Molecular and Cellular Biochemistry

, Volume 306, Issue 1–2, pp 59–69 | Cite as

Intestinal inflammation caused by magnesium deficiency alters basal and oxidative stress-induced intestinal function

  • Bradford J. Scanlan
  • Blaine Tuft
  • Justin E. Elfrey
  • Allen Smith
  • Aiping Zhao
  • Motoko Morimoto
  • Joanna J. Chmielinska
  • Maria Isabel Tejero-Taldo
  • Iu Tong Mak
  • William B. Weglicki
  • Terez Shea-DonohueEmail author


The aim of this study was to determine the effect of magnesium deficiency on small intestinal morphology and function. Rats were assigned to 4 groups and placed on magnesium sufficient or deficient diet for 1 or 3 weeks. Infiltration of neutrophils and mucosal injury were assessed in stained sections of small intestine. Magnesium deficiency alone induced a significant increase in neutrophil infiltration and increased vascular ICAM-1 expression, in the absence of changes in mucosal injury or expression of proinflammatory mediators. Magnesium deficiency was associated with hyposecretory epithelial cell responses and vascular macromolecular leak in the small intestine and lung, which was attributed partly to reduced expression of NOS-3. To determine the effect of hypomagnesmia on the intestinal responses to a known oxidative stress, groups of rats were randomized to either sham operation or superior mesenteric artery occlusion for 10 (non-injurious) or 30 (injurious) minutes followed by a 1- or 4-hour reperfusion period. In response to mesenteric ischemia/reperfusion, deficient rats showed exaggerated PMN influx, but similar mucosal injury. Intestinal ischemia in sufficient animals induced vascular macromolecular leak in the small intestine and lung at 4 hours of reperfusion, with levels similar to those observed in untreated deficient rats. Acute magnesium repletion of deficient rats 24 h before surgery attenuated the exaggerated inflammation in deficient rats. These data show that magnesium deficiency induced a subclinical inflammation in the small intestine in the absence of mucosal injury, but with significant functional changes in local and remote organs and increased sensitivity to oxidative stress.


Hypomagnesemia Oxidative stress Neutrophil Inflammation Nitric oxide 



This work was supported by NIH grants National Institutes of Health grants R01-HL-62282 and HL-65718 awarded to W.B.W. and AI 49316 to TSD, and USDA CRIS project #1235-52000-055. The opinions and assertions in this article are those of the authors and do not necessarily represent those of the U. S. Department of Defense or the U. S. Department of Agriculture.


