Skip to main content
Erschienen in: Digestive Diseases and Sciences 4/2013

01.04.2013 | Original Article

Orally Administered Phosphatidic Acids and Lysophosphatidic Acids Ameliorate Aspirin-Induced Stomach Mucosal Injury in Mice

verfasst von: Tamotsu Tanaka, Katsuya Morito, Masafumi Kinoshita, Mayumi Ohmoto, Mai Urikura, Kiyoshi Satouchi, Akira Tokumura

Erschienen in: Digestive Diseases and Sciences | Ausgabe 4/2013

Einloggen, um Zugang zu erhalten

Abstract

Background

Recent investigations revealed that lysophosphatidic acid (LPA), a phospholipid with a growth factor-like activity, plays an important role in the integrity of the gastrointestinal tract epithelium.

Aim

This paper attempts to clarify the effect of orally administered phosphatidic acid (PA) and LPA on aspirin-induced gastric lesions in mice.

Materials and Methods

Phospholipids, a free fatty acid, a diacylglycerol and a triglyceride at 1 mM (5.7 μmol/kg body weight) or 0.1 mM were orally administered to mice 0.5 h before oral administration of aspirin (1.7 mmol/kg). The total length of lesions formed on the stomach wall was measured as a lesion index. Formation of LPA from PA in the mouse stomach was examined by in vitro (in stomach lavage fluid), ex vivo (in an isolated stomach) and in vivo (in the stomach of a living mouse) examinations of phospholipase activity.

Results

Palmitic acid, dioleoyl-glycerol, olive oil and lysophosphatidylcholine did not affect the aspirin-induced lesions. In contrast, phosphatidylcholine (1 mM), LPA (1 mM) and PA (0.1, 1 mM) significantly reduced the lesion index. Evidence for formation of LPA from PA in the stomach by gastric phospholipase A2 was obtained by in vitro, ex vivo and in vivo experiments. An LPA-specific receptor, LPA2, was found to be localized on the gastric surface-lining cells of mice.

