Alterations in Gastrointestinal Barrier Function in Sepsis: The Effect of Lipopolysaccharide on Mucosal Permeability to Hydrophilic Solutes

  • M. P. Fink
Conference paper
Part of the Yearbook of Intensive Care and Emergency Medicine book series (YEARBOOK, volume 1992)


Structure and Function of Intestinal Intercellular Tight Junctions The epithelium of the gut serves as a barrier limiting the systemic absorption of intraluminal microbes and microbial products. It has been hypothesized, but certainly not proven conclusively, that derangements in the barrier function of the gut predispose critically ill patients to the development of bacteremia, fungemia, and/ or endotoxemia [1-3].


Intestinal Permeability Reactive Oxygen Metabolite Circ Shock Xanthine Dehydrogenase Mucosal Permeability 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Wilmore DW, Smith RJ, O’Dwyer ST, Jacobs DO, Ziegler TR, Wang XD (1988) The gut: a central organ after surgical stress. Surgery 104:917–923PubMedGoogle Scholar
  2. 2.
    Fink MP (1990) Leaky gut hypothesis: a historical perspective. Crit Care Med 18:579–580PubMedCrossRefGoogle Scholar
  3. 3.
    Deitch EA (1990) The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure. Arch Surg 125:403–404PubMedCrossRefGoogle Scholar
  4. 4.
    Madara JL (1989) Loosening of tight junctions: lessons from the intestine. J Clin Invest 83:1089–1094PubMedCrossRefGoogle Scholar
  5. 5.
    Madara JL, Dharmsathaphorn K (1985) Occluding junction structure-function relationships in a cultured epithelial monolayer. J Cell Biol 101:2124–2133PubMedCrossRefGoogle Scholar
  6. 6.
    Madara JL (1983) Increases in guinea pig small intestinal resistance induced by osmotic loads are accompanied by rapid alterations in absorptive-cell tight-junction structure. J Cell Biol 97:125–136PubMedCrossRefGoogle Scholar
  7. 7.
    Kingham JGC, Whorwell PJ, Loehry CA (1976) Small intestine permeability. I. Effect of ischemia and exposure to acetyl salicyiate. Gut 17:354–361Google Scholar
  8. 8.
    Madara JL, Stafford J, Barenberg D, Carlson S (1988) Functional coupling of tight junctions and microfilaments in T84 monolayers. Am J Physiol 254:416–423Google Scholar
  9. 9.
    Tagesson C, Sjodahl R, Thoren B (1978) Passage of molecules through the wall of the gastrointestinal tract. I. A simple experimental model. Scand J Gastroenterol 13:519–524PubMedCrossRefGoogle Scholar
  10. 10.
    Udall JN, Pang K, Fritze L, Kleinman R, Walker WA (1981) Development of gastro-intesti-nal mucosal barrier. I. The effect of age on intestinal permeability to macromolecules. Pediatric Res 15:241–244Google Scholar
  11. 11.
    D’Inca R, Ramage JK, Hunt RH, Perdue MH (1990) Antigen-induced mucosal damage and restitution in the small intestine of the immunized rat. Int Arch Allergy Appl Immunol 91:270–277PubMedCrossRefGoogle Scholar
  12. 12.
    Fink MP, Antonsson JB, Wang H, Rothschild HR (1991) Increased intestinal permeability in endotoxic pigs: mesenteric hypoperfusion as an etiologic factor. Arch Surg 126:211–218PubMedCrossRefGoogle Scholar
  13. 13.
    Fink MP, Kaups KL, Wang H, Rothschild HR (1991) Maintenance of superior mesenteric arterial perfusion prevents increased intestinal mucosal permeability in endotoxic pigs. Surgery 110:154–161PubMedGoogle Scholar
  14. 14.
    Bulkley GB, Kvietys PR, Parks DA, Perry MA, Granger DN (1985) Relationship of blood flow and oxygen consumption to ischemic injury in canine small intestine. Gastroenterology 89:852–857PubMedGoogle Scholar
  15. 15.
    Clark ES, Crissenger KD, Granger DN (1990) Oxidant-induced increases in mucosal permeability in developing piglets. Pediatric Res 28:28–30CrossRefGoogle Scholar
  16. 16.
    Deitch EA, Specian RD, Berg RD (1991) Endotoxin-induced bacterial translocation and mucosal permeability: Role of xanthine oxidase, complement activation, and macrophage products. Crit Care Med 19:785–791PubMedCrossRefGoogle Scholar
  17. 17.
    Ziegler TR, Smith RJ, O’Dwyer ST, Demling RH, Wilmore DW (1988) Increased intestinal permeability associated with infection in burn patients. Arch Surg 123:1313–1319PubMedCrossRefGoogle Scholar
  18. 18.
