Original article| Volume 55, ISSUE 6, P419-425, December 1996

Prostanoid biosynthesis in patients with cystic fibrosis

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      The urinary excretion rate (ng/h/1.73 m2) of prostanoids was determined with a capillary gas-liquid chromatographic mass spectrometric method in 19 patients with cystic fibrosis (CF) aged 1–29 years. Patients with CF showed an increased excretion of prostaglandin E2 metabolites (PGE-M) and thromboxane B2 and its metabolites at all ages. An imbalance in the excretion pattern of thromboxane B2 metabolites also suggested a relative impairment of β-oxidation. There was no increased excretion of dinor-6-keto-PGF, indicating normal prostacyclin biosynthesis. No correlation was found to genotype, clinical score, lung function or bacterial colonization but a significant negative relation was found between the main prostanoids in the urine and serum phospholipid levels of essential fatty acids. The results show that, contrary to the generally accepted decrease of prostanoid excretion in essential fatty acid deficiency, patients with CF increase their production parallel to the development of the deficiency. Since prostanoid synthesis is rate limited by arachidonic acid release, our data support a previously presented hypothesis about a pathological regulation of the release of arachidonic acid in CF.
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        • Hodson M.E
        • Geddes D.M
        Cystic Fibrosis.
        Chapman & Hall, Cambridge1995
        • Rommens J.M
        • Iannuzzi M.C
        • Kerem B
        • et al.
        Identification of the cystic fibrosis gene: chromosome walking and jumping.
        Science. 1989; 245: 1059-1065
        • Riordan J.R
        • Rommens J.M
        • Kerem B
        • et al.
        Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.
        Science. 1989; 245: 1066-1073
        • Welsh M.J
        • Smith A.E
        Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis.
        Cell. 1993; 73: 1251-1254
        • Clarke L.L
        • Grubb B.R
        • Yankaskas J.R
        • Cotton C.U
        • McKenzie A
        • Boucher R.C
        Relationship of a non-cystic fibrosis transmembrane conductance regulator-mediated chloride conductance to organ-level disease in Cftr (-/-) mice.
        in: Proc Natl Acad Sci USA. 91. 1994: 479-483
        • Borgo G
        • Mastella G
        • Gasparini P
        • Zorzanello A
        • Doro R
        • Pignatti P.F
        Pancreatic function and gene deletion F 508 in cystic fibrosis.
        J Med Gen. 1990; 27: 665-669
        • Kristidis P
        • Bozon D
        • Corey M
        • et al.
        Genetic determination of exocrine pancreatic function in cystic fibrosis.
        Am J Hum Gen. 1992; 50: 1178-1184
        • Higgins C.F
        • Hyde S.C
        Channeling our thoughts.
        Nature. 1991; 352: 194-195
        • Al-Awqati Q
        Regulation of ion channels by ABC transporters that secrete ATP.
        Science. 1995; 269: 805-806
        • Lloyd-Still J.D
        • Johnson S.B
        • Holman R.T
        Essential fatty acid status and fluidity of plasma phospholipids in cystic fibrosis infants.
        Am J Clin Nutr. 1991; 54: 1029-1035
        • Strandvik B
        Relation between essential fatty acid metabolism and gastrointestinal symptoms in cystic fibrosis.
        Acta Paediatr Scand. 1989; 363: 58-65
        • Strandvik B
        Long chain fatty acid metabolism and essential fatty acid deficiency with special emphasis on cystic fibrosis.
        in: Bracco U Deckelbaum R Polyunsaturated Fatty Acids in Human Nutrition. Raven Press, New York1992: 159-167
        • Christophe A.B
        • Warwick W.J
        • Holman R.T
        Serum fatty acid profiles in cystic fibrosis patients and their parents.
        Lipids. 1994; 29: 569-575
        • Carlstedt-Duke J
        • Brönnegård M
        • Strandvik B
        Pathological regulation of arachidonic acid release in cystic fibrosis: the putative basic defect.
        in: Proc Natl Acad Sci USA. 83. 1986: 920-928
        • Levistre R
        • Lemnaouar M
        • Rybkine T
        • Béréziat G
        • Masliah J
        Increase of bradykinin-stimulated arachidonic acid release in a F508 cystic fibrosis epithelial cell line.
        Biochim Biophys Acta. 1993; 1181: 233-239
        • Anderson M.P
        • Welsh M.J
        Fatty acids inhibit apical membrane chloride channels in airway epithelia.
        in: Proc Natl Acad Sci USA. 87. 1990: 7334-7738
        • Hwang T.C
        • Guggino S.E
        • Guggino W.B
        Direct modulation of secretory chloride channels by arachidonic acid and other cis unsaturated fatty acids.
        in: Proc Natl Acad Sci USA. 87. 1990: 5706-5709
        • Ordway R.W
        • Singer J.J
        • Walsh J.R
        Direct regulation of ion channels by fatty acids.
