neither PGD 2 nor U-46619 actively released PGE 2, but continuous production of PGE 2 and PGI 2 was established, and the response to PGD 2 was enhanced also in the trachea by COX inhibition. The study documented that bronchoconstriction induced by LTD 4 and PGD 2 in IPL was modulated differently by COX products. Whereas bronchoconstriction induced by LTD 4 was amplified predominantly by secondarily released TXA 2, that induced by PGD 2 was attenuated by bronchoprotective PGE 2 and PGI 2, presumably tonically produced in the airways.