    O’Dwyer ST, Michie HR, Ziegler TR, Revhaug A, Smith RJ, Wilmore DW (1988) A single dose of endotoxin increases intestinal permeability in healthy humans. Arch Surg 123:1459–1464PubMedCrossRefGoogle Scholar
  19. 19.
    Walker RI, Porvaznik MJ (1978) Disruption of the permeability barrier (zonula occludens) between intestinal epithelial cells by lethal doses of endotoxin. Infect Immun 21:655–658PubMedGoogle Scholar
  20. 20.
    Alexander JW, Boyce ST, Babcock GF et al. (1990) The process of microbial translocation. Ann Surg 212:496–512PubMedCrossRefGoogle Scholar
  21. 21.
    Hinshaw DB, Armstrong BC, Burger JM, Beals TF, Hyslop PA (1988) ATP and microfila-ments in cellular oxidant injury. Am J Pathol 132:479–488PubMedGoogle Scholar
  22. 22.
    Hinshaw DB, Burger JM, Armstrong BC, Hyslop PA (1989) Mechanism of endothelial cell shape change in oxidant injury. J Surg Res 46:339–349PubMedCrossRefGoogle Scholar
  23. 23.
    Hinshaw DB, Armstrong BC, Beals TF, Hyslop PA (1988) A cellular model of endothelial cell ischemia. J Surg Res. 44:527–537PubMedCrossRefGoogle Scholar
  24. 24.
    Zager RA (1991) Adenine nucleotide changes in kidney, liver, and small intestine during different forms of ischemic injury. Circ Res 68:185–196PubMedGoogle Scholar
  25. 25.
    Whitworth PW, Cryer HM, Garrison RN, Baumgarten TE, Harris PD (1989) Hypoperfusion of the intestinal microcirculation without decreased cardiac output during live escherichia coli sepsis in rats. Circ Shock 27:111–122PubMedGoogle Scholar
  26. 26.
    Fink MP, Cohn SM, Lee PC et al. (1989) Effect of lipopolysaccharide on intestinal intramu-cosal hydrogen ion concentration in pigs: evidence of gut ischemia in a normodynamic model of septic shock. Crit Care Med 17:641–646PubMedCrossRefGoogle Scholar
  27. 27.
    Fink MP, Rothschild HR, Deniz YF, Wang H, Lee PC, Cohn SM (1989) Systemic and mesenteric O2 metabolism in endotoxic pigs: Effect of ibuprofen and meclofenamate. J Appl Physiol 67:1950–1957PubMedGoogle Scholar
  28. 28.
    Navaratnam NRL, Morris SE, Traber DL et al. (1991) Endotoxin (LPS) increases mesenteric vascular resistance (MVR) and bacterial translocation (BT). J Trauma 30:1104–1115CrossRefGoogle Scholar
  29. 29.
    Mosenthal AC, Wang H, Bellelsle JM et al. (1991) Mesenteric hypoperfusion and decreasedmucosal ATP in porcine endotoxicosis. Surg Forum 42:39–41Google Scholar
  30. 30.
    Falk A, Myrvold HE, Lundgren O, Haglund U (1982) Mucosal lesions in the feline smallintestine in septic shock. Circ Shock 9:27–35PubMedGoogle Scholar
  31. 31.
    Falk A, Redfors S, Myrvold H, Haglund U (1985) Small intestinal mucosal lesions in feline septic shock: A study on the pathogenesis. Circ Shock 17:327–337PubMedGoogle Scholar
  32. 32.
    Schaefer CF, Lerner MR, Biber B (1991) Dose-related reduction of intestinal cytochrome a, a3induced by endotoxin in rats. Circ Shock 33:17–25PubMedGoogle Scholar
  33. 33.
    Chaudry IH, Wichterman KA, Baue AE (1979) Effect of sepsis on tissue adenine nucleotide levels. Surgery 85:205–211PubMedGoogle Scholar
  34. 34.
    Hampton WA, Townsend MC, Haybron DM, Shirmer WJ, Fry DE (1987) Effective hepatic blood flow and hepatic bioenergy status in murine peritonitis. J Surg Res 42:33–38PubMedCrossRefGoogle Scholar
  35. 35.
    Mela L, Bacalzo LV Jr, Miller LD (1971) Defective oxidative metabolism of rat liver mitochondria in hemorrhagic and endotoxin shock. Am J Physiol 220:571–577PubMedGoogle Scholar
  36. 36.