        TINS. 1991; 14: 96-100
        • Strandvik B
        • Brönnegård M
        • Gilljam H
        • Carlstedt-Duke J
        Relation between defective regulation of archidonic acid release and symptoms in cystic fibrosis.
        Scand J Gastroenterol. 1988; 23: 1-4
        • Bergström S
        • Danielsson H
        • Samuelsson B
        The enzymatic formation of prostaglandin E2 from arachidonic acid.
        Biochim Biophys Acta. 1964; 90: 207-210
        • Strandvik B
        • Brönnegård M
        • Carlstedt-Duke J
        Arachidonic acid release in CF.
        in: Mastella G Quinton P The Cellular and Molecular Basis for Cystic Fibrosis. San Fransisco Press Inc, 1988: 445-450
        • Lemen R.J
        • Gates A.J
        • Mathè A.A
        • Waring W.W
        • Hyman A.L
        • Kadowitz P.D
        Relationships among digital clubbing, disease severity, and serum prostaglandins F2a and E concentrations in cystic fibrosis patients.
        Am Rev Respir Dis. 1978; 117: 639-646
        • Chase H.P
        • Dupont J
        Abnormal levels of prostaglandins and fatty acids in blood of children with cystic fibrosis.
        Lancet. 1978; ii: 236-238
        • Lemen R.J
        • Revsin B
        • Corrigan J.J
        • Payne C.M
        • Moon M.A
        • Hokans C.M
        Abnormal prostaglandin (PG) metabolism and platelet function in cystic fibrosis (CF) patients.
        Pediatr Res. 1981; 15 (Abstract): 724
        • FitzGerald G.A
        • Pedersen A.K
        • Patrono C
        Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease.
        Circulation. 1983; 67: 1174-1177
        • Schweer H
        • Kammer J
        • Kuhl P.G
        • Seyberth H.W
        Determination of peripheral plasma prostanoid concentration: An unreliable index of ‘in vivo’ prostanoid activity.
        Eur J Clin Pharmacol. 1986; 31: 303-305
        • Cattella F
        • Nowak J
        • FitzGerald G.A
        Measurement of renal and non-renal eicosanoid synthesis.
        Am J Med. 1986; 81: 23-29
        • Shwachman H
        • Kulczycki L.L
        Long term study of one hundred and five patients with cystic fibrosis.
        Am J Dis Child. 1958; 96: 6-15
        • Engström I
        • Karlberg O
        • Swarts C.L
        Respiratory studies in children. IX. Relationships between mechanical properties of the lung, lung volumes and ventilatory capacity in healthy children 7–15 years of age.
        Acta Paediatr Scand. 1962; 51: 68-86
        • Strandvik B
        • Berg U
        • Kallner A
        • Kusoffsky E.L
        The effect on renal function of essential fatty acid supplementation in patients with cystic fibrosis.
        J Pediatr. 1989; 115: 242-250
        • Schweer H
        • Meese C.O
        • Furst O
        • Kuhl P.G
        • Seyberth H.W
        Tandem mass spectrometric determination of 11-dehydro-thromboxane B2 in plasma and urine.
        Anal Biochem. 1987; 164: 156-163
        • Seyberth H.W
        • Rascher W
        • Schweer H
        • Kuhl P.G
        • Mehls O
        • Schärer K
        Congenital hypokalemia with hypercalciuria in preterm infants: A hyperprostaglandinuric tubular syndrome different from Barrtter syndrome.
        J Pediatr. 1985; 107: 694-701
        • Seyberth H.W
        • Tulassay T
        • Kuhl P.G
        • Soeding K
        • Rascher W
        • Schweer H
        Excretion of primary prostanoids and their metabolism during acute volume expansion.
        Prostaglandins. 1988; 35: 221-232
        • Leonhardt A
        • Busch C
        • Schweer H
        • Seyberth H.W
        Reference intervals and developmental changes in urinary prostanoid excretion in healthy newborns, infants and children.
        Acta Pœdiatr. 1992; 81: 191-196
        • Ellin Å
        • van der Berg S
        • Strandvik B
        A simplified analysis of fatty acids in serum phospholipids using Seppak cartridges.
        Clin Chim Acta. 1991; 200: 59-61
        • Schweer H
        • Kammer J
        • Seyberth H.W
        Simultaneous determination of prostanoids in plasma by gas chromatography-negative ion chemical ionization mass spectrometry.
        J Chromatogr. 1985; 338: 273-280
        • Hamberg M
        Inhibition of prostaglandin synthesis in man.
        Biochem Biophys Res Commun. 1972; 49: 720-726
        • FitzGerald G.A
        • Brash A.R
        • Falardeau P
        • Oates J.A
        Estimated rate of prostacyclin secretion into the circulation in normal man.
        J Clin Invest. 1976; 68: 1272-1276
        • Catella F
        • FitzGerald G.A
        Paired analysis of urinary thromboxane B2 metabolites in humans.
