Novel function of prostaglandin D2 and its metabolites in pathogenesis of immune and allergic diseases as examined by prostaglandin D synthase gene-manipulated mice

为了检查前列腺素（PG）D2的过度产生对炎症和过敏反应的影响，我们产生了在α-肌动蛋白启动子控制下过度表达人PGD合酶的转基因（TG）小鼠。在卵清蛋白（OVA）诱导的哮喘模型中，嗜酸性粒细胞和淋巴细胞浸润到支气管肺泡灌洗液（BAL）的TG小鼠比野生型（WT）小鼠更显着，在1和3天后，OVA的挑战。尽管与WT小鼠相比，TG小鼠的IFNa水平降低，但TG小鼠的BAL液中IL-4、IL-5和嗜酸性粒细胞趋化因子的水平也显著高于WT小鼠。与WT小鼠相比，PGD 2受体基因敲除（DP-/-）小鼠的BAL液中Th 2细胞因子的增加和OVA激发后肺中淋巴细胞蓄积的程度大大降低。此外，DP-/-小鼠仅表现出嗜酸性粒细胞的边缘浸润，并且未能发展出气道高反应性。这些结果综合起来表明，PGD 2充当触发哮喘反应的介质。PGD 2也作为中枢神经系统中的主要前列腺素类产生，并作为有效的睡眠诱导物质。因此，我们研究了TG小鼠的睡眠行为。虽然WT和TG小鼠之间的睡眠/清醒模式没有观察到差异，但在剪尾刺激后，在TG小鼠中观察到非快速眼动（NREM）睡眠的显著时间依赖性增加。TG小鼠NREM睡眠的诱导与脑中PGD 2的产生呈正相关。在剪尾后，WT小鼠的睡眠和脑中的PGD 2含量基本上没有变化。TG小鼠的这些结果表明PGD 2、PGD合成酶及其基因参与NREM睡眠的调节。

To examine the effects of overproduction of prostaglandin (PG) D2 on the inflammatory and allergic reactions, we generated transgenic (TG) mice that over-expressed human PGD synthase under the control of the a-actin promotor. In an ovalbumin (OVA)-induced asthma model, eosinophils and lymphocytes infiltrated into the bronchoalveolar lavage (BAL) fluid of TG mice more significantly than that of the wild-type (WT) mice, at 1 and 3 days after OVA-challenge. The levels of IL-4, IL-5 and eotaxin in the BAL fluid were also significantly higher in TG mice than those in WT mice, although the IFNa level was decreased in TG mice as compared with WT mice. The increases in Th2 cytokines in the BAL fluid and the extent of lymphocyte accumulation in the lung after OVA-challenge were greatly reduced in PGD2 receptor gene-knockout (DP-/-) mice compared with those in WT mice. Moreover, DP-/- mice showed only marginal infiltration of eosinophils and failed to develop airway hyperreactivity. These results, taken together, indicate that PGD2 acts as a mediator to trigger asthmatic responses. PGD2 is also produced as a major prostanoid in the central nervous system and acts as a potent sleep-inducing substance. We therefore studied the sleep behavior of TG mice. Although no difference was observed in the sleep/awake patterns between WT and TG mice, a striking time-dependent increase in non-rapid eye movement (NREM) sleep was observed in TG mice after stimulation by tail clipping. Induction of NREM sleep in TG mice was positively correlated with the PGD2 production in the brain. Sleep and PGD2 content in the brain were essentially unchanged in WT mice after tail clipping. These results with TG mice demonstrate the involvement of PGD2, PGD synthase, and its gene in the regulation of NREM sleep.