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

Leukotriene D4 (LTD4)-induced bronchoconstriction in guinea-pig airways has a cyclooxygenase (COX)-dependent component. The main objective of this study was to establish if prostaglandin (PG) D2-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 LTD4 and PGD2 were investigated in the perfused and ventilated guinea-pig lung (IPL). Both LTD4-induced bronchoconstriction and thromboxane (TX) A2 release was suppressed by COX inhibitors or by TX synthesis inhibition. The release of additional COX products following CysLT1 receptor activation by LTD4 was established by measurements of immunoreactive 6-keto PGF1α (a stable metabolite of PGI2) and PGE2. In contrast, TP receptor-mediated bronchoconstriction by PGD2 was somewhat enhanced by COX inhibitors, and there was no measurable release of COX products after TP receptor activation with U-46619. PGE2 was bronchoprotective in IPL as it inhibited the histamine-induced bronchoconstriction. In the isolated guinea-pig trachea, neither PGD2 nor U-46619 actively released PGE2, but continuous production of PGE2 and PGI2 was established, and the response to PGD2 was enhanced also in the trachea by COX inhibition. The study documented that bronchoconstriction induced by LTD4 and PGD2 in IPL was modulated differently by COX products. Whereas bronchoconstriction induced by LTD4 was amplified predominantly by secondarily released TXA2, that induced by PGD2 was attenuated by bronchoprotective PGE2 and PGI2, presumably tonically produced in the airways.