Nishimura H, Tokuyama K, Inoue Y, Arakawa H, Kato M, Mochizuki H, Morikawa A
Department of Pediatrics, Gunma University School of Medicine, Maebashi, Japan.
Prostaglandins Other Lipid Mediat. 2001 Aug;66(1):1-15. doi: 10.1016/s0090-6980(01)00115-0.
Although prostaglandin D2 (PGD2), 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.
We wanted to evaluate the relative potency of PGD2 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 A2 receptors (TP receptors) in inducing these airway responses was also examined.
Anesthetized and mechanically ventilated guinea pigs were given i.v. Evans blue dye (EB dye) and, 1 min later, PGD2 (30, 100, 300 or 1,000 nmol/kg). For comparison, the effect of 150 nmol/kg histamine or 2 nmol/kg leukotriene D4 (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 microg/kg) or ONO-3708 (10 mg/kg), or a thromboxane A2 synthase inhibitor, OKY-046 (30 mg/kg), was pretreated before giving PGD2.
Injection of PGD2 produced an immediate and dose-dependent increase in RL (peaking within 1 min), which was significant at all doses studied. At 1,000 nmol/kg, PGD2 induced a later increase in R(L), starting at 3 min and reaching a second peak at 8 min. By contrast, only PGD2 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 PGD2 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 PGD2 were completely abolished by S-1452 and ONO-3708, but not by OKY-046.
PGD2 may induce airway microvascular leakage by directly stimulating TP receptors without generating TXA2 in guinea pigs. Microvascular leakage may play a role in the development of allergic airway inflammation caused by PGD2.
尽管前列腺素D2（PGD2）是一种肥大细胞衍生的炎症介质，可能引发过敏性气道炎症，但其诱导气道微血管渗漏（气道炎症的一个组成部分）的效力及其机制尚不清楚。
我们希望评估PGD2与气流阻塞相比导致微血管渗漏的相对效力，因为在哮喘等过敏性气道疾病中这两种反应会同时发生。还研究了血栓素A2受体（TP受体）在诱导这些气道反应中的作用。
对麻醉并机械通气的豚鼠静脉注射伊文思蓝染料（EB染料），1分钟后注射PGD2（30、100、300或1000 nmol/kg）。为作比较，还研究了150 nmol/kg组胺或2 nmol/kg白三烯D4（LTD4）的作用。测量肺阻力（R(L)）6分钟（部分动物为25分钟），然后取出肺脏以计算气道内渗出的EB染料量，作为渗漏的标志物。在部分动物中，在注射PGD2前预先给予特异性TP受体拮抗剂S-1452（10 μg/kg）或ONO-3708（10 mg/kg），或血栓素A2合酶抑制剂OKY-046（30 mg/kg）。
注射PGD2后立即出现R(L)剂量依赖性增加（1分钟内达到峰值），在所研究的所有剂量下均显著。在1000 nmol/kg时，PGD2在3分钟开始诱导R(L)后期增加，并在8分钟达到第二个峰值。相比之下，仅300和1000 nmol/kg剂量的PGD2导致EB染料渗出显著增加。与气流阻塞相比，1000 nmol/kg PGD2诱导渗漏的相对效力在大多数气道水平与组胺相当，但低于LTD4。PGD2引起的两种反应均被S-1452和ONO-3708完全消除，但未被OKY-046消除。
在豚鼠中，PGD2可能通过直接刺激TP受体而不产生血栓素A2来诱导气道微血管渗漏。微血管渗漏可能在PGD2引起的过敏性气道炎症发展中起作用。
