Prostaglandin D2 Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury
Prostaglandin D2 Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury
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DOI：
10.1523/jneurosci.0321-07.2007
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发表时间：
2007-04
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影响因子：
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通讯作者：
Hidetoshi Taniguchi;I. Mohri;Hitomi Okabe-Arahori;K. Aritake;Kazuko Wada;T. Kanekiyo;S. Narumiya;M. Nakayama;K. Ozono;Y. Urade;M. Taniike
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文献类型：
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作者：
Hidetoshi Taniguchi;I. Mohri;Hitomi Okabe-Arahori;K. Aritake;Kazuko Wada;T. Kanekiyo;S. Narumiya;M. Nakayama;K. Ozono;Y. Urade;M. Taniike
前列腺素D2(PGD)是由造血型前列腺素D合成酶(HPGDS)或脂钙素型前列腺素D2(L-PGDS)合成的，取决于产生前列腺素D2的器官，并与Dp1或DP2受体特异性结合。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，缺氧缺血后10min，脑内PGD2的生成量是假手术组的90倍。与野生型HIE小鼠相比，L-PGDS或DP2基因敲除小鼠的脑梗塞面积无明显变化，而HPGDS-L-PGDS双基因敲除或Dp1基因敲除小鼠的脑梗塞面积明显增加。在复氧10min时，L-PGDS、HPGDS、HPGDS-L-PGDS基因敲除小鼠的PGD2水平分别为野生型的46%、7%和1%，提示脑梗塞范围与PGD2生成量呈负相关。DP1R仅在复氧1h表达于内皮细胞，缺氧后脑血流量下降较快，复氧后达不到基线水平。HPGDS-L-PGDS和Dp1基因敲除小鼠复氧1h后内皮细胞损伤严重。在新生儿HIE脑内，HPGDS阳性小胶质细胞数量增多。结论：PGD2可能主要通过DP1受体抑制内皮细胞变性，对新生大鼠缺氧缺血性脑损伤具有保护作用。
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 DP1 receptors by preventing endothelial cell degeneration.