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  • Title: COX-1 and COX-2 contributions to basal and IL-1 beta-stimulated prostanoid synthesis in human neonatal cerebral microvascular endothelial cells.
    Author: Parfenova H, Levine V, Gunther WM, Pourcyrous M, Leffler CW.
    Journal: Pediatr Res; 2002 Sep; 52(3):342-8. PubMed ID: 12193665.
    Abstract:
    Mechanisms of endothelium-dependent regulation of cerebral circulation in human neonates are poorly understood owing to the lack of experimental data. Prostanoids, the products of the cyclooxygenase (COX) pathway, appear to be important regulators of blood flow in neonates. COX activity in cultured endothelial cells from small (60-300 microm) and large (>300 microm) microvessels from the autopsy specimens of neonatal human cerebral cortex and cerebellum (22-26 wk gestational age) was detected as production of vasodilator prostanoids, prostacyclin [as 6-keto-prostaglandin (PG) F(1 alpha)] and PGE(2) from arachidonic acid. Treatment of neonatal human cerebral microvascular endothelial cells (hCMVEC) with IL-1 beta (50 ng/mL, 17 h) stimulated COX activity 5- to 20-fold. Basal and IL-1 beta-stimulated COX activities were inhibited by NS-398, indicating substantial COX-2 contribution to endothelial prostanoid synthesis in neonatal human brain cortex and cerebellum at rest and when mimicking the inflammatory conditions. Increased COX-2-linked activity in response to IL-1 beta was observed in hCMVEC from both cerebrum and cerebellum (5- to 20-fold), while under the same conditions elevated COX-1-linked activity was detected only in hCMVEC from cerebellum (5- to 10-fold). In IL-1 beta-treated hCMVEC, a shift toward PGE(2) as the major vasodilator product of the COX pathway was observed. Acute treatment with the protein tyrosine kinase inhibitor, tyrphostin 25, inhibited basal and IL-1 beta-induced COX activities, suggesting the importance of posttranslational modifications in endothelial COX-2 activation in human brain. Altogether, these data indicate that both COX-1 and COX-2 contribute to endothelial prostanoid synthesis in the neonatal human brain under basal conditions and in response to proinflammatory cytokine IL-1 beta.
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