Journal of Gastroenterology

, Volume 44, Supplement 19, pp 1–7 | Cite as

The enteropathy of prostaglandin deficiency

  • David H. Adler
  • John A. PhillipsIII
  • Joy D. Cogan
  • Tina M. Iverson
  • Nathalie Schnetz-Boutaud
  • Jeffrey A. Stein
  • David A. Brenner
  • Ginger L. Milne
  • Jason D. Morrow
  • Oliver Boutaud
  • John A. Oates
International Forum 1

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 ulcer prostaglandins leukotrienes cytosolic phospholipase A2 nonsteroidal antiinflammatory drugs 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Maiden L, Thjodleifsson B, Seigal A, Bjarnason II, Scott D, Birgisson S, et al. Long-term effects of nonsteroidal antiinflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study. Clin Gastroenterol Hepatol 2007;5:1040–1045.PubMedCrossRefGoogle Scholar
  2. 2.
    Matsumoto T, Kudo T, Esaki M, Yano T, Yamamoto H, Sakamoto C, et al. Prevalence of non-steroidal anti-inflammatory drug-induced enteropathy determined by double-balloon endoscopy: a Japanese multicenter study. Scand J Gastroenterol 2008;43:490–496.PubMedCrossRefGoogle Scholar
  3. 3.
    Graham DY, Opekun AR, Willingham FF, Qureshi WA. Visible small-intestinal mucosal injury in chronic NSAID users. Clin Gastroenterol Hepatol 2005;3:55–59.PubMedCrossRefGoogle Scholar
  4. 4.
    Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Zlotnick S, Fort JG. Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo. Clin Gastroenterol Hepatol 2005;3:133–141.PubMedCrossRefGoogle Scholar
  5. 5.
    Hayashi Y, Yamamoto H, Kita H, Sunada K, Sato H, Yano T, et al. Non-steroidal anti-inflammatory drug-induced small bowel injuries identified by double-balloon endoscopy. World J Gastroenterol. 2005;11:4861–4864.PubMedGoogle Scholar
  6. 6.
    Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971;231:232–235.PubMedGoogle Scholar
  7. 7.
    Somasundaram S, Hayllar H, Rafi S, Wrigglesworth JM, Macpherson AJ, Bjarnason I. The biochemical basis of nonsteroidal anti-inflammatory drug-induced damage to the gastrointestinal tract: a review and a hypothesis. Scand J Gastroenterol 1995;30:289–299.PubMedCrossRefGoogle Scholar
  8. 8.
    Whittle BJ. Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology 1981;80:94–98.PubMedGoogle Scholar
  9. 9.
    Morrow JD, Minton TA. Improved assay for the quantification of 11-dehydrothromboxane B2 by gas chromatography-mass spectrometry. J Chromatogr 1993;612:179–185.PubMedCrossRefGoogle Scholar
  10. 10.
    Morrow JD, Prakash C, Awad JA, Duckworth TA, Zackert WE, Blair IA, et al. Quantification of the major urinary metabolite of prostaglandin D2 by a stable isotope dilution mass spectrometric assay. Anal Biochem 1991;193:142–148.PubMedCrossRefGoogle Scholar
  11. 11.
    Murphey LJ, Williams MK, Sanchez SC, Byrne LM, Csiki I, Oates JA, et al. Quantification of the major urinary metabolite of PGE2 by a liquid chromatographic/mass spectrometric assay: determination of cyclooxygenase-specific PGE2 synthesis in healthy humans and those with lung cancer. Anal Biochem 2004;334:266–275.PubMedCrossRefGoogle Scholar
  12. 12.
    Nakayama T, Soma M, Watanabe Y, Hasimu B, Sato M, Aoi N, et al. Splicing mutation of the prostacyclin synthase gene in a family associated with hypertension. Biochem Biophys Res Commun 2002;297:1135–1139.PubMedCrossRefGoogle Scholar
  13. 13.
    Mizugaki M, Hishinuma T, Suzuki N. Determination of leukotriene E4 in human urine using liquid chromatography-tandem mass spectrometry. J Chromatogr B Biomed Sci Appl 1999;729:279–285.PubMedCrossRefGoogle Scholar
  14. 14.
    Daniel VC, Minton TA, Brown NJ, Nadeau JH, Morrow JD. Simplified assay for the quantification of 2,3-dinor-6-ketoprostaglandin F1 alpha by gas chromatography-mass-spectrometry. J Chromatogr B Biomed Appl 1994;653:117–122.PubMedCrossRefGoogle Scholar
  15. 15.
    Fitzgerald GA, Healy C, Daugherty J. Thromboxane A2 biosynthesis in human disease. Fed Proc 1987;46:154–158.PubMedGoogle Scholar
  16. 16.
    Yin H, Porter NA, Morrow JD. Separation and identification of F2-isoprostane regioisomers and diastereomers by novel liquid chromatographic/mass spectrometric methods. J Chromatogr B Anal Technol Biomed Life Sci 2005;827:157–164.CrossRefGoogle Scholar
  17. 17.
    Boutaud O, Aronoff DM, Richardson JH, Marnett LJ, Oates JA. Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H(2) synthases. Proc Natl Acad Sci U S A 2002;99:7130–7135.PubMedCrossRefGoogle Scholar
  18. 18.