Conclusion

Pretreatment with PA-rich diets may prevent nonsteroidal anti-inflammatory drug-induced stomach ulcers.
Literatur
1.
Zurück zum Zitat Moolenaar WH, van Meeteren LA, Giepmans BNG. The ins and outs of lysophosphatidic acid signaling. BioEssays. 2004;26:870–881.PubMedCrossRef Moolenaar WH, van Meeteren LA, Giepmans BNG. The ins and outs of lysophosphatidic acid signaling. BioEssays. 2004;26:870–881.PubMedCrossRef
2.
Zurück zum Zitat Tokumura A. Physiological significance of lysophospholipids that act on the lumen side of mammalian lower digestive tracts. J Health Sci. 2011;57:115–128.CrossRef Tokumura A. Physiological significance of lysophospholipids that act on the lumen side of mammalian lower digestive tracts. J Health Sci. 2011;57:115–128.CrossRef
3.
Zurück zum Zitat Sturm A, Sudermann T, Schulte K-M, Goebell H, Dignass AU. Modulation of intestinal epithelial wound healing in vitro and in vivo by lysophosphatidic acid. Gastroenterology. 1999;117:368–377.PubMedCrossRef Sturm A, Sudermann T, Schulte K-M, Goebell H, Dignass AU. Modulation of intestinal epithelial wound healing in vitro and in vivo by lysophosphatidic acid. Gastroenterology. 1999;117:368–377.PubMedCrossRef
4.
Zurück zum Zitat Deng W, Balazs L, Wang D-A, van Middlesworth L, Tigyi G, Johnson LR. Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis. Gastroenterology. 2002;123:206–216.PubMedCrossRef Deng W, Balazs L, Wang D-A, van Middlesworth L, Tigyi G, Johnson LR. Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis. Gastroenterology. 2002;123:206–216.PubMedCrossRef
5.
Zurück zum Zitat Deng W, Shuyu E, Tsukahara R, et al. The lysophosphatidic acid type 2 receptor is required for protection against radiation-induced intestinal injury. Gastroenterology. 2007;132:1834–1851.PubMedCrossRef Deng W, Shuyu E, Tsukahara R, et al. The lysophosphatidic acid type 2 receptor is required for protection against radiation-induced intestinal injury. Gastroenterology. 2007;132:1834–1851.PubMedCrossRef
6.
Zurück zum Zitat Adachi M, Horiuchi G, Ikematsu N, et al. Intragastrically administered lysophosphatidic acid protect against gastric ulcer in rats under water-immersion restraint stress. Dig Dis Sci. 2011;56:2252–2261.PubMedCrossRef Adachi M, Horiuchi G, Ikematsu N, et al. Intragastrically administered lysophosphatidic acid protect against gastric ulcer in rats under water-immersion restraint stress. Dig Dis Sci. 2011;56:2252–2261.PubMedCrossRef
7.
Zurück zum Zitat Li C, Dandridge KS, Di A, et al. Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through CFTR-dependent protein interactions. J Exp Med. 2005;202:975–986.PubMedCrossRef Li C, Dandridge KS, Di A, et al. Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through CFTR-dependent protein interactions. J Exp Med. 2005;202:975–986.PubMedCrossRef
8.
Zurück zum Zitat Singla A, Dwivedi A, Saksena S, et al. Mechanisms of lysophosphatidic acid (LPA) mediated stimulation of intestinal apical Cl−/OH− exchange. Am J Physiol Gastrointest Liver Physiol. 2010;298:G182–G189.PubMedCrossRef Singla A, Dwivedi A, Saksena S, et al. Mechanisms of lysophosphatidic acid (LPA) mediated stimulation of intestinal apical Cl/OH exchange. Am J Physiol Gastrointest Liver Physiol. 2010;298:G182–G189.PubMedCrossRef
9.
Zurück zum Zitat Singla A, Kumar A, Priyamvada S, et al. LPA stimulates intestinal DRA gene transcription via LPA2 receptor, PI3 K/AKT, and c-Fos-dependent pathway. Am J Physiol Gastrointest Liver Physiol. 2012;302:G618–G627.PubMedCrossRef Singla A, Kumar A, Priyamvada S, et al. LPA stimulates intestinal DRA gene transcription via LPA2 receptor, PI3 K/AKT, and c-Fos-dependent pathway. Am J Physiol Gastrointest Liver Physiol. 2012;302:G618–G627.PubMedCrossRef
10.
Zurück zum Zitat Okudaira S, Yukiura H, Aoki J, et al. Biological roles of lysophosphatidic acid signaling through its production by autotaxin. Biochimie. 2010;92:698–706.PubMedCrossRef Okudaira S, Yukiura H, Aoki J, et al. Biological roles of lysophosphatidic acid signaling through its production by autotaxin. Biochimie. 2010;92:698–706.PubMedCrossRef
11.
Zurück zum Zitat Sugiura T, Nakane S, Kishimoto S, Waku K, Yoshioka Y, Tokumura A. Lysophosphatidic acid, a growth factor-like lipid, in the saliva. J Lipid Res. 2002;43:2049–2055.PubMedCrossRef Sugiura T, Nakane S, Kishimoto S, Waku K, Yoshioka Y, Tokumura A. Lysophosphatidic acid, a growth factor-like lipid, in the saliva. J Lipid Res. 2002;43:2049–2055.PubMedCrossRef
12.
Zurück zum Zitat Tanaka T, Horiuchi G, Matsuoka M, et al. Formation of lysophosphatidic acid, a wound-healing lipid, during digestion of cabbage leaves. Biosci Biotechnol Biochem. 2009;73:1293–1300.PubMedCrossRef Tanaka T, Horiuchi G, Matsuoka M, et al. Formation of lysophosphatidic acid, a wound-healing lipid, during digestion of cabbage leaves. Biosci Biotechnol Biochem. 2009;73:1293–1300.PubMedCrossRef
