Acute effects of prostaglandin D 2 to induce airflow obstruction and airway microvascular leakage in guinea pigs: role of thromboxane A 2 receptors

Abstract

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/kg). For comparison, the effect of 150 nmol/kg histamine or 2 nmol/kg leukotriene D 4 (LTD 4) 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 μg/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 nmol/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/kg 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 LTD 4. 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 TXA 2 in guinea pigs. Microvascular leakage may play a role in the development of allergic airway inflammation caused by PGD 2.