    Leslie CC, Gelb MH. Assaying phospholipase A2 activity. Methods Mol Biol 2004;284:229–242.PubMedGoogle Scholar
  19. 19.
    Adler DH, Cogan JD, Phillips JA, Schnetz-Boutaud N, Milne GL, Iverson T, et al. Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction. J Clin Invest 2008;118:2121–2131.PubMedGoogle Scholar
  20. 20.
    Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C. Lowdose aspirin for the prevention of atherothrombosis. N Engl J Med 2005;353:2373–2383.PubMedCrossRefGoogle Scholar
  21. 21.
    Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999;340:1888–1899.PubMedCrossRefGoogle Scholar
  22. 22.
    Masuda S, Murakami M, Ishikawa Y, Ishii T, Kudo I. Diverse cellular localizations of secretory phospholipase A2 enzymes in several human tissues. Biochim Biophys Acta 2005;1736:200–210.PubMedGoogle Scholar
  23. 23.
    Ni Z, Okeley NM, Smart BP, Gelb MH. Intracellular actions of group IIA secreted phospholipase A2 and group IVA cytosolic phospholipase A2 contribute to arachidonic acid release and prostaglandin production in rat gastric mucosal cells and transfected human embryonic kidney cells. J Biol Chem 2006;281:16245–16255.PubMedCrossRefGoogle Scholar
  24. 24.
    Rainsford KD. Inhibition by leukotriene inhibitors, and calcium and platelet-activating factor antagonists, of acute gastric and intestinal damage in arthritic rats and in cholinomimetic-treated mice. J Pharm Pharmacol 1999;51:331–339.PubMedCrossRefGoogle Scholar
  25. 25.
    Kramer RM, Roberts EF, Manetta JV, Hyslop PA, Jakubowski JA. Thrombin-induced phosphorylation and activation of Ca(2+) sensitive cytosolic phospholipase A2 in human platelets. J Biol Chem 1993;268:26796–26804.PubMedGoogle Scholar
  26. 26.
    Bartoli F, Lin HK, Ghomashchi F, Gelb MG, Jain MK, Apitz-Castro R. Tight bindings inhibitors of 85-kDa phospholipase A2 but not 14-kDa phospholipase A2 inhibit release of free arachidonate in thrombin-stimulated human platelets. J Biol Chem 1994;269:15625–15630.PubMedGoogle Scholar
  27. 27.
    Coffey MJ, Coles B, Locke M, Bermudez-Fajardo A, Williams PC, Jarvis GE, et al. Interactions of 12-lipoxygenase with phospholipase A2 isoforms following platelet activation through the glycoprotein VI collagen receptor. FEBS Lett 2004;576:165–168.PubMedCrossRefGoogle Scholar
  28. 28.
    Wong DA, Kita Y, Uozumi N, Shimizu T. Discrete role for cytosolic phospholipase A(2) alpha in platelets: studies using single and double mutant mice of cytosolic and group IIA secretory phospholipase A(2). J Exp Med 2002;196:349–357.PubMedCrossRefGoogle Scholar
  29. 29.
    Bonventre JV, Huang Z, Taheri MR, O’Leary E, Li E, Moskowitz MA, et al. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature (Lond) 1997;390:622–625.CrossRefGoogle Scholar
  30. 30.
    Bonventre JV. The 85-kD cytosolic phospholipase A2 knockout mouse: a new tool for physiology and cell biology. J Am Soc Nephrol. 1999;10:404–412.PubMedGoogle Scholar
  31. 31.
    Sapirstein A, Bonventre JV. Specific physiological roles of cytosolic phospholipase A(2) as defined by gene knockouts. Biochim Biophys Acta 2000;1488:139–148.PubMedGoogle Scholar
  32. 32.
    Bonventre J. Cytosolic phospholipase A2 alpha reigns supreme in arthritis and bone resorption. Trends Immunol 2004;25:116–119.PubMedCrossRefGoogle Scholar
  33. 33.
    Haq S, Kilter H, Michael A, Tao J, O’Leary E, Sun XM, et al. Deletion of cytosolic phospholipase A2 promotes striated muscle growth. Nat Med 2003;9:944–951.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2009

Authors and Affiliations

  • David H. Adler
    • 1
  • John A. PhillipsIII
    • 2
  • Joy D. Cogan
    • 2
  • Tina M. Iverson
    • 3
  • Nathalie Schnetz-Boutaud
    • 6
  • Jeffrey A. Stein
    • 4
  • David A. Brenner
    • 5
  • Ginger L. Milne
    • 1
  • Jason D. Morrow
    • 1
  • Oliver Boutaud
    • 1
  • John A. Oates
    • 1
  1. 1.Departments of Medicine and Pharmacology, Division of Clinical PharmacologyVanderbilt University, Vanderbilt Medical CenterNashvilleUSA
  2. 2.Department of Pediatrics, Division of Medical GeneticsVanderbilt Medical CenterNashvilleUSA
  3. 3.Department of PharmacologyVanderbilt University, Vanderbilt Medical CenterNashvilleUSA
  4. 4.Department of Medicine, Division of Digestive and Liver DiseasesColumbia UniversityNew YorkUSA
  5. 5.School of MedicineUniversity of California, San DiegoLa JollaUSA
  6. 6.Center for Human Genetics ResearchVanderbilt University, Vanderbilt Medical CenterNashvilleUSA

Personalised recommendations