13.
Zurück zum Zitat Tanaka T, Kassai A, Ohmoto M, et al. Quantification of phosphatidic acid in foodstuffs using a thin-layer-chromatography-imaging technique. J Agric Food Chem. 2012;60:4156–4161.PubMedCrossRef Tanaka T, Kassai A, Ohmoto M, et al. Quantification of phosphatidic acid in foodstuffs using a thin-layer-chromatography-imaging technique. J Agric Food Chem. 2012;60:4156–4161.PubMedCrossRef
14.
Zurück zum Zitat Taha AS, McCloskey C, Prasada R, Bezlyak V, et al. Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase III, randomized, double-blind, placebo-controlled trial. Lancet. 2009;374:119–125.PubMedCrossRef Taha AS, McCloskey C, Prasada R, Bezlyak V, et al. Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase III, randomized, double-blind, placebo-controlled trial. Lancet. 2009;374:119–125.PubMedCrossRef
15.
Zurück zum Zitat Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn’t the stomach digest itself? Physiol Rev. 2008;88:1547–1565.PubMedCrossRef Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn’t the stomach digest itself? Physiol Rev. 2008;88:1547–1565.PubMedCrossRef
16.
Zurück zum Zitat Musumba C, Pritchard DM, Pirmohamed M. Cellular and molecular mechanisms of NSAID-induced peptic ulcers. Aliment Pharmacol Ther. 2009;30:517–531.PubMedCrossRef Musumba C, Pritchard DM, Pirmohamed M. Cellular and molecular mechanisms of NSAID-induced peptic ulcers. Aliment Pharmacol Ther. 2009;30:517–531.PubMedCrossRef
17.
Zurück zum Zitat Lichtenberger LM, Barron M, Marathi U. Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity. Drugs Today. 2009;45:877–890.PubMed Lichtenberger LM, Barron M, Marathi U. Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity. Drugs Today. 2009;45:877–890.PubMed
18.
Zurück zum Zitat Tomisato W, Tanaka K, Katsu T, et al. Membrane permeabilization by non-steroidal anti-inflammatory drugs. Biochem Biophys Res Commun. 2004;323:1032–1039.PubMedCrossRef Tomisato W, Tanaka K, Katsu T, et al. Membrane permeabilization by non-steroidal anti-inflammatory drugs. Biochem Biophys Res Commun. 2004;323:1032–1039.PubMedCrossRef
19.
Zurück zum Zitat Maity P, Bindu S, Dey S, et al. Indomethacin, a non-steroidal anti-inflammatory drug, develops gastropathy by inducing reactive oxygen species-mediated mitochondrial pathology and associated apoptosis in gastric mucosa. J Biol Chem. 2009;284:3058–3068.PubMedCrossRef Maity P, Bindu S, Dey S, et al. Indomethacin, a non-steroidal anti-inflammatory drug, develops gastropathy by inducing reactive oxygen species-mediated mitochondrial pathology and associated apoptosis in gastric mucosa. J Biol Chem. 2009;284:3058–3068.PubMedCrossRef
20.
Zurück zum Zitat Somasundaram S, Rafi S, Hayllar J, et al. Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID induced injury to the rat intestine. Gut. 1997;41:344–353.PubMedCrossRef Somasundaram S, Rafi S, Hayllar J, et al. Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID induced injury to the rat intestine. Gut. 1997;41:344–353.PubMedCrossRef
21.
Zurück zum Zitat Tomisato W, Tsutsumi S, Hoshino T, et al. Role of direct cytotoxic effects of NSAIDs in the induction of gastric lesions. Biochem Pharmacol. 2004;67:575–585.PubMedCrossRef Tomisato W, Tsutsumi S, Hoshino T, et al. Role of direct cytotoxic effects of NSAIDs in the induction of gastric lesions. Biochem Pharmacol. 2004;67:575–585.PubMedCrossRef
22.
Zurück zum Zitat Tanaka T, Tsutsui H, Hirano K, Koike T, Tokumura A, Satouchi K. Quantitative analysis of lysophosphatidic acid by time-of-flight mass spectrometry using a phosphate-capture molecule. J Lipid Res. 2004;45:2145–2150.PubMedCrossRef Tanaka T, Tsutsui H, Hirano K, Koike T, Tokumura A, Satouchi K. Quantitative analysis of lysophosphatidic acid by time-of-flight mass spectrometry using a phosphate-capture molecule. J Lipid Res. 2004;45:2145–2150.PubMedCrossRef
23.
Zurück zum Zitat Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959;37:911–917.PubMedCrossRef Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959;37:911–917.PubMedCrossRef
24.
Zurück zum Zitat Chalvardjian A, Rudnicki E. Determination of lipid phosphorus in the nanomolar range. Anal Biochem. 1970;36:225–230.PubMedCrossRef Chalvardjian A, Rudnicki E. Determination of lipid phosphorus in the nanomolar range. Anal Biochem. 1970;36:225–230.PubMedCrossRef
25.
Zurück zum Zitat Inoue M, Adachi M, Shimizu Y, Tsutsumi T, Tokumura A. Comparison of lysophospholipid levels in rat feces with those in a standard chow. J Agric Food Chem. 2011;59:7062–7067.PubMedCrossRef Inoue M, Adachi M, Shimizu Y, Tsutsumi T, Tokumura A. Comparison of lysophospholipid levels in rat feces with those in a standard chow. J Agric Food Chem. 2011;59:7062–7067.PubMedCrossRef
26.