  1. 1.
    Dube L, Granry JC (2003) The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: a review: [L’usage therapeutique du magnesium en anesthesiologie, reanimation et medecine d’urgence]. Can J Anesth 50:732–746PubMedCrossRefGoogle Scholar
  2. 2.
    Noronha L, Matuschak G (2002) Magnesium in critical illness: metabolism, assessment, and treatment. Intensive Care Medicine 28:667–679PubMedCrossRefGoogle Scholar
  3. 3.
    Tosiello L (1996) Hypomagnesemia and diabetes mellitus. A review of clinical implications. Arch Intern Med 156:1143–1148PubMedCrossRefGoogle Scholar
  4. 4.
    Kahraman S, Ozgurtas T, Kayali H, Atabey C, Kutluay T, Timurkaynak E (2003) Monitoring of serum ionized magnesium in neurosurgical intensive care unit: preliminary results. Clinica Chimica Acta 334:211–215CrossRefGoogle Scholar
  5. 5.
    Kramer JH, Mak IT, Phillips TM, Weglicki WB (2003) Dietary magnesium intake influences circulating pro-inflammatory neuropeptide levels and loss of myocardial tolerance to postischemic stress. Exp Biol Med (Maywood) 228:665–673Google Scholar
  6. 6.
    Weglicki WB, Phillips TM (1992) Pathobiology of magnesium deficiency: a cytokine/neurogenic inflammation hypothesis. Am J Physiol 263:R734–R737PubMedGoogle Scholar
  7. 7.
    Weglicki WB, Bloom S, Cassidy MM, Freedman AM, Atrakchi AH, Dickens BF (1992) Antioxidants and the cardiomyopathy of Mg-deficiency. Am J Cardiovasc Pathol 4:210–215PubMedGoogle Scholar
  8. 8.
    Wiles ME, Wagner TL, Weglicki WB (1997) Effect of acute magnesium deficiency (MgD) on aortic endothelial cell (EC) oxidant production. Life Sci 60:221–236PubMedCrossRefGoogle Scholar
  9. 9.
    Moore FA, Haenel JB, Moore EE, Whitehill TA (1992) Incommensurate oxygen consumption in response to maximal oxygen availability predicts postinjury multiple organ failure. J Trauma 33:58–65PubMedCrossRefGoogle Scholar
  10. 10.
    Rehrig S, Fleming SD, Anderson J, Guthridge JM, Rakstang J, McQueen CE, Holers VM, Tsokos GC, Shea-Donohue T (2001) Complement inhibitor, complement receptor 1-related gene/protein y-Ig attenuates intestinal damage after the onset of mesenteric ischemia/reperfusion injury in mice. J Immunol 167:5921–5927PubMedGoogle Scholar
  11. 11.
    Stojadinovic A, Kiang J, Smallridge R, Galloway R, Shea-Donohue T (1995) Induction of heat-shock protein 72 protects against ischemia/reperfusion in rat small intestine. Gastroenterology 109:505–515PubMedCrossRefGoogle Scholar
  12. 12.
    Ward DT, Lawson SA, Gallagher CM, Conner WC, Shea-Donohue T (2000) Sustained nitric oxide production via l-arginine administration ameliorates effects of intestinal ischemia-reperfusion. J Surg Res 89:13–19PubMedCrossRefGoogle Scholar
  13. 13.
    Hernandez LA, Grisham MB, Twohig B, Arfors KE, Harlan JM, Granger DN (1987) Role of neutrophils in ischemia-reperfusion-induced microvascular injury. Am J Physiol 253:H699–H703PubMedGoogle Scholar
  14. 14.
    Bienvenu K, Hernandez L, Granger DN (1992) Leukocyte adhesion and emigration in inflammation. Ann NY Acad Sci 664:388–399PubMedCrossRefGoogle Scholar
  15. 15.
    Grisham MB, Hernandez LA, Granger DN (1986) Xanthine oxidase and neutrophil infiltration in intestinal ischemia. Am J Physiol 251:G567–G574PubMedGoogle Scholar
  16. 16.
    Kubes P, Hunter J, Granger DN (1992) Ischemia/reperfusion-induced feline intestinal dysfunction: importance of granulocyte recruitment. Gastroenterology 103:807–812PubMedGoogle Scholar
  17. 17.
    Hayward R, Lefer AM (1998) Time course of endothelial-neutrophil interaction in splanchnic artery ischemia-reperfusion. Am J Physiol Heart Circ Physiol 275:H2080–H2086Google Scholar
  18. 18.
    Mak IT, Komarov AM, Wagner TL, Stafford RE, Dickens BF, Weglicki WB (1996) Enhanced NO production during Mg deficiency and its role in mediating red blood cell glutathione loss. Am J Physiol 271:C385–C390PubMedGoogle Scholar
  19. 19.
    Mak IT, Dickens BF, Komarov AM, Wagner TL, Phillips TM, Weglicki WB (1997) Activation of the neutrophil and loss of plasma glutathione during Mg-deficiency–modulation by nitric oxide synthase inhibition. Mol Cell Biochem 176:35–39PubMedCrossRefGoogle Scholar
  20. 20.
    Tavaf-Motamen H, Miner TJ, Starnes BW, Shea-Donohue T (1998) Nitric oxide mediates acute lung injury by modulation of inflammation. J Surg Res 78:137–142PubMedCrossRefGoogle Scholar
  21. 21.
    Bussiere FI, Gueux E, Rock E, Mazur A, Rayssiguier Y (2002) Protective effect of calcium deficiency on the inflammatory response in magnesium-deficient rats. Eur J Nutr 41:197–202PubMedCrossRefGoogle Scholar
