Prostanoid biosynthesis by blood monocytes of children with hyperprostaglandin E syndrome.
Hyperprostaglandin E syndrome (HPS), the prenatal variant of Bartter's syndrome, is characterized by a marked and selective stimulation of prostaglandin E (PGE2) synthesis. In the study group HPS patients showed increased urinary levels of PGE2, an index of renal, and of 11 alpha-hydroxy-9,15-dioxo-2,3,4,5,20-pentanor-19-carboxyprostano ic acid (PGE-M), an index of systemic PGE2 synthesis of 470% and of 570%, respectively. In addition, plasma concentration of PGE-M was also elevated 6.3-fold when compared with a control group. The urinary levels of other prostanoids were unaltered. During indomethacin treatment in both groups prostanoid excretion rates were suppressed to similar levels. To investigate the origin of stimulated prostanoid biosynthesis in HPS patients CD14+ monocytes were isolated from plasma samples, and the prostanoid synthesis was analyzed. The pattern and amounts of metabolites synthesized from endogenous arachidonic acid pools did not vary significantly between monocytes of the HPS and the control group. Thromboxane A2 (TXA2) was formed as the major prostanoid product. Using PGH2 as an exogenous substrate, again no difference in PGE2 biosynthesis was observed, indicating no difference in PGE-synthetic activity between both groups. Additionally, mRNA expression analysis of CD14+ monocytes via RT-PCR delineated the constitutive expression of cyclooxygenase-1, cyclooxygenase-2, and thromboxane synthase mRNA in cells from HPS patients and controls without statistical differences between these two groups. In conclusion, our data show that monocytes are not the source for the increased PGE2 biosynthesis in children with HPS, and a genetic defect in PGE synthesis can be excluded as the primary event in the pathogenesis in HPS.
Nüsing
R M
RM
Department of Pediatrics, Philipps University Marburg, Germany.
Schaub
T P
TP
Klein
T
T
Schweer
H
H
Seyberth
H W
HW
D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005260:Female; D006801:Humans; D007223:Infant; D007527:Isoenzymes / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000097:blood; D008297:Male; D008565:Membrane Proteins; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011453:Prostaglandins / Q000096:biosynthesis* / Q000097:blood / Q000652:urine; D011458:Prostaglandins E / Q000097:blood*; D012194:RNA-Directed DNA Polymerase; D013930:Thromboxane-A Synthase / Q000235:genetics
D007527:Isoenzymes; D018950:Lipopolysaccharide Receptors; D008565:Membrane Proteins; D011453:Prostaglandins; D011458:Prostaglandins E; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D012194:RNA-Directed DNA Polymerase; D013930:Thromboxane-A Synthase