Journal of Gastroenterology

, Volume 44, Supplement 19, pp 1–7

The enteropathy of prostaglandin deficiency

Authors

  • David H. Adler
    • Departments of Medicine and Pharmacology, Division of Clinical PharmacologyVanderbilt University, Vanderbilt Medical Center
  • John A. PhillipsIII
    • Department of Pediatrics, Division of Medical GeneticsVanderbilt Medical Center
  • Joy D. Cogan
    • Department of Pediatrics, Division of Medical GeneticsVanderbilt Medical Center
  • Tina M. Iverson
    • Department of PharmacologyVanderbilt University, Vanderbilt Medical Center
  • Nathalie Schnetz-Boutaud
    • Center for Human Genetics ResearchVanderbilt University, Vanderbilt Medical Center
  • Jeffrey A. Stein
    • Department of Medicine, Division of Digestive and Liver DiseasesColumbia University
  • David A. Brenner
    • School of MedicineUniversity of California, San Diego
  • Ginger L. Milne
    • Departments of Medicine and Pharmacology, Division of Clinical PharmacologyVanderbilt University, Vanderbilt Medical Center
  • Jason D. Morrow
    • Departments of Medicine and Pharmacology, Division of Clinical PharmacologyVanderbilt University, Vanderbilt Medical Center
  • Oliver Boutaud
    • Departments of Medicine and Pharmacology, Division of Clinical PharmacologyVanderbilt University, Vanderbilt Medical Center
  • John A. Oates
    • Departments of Medicine and Pharmacology, Division of Clinical PharmacologyVanderbilt University, Vanderbilt Medical Center
International Forum 1

DOI: 10.1007/s00535-008-2253-y

Cite this article as:
Adler, D.H., Phillips, J.A., Cogan, J.D. et al. J Gastroenterol (2009) 44: 1. doi:10.1007/s00535-008-2253-y
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Abstract

Background

Small intestinal ulcers are frequent complications of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). We present here a genetic deficiency of eicosanoid biosynthesis that illuminates the mechanism of NSAID-induced ulcers of the small intestine.

Methods

Eicosanoids and metabolites were measured by isotope dilution with mass spectrometry. cDNA was obtained by reverse transcription and sequenced following amplification with RT-PCR.

Results

We investigated the cause of chronic recurrent small intestinal ulcers, small bowel perforations, and gastrointestinal blood loss in a 45-year-old man who was not taking any cyclooxygenase inhibitor. Prostaglandin metabolites in urine were significantly depressed. Serum thromboxane B2 (TxB2) production was 4.6% of normal controls (P < 0.006), and serum 12-HETE was 1.3% of controls (P < 0.005). Optical platelet aggregation with simultaneous monitoring of ATP release demonstrated absent granule secretion in response to ADP and a blunted aggregation response to ADP and collagen, but normal response to arachidonic acid (AA). LTB4 biosynthesis by ionophore-activated leukocytes was only 3% of controls, and urinary LTE4 was undetectable. These findings suggested deficient AA release from membrane phospholipids by cytosolic phospholipase A2-α (cPLA2-α), which regulates cyclooxygenase- and lipoxygenase-mediated eicosanoid production by catalyzing the release of their substrate, AA. Sequencing of cPLA2-α cDNA demonstrated two heterozygous nonsynonymous single-base-pair mutations: Ser111Pro (S111P) and Arg485His (R485H), as well as a known single nucleotide polymorphism (SNP), Lys651Arg (K651R).

Conclusions

Characterization of this cPLA2-α deficiency provides support for the importance of prostaglandins in protecting small intestinal integrity and indicates that loss of prostaglandin biosynthesis is sufficient to produce small intestinal ulcers.

Key words

small intestinal ulcerprostaglandinsleukotrienescytosolic phospholipase A2nonsteroidal antiinflammatory drugs

Copyright information

© Springer Japan 2009