Zurück zum Zitat Morishige J, Urikura M, Takagi H, et al. A clean-up technology for the simultaneous determination of lysophosphatidic acid and sphingosine-1-phosphate by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using a phosphate-capture molecule, Phos-tag. Rapid Commun Mass Spectrom. 2010;24:1075–1084.PubMedCrossRef Morishige J, Urikura M, Takagi H, et al. A clean-up technology for the simultaneous determination of lysophosphatidic acid and sphingosine-1-phosphate by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using a phosphate-capture molecule, Phos-tag. Rapid Commun Mass Spectrom. 2010;24:1075–1084.PubMedCrossRef
27.
Zurück zum Zitat Tanaka K, Tomisato W, Hoshino T, et al. Involvement of intracellular Ca2+ levels in nonsteroidal anti-inflammatory drug-induced apoptosis. J Biol Chem. 2005;280:31059–31067.PubMedCrossRef Tanaka K, Tomisato W, Hoshino T, et al. Involvement of intracellular Ca2+ levels in nonsteroidal anti-inflammatory drug-induced apoptosis. J Biol Chem. 2005;280:31059–31067.PubMedCrossRef
28.
Zurück zum Zitat Dunjic BS, Axelson J, Ar’rajab A, Larsson K, Bengmark S. Gastroprotective capacity of exogenous phosphatidylcholine in experimentally induced chronic gastric ulcers in rats. Scand J Gastroenterol. 1993;28:89–94.PubMedCrossRef Dunjic BS, Axelson J, Ar’rajab A, Larsson K, Bengmark S. Gastroprotective capacity of exogenous phosphatidylcholine in experimentally induced chronic gastric ulcers in rats. Scand J Gastroenterol. 1993;28:89–94.PubMedCrossRef
29.
Zurück zum Zitat Holm BA, Keicher L, Liu M, Sokolowski J, Enhorning G. Inhibition of pulmonary surfactant function by phospholipases. J Appl Physiol. 1991;71:317–321.PubMed Holm BA, Keicher L, Liu M, Sokolowski J, Enhorning G. Inhibition of pulmonary surfactant function by phospholipases. J Appl Physiol. 1991;71:317–321.PubMed
30.
Zurück zum Zitat Lichtenberger LM, Wang Z-M, Romero JJ, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury. Nature Med. 1995;1:154–158.PubMedCrossRef Lichtenberger LM, Wang Z-M, Romero JJ, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury. Nature Med. 1995;1:154–158.PubMedCrossRef
31.
Zurück zum Zitat He D, Natarajan V, Stern R, et al. Lysophosphatidic acid-induced transactivation of epidermal growth factor receptor regulates cyclo-oxygenase-2 expression and prostaglandin E2 release via C/EBP β in human bronchial epithelial cells. Biochem J. 2008;412:153–162.PubMedCrossRef He D, Natarajan V, Stern R, et al. Lysophosphatidic acid-induced transactivation of epidermal growth factor receptor regulates cyclo-oxygenase-2 expression and prostaglandin E2 release via C/EBP β in human bronchial epithelial cells. Biochem J. 2008;412:153–162.PubMedCrossRef
32.
Zurück zum Zitat Murph MM, Liu W, Yu S, et al. Lysophosphatidic acid-induced transcriptional profile represents serous epithelial ovarian carcinoma and worsened prognosis. PLoS ONE. 2009;4:e5583.PubMedCrossRef Murph MM, Liu W, Yu S, et al. Lysophosphatidic acid-induced transcriptional profile represents serous epithelial ovarian carcinoma and worsened prognosis. PLoS ONE. 2009;4:e5583.PubMedCrossRef
33.
Zurück zum Zitat Tojo H, Ying Z, Okamoto M. Purification and characterization of guinea pig gastric phospholipase A2 of the pancreatic type. Eur J Biochem. 1993;215:81–90.PubMedCrossRef Tojo H, Ying Z, Okamoto M. Purification and characterization of guinea pig gastric phospholipase A2 of the pancreatic type. Eur J Biochem. 1993;215:81–90.PubMedCrossRef
34.
Zurück zum Zitat Uthe JF, Magee WL. Phospholipase A2: action on purified phospholipids as affected by deoxycholate and divalent cations. Can J Biochem. 1971;49:776–784.PubMedCrossRef Uthe JF, Magee WL. Phospholipase A2: action on purified phospholipids as affected by deoxycholate and divalent cations. Can J Biochem. 1971;49:776–784.PubMedCrossRef
35.
Zurück zum Zitat Foster DA. Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells. Biochim Biophys Acta. 2009;1791:949–955.PubMedCrossRef Foster DA. Phosphatidic acid signaling to mTOR: signals for the survival of human cancer cells. Biochim Biophys Acta. 2009;1791:949–955.PubMedCrossRef
36.
Zurück zum Zitat Cheney G. Rapid healing of peptic ulcers in patients receiving fresh cabbage juice. Calif Med. 1949;70:10–15.PubMed Cheney G. Rapid healing of peptic ulcers in patients receiving fresh cabbage juice. Calif Med. 1949;70:10–15.PubMed
Metadaten
Titel
Orally Administered Phosphatidic Acids and Lysophosphatidic Acids Ameliorate Aspirin-Induced Stomach Mucosal Injury in Mice
verfasst von
Tamotsu Tanaka
Katsuya Morito
Masafumi Kinoshita
Mayumi Ohmoto
Mai Urikura
Kiyoshi Satouchi
Akira Tokumura
Publikationsdatum
01.04.2013
Verlag
Springer US
Erschienen in
Digestive Diseases and Sciences / Ausgabe 4/2013
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-012-2475-y