        Thromb Res. 1987; 47: 647-656
        • Friedman Z
        Essential fatty acids revisited.
        Am J Child. 1980; 134: 397-408
        • Lerner R
        • Lindström P
        • Berg A
        • Johansson E
        • Rosendahl K
        • Palmblad J
        Development and characterization of essential fatty acid deficiency in human endothelial cells in culture.
        in: Proc Natl Acad Sci USA. 92. 1995: 1147-1151
        • Friedman Z
        Effects of dietary variation in linoleic acid content on prostaglandin synthesis in infants.
        in: Essential Fatty Acids and Prostaglandins. 20. Pergamon Press, Oxford1981: 59-66
        • Gilljam H
        • Strandvik B
        • Ellin Å
        • Wiman L.-G
        Increased mole fraction of arachidonic acid in bronchial phospholipids in patients with cystic fibrosis.
        Scand J Clin Invest. 1986; 46: 511-518
        • Saak A
        • Schönfeld W
        • Knöller J
        • Steinkamp G
        • von der Hardt H
        • König W
        Generation and metabolism of leukotrienes in granulocytes of patients with cystic fibrosis.
        Int Arch Allergy Appl Immunol. 1990; 93: 227-236
        • Shimizu T
        • Hansson G
        • Strandvik B
        Defective inhibition by dexamethasone of leukotriene B4 and C4 production by leukocytes in patients with cystic fibrosis.
        Prostaglandins Leukot Essent Fatty Acids. 1994; 51: 407-410
        • Chen H.W
        • Hendrich S
        • Cook L.R
        Vitamin E deficiency increases serum thromboxane A2, platelet arachidonate and lipid peroxidation in male Sprague-Dawley rats.
        Prostaglandins Leukot Essent Fatty Acids. 1994; 51: 11-17
        • Roscher A
        • Hadorn B
        Regulation of β-receptor-mediated biological signals on the cellular level.
        in: Kaiser D Approaches to Cystic Fibrosis Research. Maizena Diät GmbH, Berlin1981: 61-67
        • Lászlo A
        • Németh M
        • Gyurkovits K
        Activity of phospholipase A in serum from patients with cystic fibrosis.
        Clin Chim Acta. 1993; 214: 105-107
        • Breslow J.L
        • Epstein J
        • Fontaine J.H
        • Forbes G.B
        Enhanced dexamethasone resistance in cystic fibrosis cells: potential use for heterozygote detection and prenatal diagnosis.
        Science. 1978; 201: 180-182
        • Emilie D
        • Crevon M.C
        • Chicheportiche R
        • et al.
        Cystic fibrosis patients' B-lymphocyte response is resistant to the in vitro enhancing effect of corticosteroids.
        Eur J Clin Invest. 1990; 20: 620-626
        • Samuels C.E
        • Robinson P.G
        • Elliott R.B
        Decreased inhibition of platelet aggregation by PGE1 in children with cystic fibrosis and their parents.
        Prostaglandins. 1975; 10: 617-621
        • Stead R.J
        • Barradas M.A
        • Mikhailidis D.P
        • et al.
        Platelet hyperaggregability in cystic fibrosis.
        Prostaglandins Leukot Med. 1987; 26: 91-103
        • Hoof T
        • Demmer A
        • Hadam M.R
        • Riordan J.R
        • Tummler B
        Cystic fibrosis-type mutation analysis in the ATP-binding casette transporter signature of human P-glycoprotein MDR1.
        J Biol Chem. 1994; 269: 20575-20583
        • Valverde M.A
        • Diaz M
        • Sepúlveda F.V
        • Gill D.R
        • Hyde S.C
        • Higgins C.F
        Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein.
        Nature. 1992; 355: 830-833
        • Rasola A
        • Galieta L.J.V
        • Gruenert D.C
        • Romeo G
        Volume-sensitive chloride currents in four epithelial cell lines are not directly correlated to the expression of the MDR1 gene.
        J Biol Chem. 1993; 269: 1432-1436
        • Berr F
        • Meier P.J
        • Stieger B
        Evidence for the presence of a phosphatidylcholine translocator in isolated rat liver canalicular plasma membrane vesicles.
        J Biol Chem. 1993; 268: 3976-3979
        • Leier I
        • Jedlitschky G
        • Buchholz U
        • Keppler D
        Characterization of the ATP-dependent leukotriene C4 export carrier in mastocytoma cells.
        Eur J Biochem. 1994; 220: 599-606
        • Higgins C.F
        • Gottesman M.M
        Is the multidrug transporter a flippase?.
        TIBS. 1992; 17: 18-21
        • Stubbs C.D
        Membrane fluidity: Structure and dynamics of membrane lipids.
        Ess Biochem. 1983; 19: 1-39
        • Doige C.A
        • Ames G.F.-L
        ATP-dependent transport systems in bacteria and humans: Relevance to cystic fibrosis and multidrug resistance.
        Ann Rev Microbiol. 1993; 47: 291-319