The effect of prostaglandin D2 in neonatal hypoxic-ischemic injury

前列腺素D2（PGD）由造血PGD合酶（HPGDS）或脂质运载蛋白型PGDS（L-PGDS）合成，取决于其产生的器官，并特异性结合DP1或DP2受体。我们研究了PGD2在新生小鼠缺氧缺血性脑病（HIE）发病机制中的作用。在野生型小鼠中，缺氧-缺血使大脑中PGD2的产生增加了90倍，与停止缺氧后10分钟的假手术大脑中的水平相比。然而，与野生型HIE脑相比，L-PGDS或DP 2基因敲除小鼠脑梗死的大小没有改变，而HPGDS-L-PGDS双基因敲除或DP 1基因敲除小鼠脑梗死的大小显著增加。在L-PGDS，HPGDS，HPGDS-L-PGDS基因敲除小鼠在10分钟的再氧合的PGD2水平分别为46%，7%和1%，在野生型的，这表明梗死面积是成反比的PGD2生产量。DP1受体仅在复氧后1 h的内皮细胞中表达，并且在HPGDS-L-PGDS基因敲除小鼠中，脑血流量在缺氧开始后下降得更快，并且在复氧后没有恢复到基线水平。HPGDS-L-PGDS和DP1基因敲除小鼠在复氧1 h后内皮细胞严重受损。在人类新生儿HIE脑中，HPGDS阳性小胶质细胞数量增加。总之，PGD2可能主要通过DPI受体通过防止内皮细胞变性来保护新生儿脑免受缺氧缺血损伤。

Prostaglandin D2 (PGD) is synthesized by hematopoietic PGD synthase (HPGDS) or lipocalin-type PGDS (L-PGDS), depending on the organ in which it is produced, and binds specifically to either DP1 or DP2 receptors. We investigated the role of PGD2 in the pathogenesis of hypoxic-ischemic encephalopathy (HIE) in neonatal mice at postnatal day 7. In wild-type mice, hypoxia-ischemia increased PGD2 production in the brain up to 90-fold compared with the level in sham-operated brains at 10 min after cessation of hypoxia. Whereas the size of the infarct was not changed in L-PGDS or DP2 knock-out mouse brains compared with that in the wild-type HIE brains, it was significantly increased in HPGDS-L-PGDS double knock-out or DP1 knock-out mice. The PGD2 level in L-PGDS, HPGDS, and HPGDS-L-PGDS knock-out mice at 10 min of reoxygenation was 46, 7, and 1%, respectively, of that in the wild-type ones, indicating the infarct size to be in inverse relation to the amount of PGD2 production. DP1 receptors were exclusively expressed in endothelial cells after 1 h of reoxygenation, and cerebral blood flow decreased more rapidly after the onset of hypoxia and did not return to the baseline level after reoxygenation in HPGDS-L-PGDS knock-out mice. Endothelial cells were severely damaged in HPGDS-L-PGDS and DP1 knock-out mice after 1 h of reoxygenation. In the human neonatal HIE brain, HPGDS-positive microglia were increased in number. In conclusion, it is probable that PGD2 protected the neonatal brain from hypoxic-ischemic injury mainly via DPI receptors by preventing endothelial cell degeneration.