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

Leukotriene D-4 (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) 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 LTD4 and PGD(2) were investigated ill the perfused and ventilated guinea-pig lung (IPL). Both LTD4-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 LTD4 was established by measurements of immunoreactive 6-keto PGF(1a) (a stable metabolite of PGI(2)) and PGE(2). In contrast, TP receptor-mediated bronchoconstriction by PGD(2) was some what 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 ill the trachea by COX inhibition. The Study documented that bronchoconstriction induced by LTD4 and PGD(2) in IPL was modulated differently by COX products. Whereas bronchoconstriction induced by LTD4 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. (C) 2009 Published by Elsevier Inc.