| セッション情報 |
International Forum 1(Gastrointestinal tract) 1.Prostaglandins and gastrointestinal mucosa
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| タイトル |
IF1-1-I (Keynote lecture) The Enteropathy of Prostaglandin Deficiency
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| 演者 |
David H.Adler（Departments of Medicine and PharmacologyDivision of Clinical Pharmacology^1） |
| 共同演者 |
John A.Phillips III（Department of PediatricsDivision of Medical Genetics^2）, Joy D.Cogan（Department of PediatricsDivision of Medical Genetics^2）, Tina Iverson（Department of PharmacologyVanderbilt University^3）, Jason D.Morrow（Departments of Medicine and PharmacologyDivision of Clinical Pharmacology^1）, Olivier Boutaud（Departments of Medicine and PharmacologyDivision of Clinical Pharmacology^1）, John A.Oates（Departments of Medicine and PharmacologyDivision of Clinical Pharmacology^1） |
| 抄録 |
Background ： Small intestinal ulcers were recognized early as a complication of NSAIDs in rodents． Theincidence and complications of small intestinal ulcers attributable to NSAIDs and COX-2 inhibitors in hu-mans have been demonstrated more recentlyand these ulcers have been attributed to loss of the protec-tive action of a prostaglandin．Investigation ： lt was in the context of this understanding of small intestinal ulcers as a consequence ofprostaglandin deficiency that we investigated the cause of chronic recurrent small intestinal ulcerssmallbowel perforationsand gastrointestinal blood loss in an otherwise healthy 45 year old male who was nottaking any cyclooxygenase inhibitor． The products of cycloxygenase and lipoxygenase pathways wereanalyzed by mass spectrometry． Prostaglandin metabolites in urine were significantly depressed． Serumthromboxane B2 （TxB2） production was 4.6% of normal controls （p〈0.006） and serum 12-HETE was 1.3 %of controls （p〈 O．005） ． Optical platelet aggregation with simultaneous luminescence monitoring of ATP re-lease demonstrated absent granule secretion in response to ADP and a blunted aggregation response toADP and collagenbut normal response to AA． Ex vivo TxB2 production by washed platelets from deu-terated AA was normalbut AA-triggered endogenous AA release was remarkably depressed． LTB4 bio-synthesis by ionophore activated leukocytes was only 3% of controls and urinary LTE4 was undetectable．These concerted findings suggested normal COX-1 functionbut deficient endogenous AA release fromcytosolic phospholipase A2-a （cPLA2-ct） which regulates cyclooxygenase and lipoxygenase mediated ei-cosanoid production by catalyzing the release of their substratearachidonic acid （AA）from membranephospholipids． The patient’s mean total platelet PLA2 activity was O．77±O．32 pmol／min／50pg protein vs．2．83±O47 pmol／min／50pg protein for controls （p〈ODOO5）． Western blot analysis of platelet protein com-pared with controls demonstrated decreased cPLA2-ct with the expected molecular weight． Sequencing ofcPLA2-ct cDNA demonstrated 2 heterozygous non-synonymous single base pair mutations ： SerllIPro （S111P） and Arg485His （R485H）as well as a known SNP ： Lys651Arg （K651R）． Genetic analysis demon-strated that the patient’s mother possessed the heterozygous SlllP mutation and sister possessed boththe heterozygous R485H mutation and the K651R SNP．Conclusion ：・ We describe a novel compound heterozygous mutation of cPLA2-ct resulting in decreasedeicosanoid productionmultiple recurrent small intestinal ulcersabsence of platelet granule secretionandchronic gastrointestinal blood loss． Characterization of this deficiency provides support for the importanceof prostaglandins in protecting small intestinal integrityand has the potential for elucidating the humanbiology and pathophysiology of cPLA2一α． The limited information on the mechanism of the protective ef-fects of prostaglandins on the sma11 intestine will be discussed． The findings provide a highly relevant per-spective for any considerations of the development of drugs that target cPLA2-oL［Supported by NIH grants GM-1543エUOエHL65962 and MOI RR-00095］ |
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