Acute effects of prostaglandin D2 to induce airflow obstruction and airway microvascular leakage in guinea pigs:: role of thromboxane A2 receptors

Background. Although prostaglandin D-2 (PGD(2)), a mast cell-derived inflammatory mediator, may trigger allergic airway inflammation, its potency and the mechanism by which it induces airway microvascular leakage, a component of airway inflammation, is not clear. Objective: We wanted to evaluate the relative potency of PGD(2) to cause microvascular leakage as compared to airflow obstruction, because both responses were shown to occur simultaneously in allergic airway diseases such as asthma. The role of thromboxane A(2) receptors (TP receptors) in inducing these airway responses was also examined. Methods: Anesthetized and mechanically ventilated guinea pigs were given i.v. Evans blue dye (EB dye) and, 1 min later, PGD(2) (30, 100, 300 or 1,000 nmol/ka). For comparison, the effect of 150 nmol/kg histamine or 2 nmol/kg leukotriene D-4 (LTD4) was also examined. Lung resistance (R-L) was measured for 6 min (or 25 min for selected animals) and the lungs were removed to calculate the amount of extravasated EB dye into the airways as a marker of leakage. In some of the animals, specific TP receptor antagonists, S-1452 (10 mug/kg) or ONO-3708 (10 mg/kg), or a thromboxane A(2) synthase inhibitor, OKY-046 (30 mg/kg), was pretreated before giving PGD(2). Results: Injection of PGD(2) produced an immediate and dose-dependent increase in R-L (peaking within 1 min), which was significant at all doses studied. At 1,000 mol/kg, PGD(2) induced a later increase in R-L, starting at 3 min and reaching a second peak at 8 min. By contrast, only PGD(2) at doses of 300 and 1,000 nmol/k- produced a significant increase in EB dye extravasation. The relative potency of 1,000 nmol/kg PGD(2) to induce leakage as compared to airflow obstruction was comparable to histamine at most of airway levels, but less than LTD4. Both responses caused by PGD(2) were completely abolished by S-1452 and ONO-3708, but not by OKY-046. Conclusion: PGD(2) may induce airway microvascular leakage by directly stimulating TP receptors without generating TYA(2) in guinea pigs. Microvascular leakage may play a role in the development of allergic airway inflammation caused by PGD(2). (C) 2001 Elsevier Science Inc. All rights reserved.