  22. 22.
    Mak IT, Komarov AM, Kramer JH, Weglicki WB (2000) Protective mechanisms of Mg-gluconate against oxidative endothelial cytotoxicity. Cell Mol Biol (Noisy -le-grand) 46:1337–1344Google Scholar
  23. 23.
    Murphy E, Steenbergen C, Levy LA, Raju B, London RE (1989) Cytosolic free magnesium levels in ischemic rat heart. J Biol Chem 264:5622–5627PubMedGoogle Scholar
  24. 24.
    Mak IT, Stafford R, Weglicki WB (1994) Loss of red blood cell glutathione during Mg deficiency: prevention by vitamin E, D-propranolol, and chloroquine. Am J Physiol 267:C1366–C1370PubMedGoogle Scholar
  25. 25.
    Bussiere FI, Tridon A, Zimowska W, Mazur A, Rayssiguier Y (2003) Increase in complement component C3 is an early response to experimental magnesium deficiency in rats. Life Sci 73:499–507PubMedCrossRefGoogle Scholar
  26. 26.
    Kubes P, Ward PA (2000) Leukocyte recruitment and the acute inflammatory response. Brain Pathol 10:127–135PubMedCrossRefGoogle Scholar
  27. 27.
    Fleming SD, Starnes BW, Kiang JG, Stojadinovic A, Tsokos GC, Shea-Donohue T (2002) Heat stress protection against mesenteric I/R-induced alterations in intestinal mucosa in rats. J Appl Physiol 92:2600–2607PubMedGoogle Scholar
  28. 28.
    Anderson J, Fleming SD, Rehrig S, Tsokos GC, Basta M, Shea-Donohue T (2005) Intravenous immunoglobulin attenuates mesenteric ischemia-reperfusion injury. Clin Immunol 114:137–146PubMedCrossRefGoogle Scholar
  29. 29.
    Sato N, Kozar RA, Zou L, Weatherall JM, Attuwaybi B, Moore-Olufemi SD, Weisbrodt NW, Moore FA (2005) peroxisome proliferator-activated receptor gamma mediates protection against cyclooxygenase-2-induced gut dysfunction in a rodent model of mesenteric ischemia/reperfusion. Shock 24:462–469PubMedCrossRefGoogle Scholar
  30. 30.
    Wallace JL, Devchand PR (2005) Emerging roles for cyclooxygenase-2 in gastrointestinal mucosal defense. Br J Pharmacol 145:275–282PubMedCrossRefGoogle Scholar
  31. 31.
    Blikslager AT, Roberts MC, Rhoads JM, Argenzio RA (1997) Prostaglandins I2 and E2 have a synergistic role in rescuing epithelial barrier function in porcine ileum. J Clin Invest 100:1928–1933PubMedCrossRefGoogle Scholar
  32. 32.
    McCafferty DM, Mudgett JS, Swain MG, Kubes P (1997) Inducible nitric oxide synthase plays a critical role in resolving intestinal inflammation. Gastroenterology 112:1022–1027PubMedCrossRefGoogle Scholar
  33. 33.
    Miner TJ, Tavaf-Motamen H, Stojadinovic A, Shea-Donohue T (1999) Ischemia-reperfusion protects the rat small intestine against subsequent injury. J Surg Res 82:1–10PubMedCrossRefGoogle Scholar
  34. 34.
    Chen Y, Lui VCH, Rooijen NV, Tam PKH (2004) Depletion of intestinal resident macrophages prevents ischaemia reperfusion injury in gut. Gut 53:1772–1780PubMedCrossRefGoogle Scholar
  35. 35.
    Fleming SD, Mastellos D, Karpel-Massler G, Shea-Donohue T, Lambris JD, Tsokos GC (2003) C5a causes limited, polymorphonuclear cell-independent, mesenteric ischemia/reperfusion-induced injury. Clin Immunol 108:263–273PubMedCrossRefGoogle Scholar
  36. 36.
    Fleming SD, Shea-Donohue T, Guthridge JM, Kulik L, Waldschmidt TJ, Gipson MG, Tsokos GC, Holers VM (2002) Mice deficient in complement receptors 1 and 2 lack a tissue injury-inducing subset of the natural antibody repertoire. J Immunol 169:2126–2133PubMedGoogle Scholar
  37. 37.
    Lawson S, Ward DT, Conner C, Gallagher C, Tsokos G, Shea-Donohue T (2002) Diabetic hyperglycemia: a facilitating factor in systemic capillary leak. J Surg Res 105:95–101PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Bradford J. Scanlan
    • 1
  • Blaine Tuft
    • 2
  • Justin E. Elfrey
    • 3
  • Allen Smith
    • 4
  • Aiping Zhao
    • 3
  • Motoko Morimoto
    • 3
  • Joanna J. Chmielinska
    • 5
  • Maria Isabel Tejero-Taldo
    • 5
  • Iu Tong Mak
    • 5
  • William B. Weglicki
    • 5
  • Terez Shea-Donohue
    • 3
    Email author
  1. 1.Department of SurgeryWalter Reed Army Medical CenterWashingtonUSA
  2. 2.Department of PediatricsWalter Reed Army Medical CenterWashingtonUSA
  3. 3.Department of Medicine & The Mucosal Biology Research CenterUniversity of Maryland, School of MedicineBaltimoreUSA
  4. 4.Beltsville Human Nutrition Research CenterNutrient Requirements and Functions Laboratory, ARS, USDABeltsvilleUSA
  5. 5.Division of Experimental Medicine, Department of Biochemistry and Molecular BiologyGeorge Washington University Medical CenterWashingtonUSA

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