Weitere Artikel der Ausgabe 4/2013

Digestive Diseases and Sciences 4/2013 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Positiver FIT: Die Ursache liegt nicht immer im Dickdarm

27.05.2024 Blut im Stuhl Nachrichten

Immunchemischer Stuhltest positiv, Koloskopie negativ – in solchen Fällen kann die Blutungsquelle auch weiter proximal sitzen. Ein Forschungsteam hat nachgesehen, wie häufig und in welchen Lokalisationen das der Fall ist.

GLP-1-Agonisten können Fortschreiten diabetischer Retinopathie begünstigen

24.05.2024 Diabetische Retinopathie Nachrichten

Möglicherweise hängt es von der Art der Diabetesmedikamente ab, wie hoch das Risiko der Betroffenen ist, dass sich sehkraftgefährdende Komplikationen verschlimmern.

Mehr Lebenszeit mit Abemaciclib bei fortgeschrittenem Brustkrebs?

24.05.2024 Mammakarzinom Nachrichten

In der MONARCHE-3-Studie lebten Frauen mit fortgeschrittenem Hormonrezeptor-positivem, HER2-negativem Brustkrebs länger, wenn sie zusätzlich zu einem nicht steroidalen Aromatasehemmer mit Abemaciclib behandelt wurden; allerdings verfehlte der numerische Zugewinn die statistische Signifikanz.

ADT zur Radiatio nach Prostatektomie: Wenn, dann wohl länger

24.05.2024 Prostatakarzinom Nachrichten

Welchen Nutzen es trägt, wenn die Strahlentherapie nach radikaler Prostatektomie um eine Androgendeprivation ergänzt wird, hat die RADICALS-HD-Studie untersucht. Nun liegen die Ergebnisse vor. Sie sprechen für länger dauernden Hormonentzug.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.