    Astiz M, Rackow EC, Weil MH, Schumer W (1988) Early impairment of oxidative metabolism and energy production in severe sepsis. Circ Shock 26:311–320PubMedGoogle Scholar
  37. 37.
    van Lanschot JJB, Mealy K, Wilmore DW (1990) The effects of tumor necrosis factor on intestinal structure and metabolism. Ann Surg 212:663–670PubMedCrossRefGoogle Scholar
  38. 38.
    Hsueh W, Gonzalez-Crussi F, Arroyave JL (1987) Platelet activating factor is an endogenous mediator for bowel necrosis in endotoxemia. FASEB J 1:403–405PubMedGoogle Scholar
  39. 39.
    Kampp M, Lundgren O (1968) Blood flow and flow distribution in the small intestine of the cat as analyzed by the Kr85 washout technique. Acta Physiol Scan 72:282–296CrossRefGoogle Scholar
  40. 40.
    Bohlen HG (1980) Intestinal tissue PO2 and microvascular responses during glucose exposure. Am J Physiol 238:164–171Google Scholar
  41. 41.
    Lundgren O, Svanvik J (1973) Mucosal hemodynamics in the small intestine of the cat during reduced perfusion pressure. Acta Physiol Scand 88:551–563PubMedCrossRefGoogle Scholar
  42. 42.
    Spragg RG, Hinshaw DB, Hyslop PA, Schraufstatter IU, Cochrane CG (1985) Alterations in adenosine triphosphate and energy charge in cultured endothelial and P388D1 cells and oxi-dant injury. J Clin Invest 76:1471–1476PubMedCrossRefGoogle Scholar
  43. 43.
    Hinshaw DB, Burger JM, Delius RE, Hyslop PA (1990) Mechanism of protection of oxidant-injured endothelial cells by glutamine. Surgery 108:298–305PubMedGoogle Scholar
  44. 44.
    Schmelling DJ, Caty MG, Oldham KT, Guice KS, Hinshaw DB (1989) Evidence for neutro-phil-related acute lung injury after intestinal ischemia-reperfusion. Surgery 106:195–202Google Scholar
  45. 45.
    Hyslop PA, Hinshaw DB, Halsey WA Jr et al. (1988) Mechanisms of oxidant-mediated cell injury: the glycolytic and mitochondrial pathways of ADP phosphorylation are major intra-cellular targets inactivated by hydrogen peroxide. J Biol Chem 263:1665–1675PubMedGoogle Scholar
  46. 46.
    Broadie AE, Reed DJ (1987) Reversible oxidation of glyceraldehyde 3-phosphate dehydrogen-ase thiols in human lung carcinoma cells by hydrogen peroxide. Biochem Biophys Res Commun 148:120–125CrossRefGoogle Scholar
  47. 47.
    Baker MS, Feigan J, Lowther DA (1989) The mechanism of chondrocyte hydrogen peroxide damage: depletion of intracellular ATP due to suppression of glycolysis caused by oxidation of glyceraldehyde 3-phosphate dehydrogenase. J Rheumatol 16:7–14PubMedGoogle Scholar
  48. 48.
    Hinshaw DB, Sklar LA, Bohl B et al. (1986) Cytoskeletal and morphological impact of cellular oxidant injury. Am J Pathol 123:454–464PubMedGoogle Scholar
  49. 49.
    Carden DL, Smith JK, Zimmerman BJ, Korthuis RJ, Granger DN (1989) Reperfusion injury following circulatory collapse: the role of reactive oxygen metabolites. J Crit Care 4:294–307CrossRefGoogle Scholar
  50. 50.
    Parks DA, Granger DN (1986) Contributions of ischemia and reperfusion to mucosal lesion formation. Am J Physiol 250:749–753Google Scholar
  51. 51.
    Grisham MB, Hernandez LA, Granger DN (1986) Xanthine oxidase and neutrophil infiltration in intestinal ischemia. Am J Physiol 251:567–574Google Scholar
  52. 52.
    Deitch EA, Taylor M, Grisham M, Ma L, Bridges W, Berg R (1989) Endotoxin induces bacterial translocation and increases xanthine oxidase activity. J Trauma 29:1679–1683PubMedCrossRefGoogle Scholar
  53. 53.
    Deitch EA, Ma WJ, Ma L, Berg R, Specian RD (1989) Endotoxin-induced bacterial translocation: A study of mechanisms. Surgery 106:292–300PubMedGoogle Scholar
  54. 54.
    Deitch EA, Ma L, Ma WJ et al. (1989) Inhibition of endotoxin-induced bacterial translocation in mice. J Clin Invest 84:36–42PubMedCrossRefGoogle Scholar
  55. 55.
    Arvidsson S, Falk K, Marklund S, Haglund U (1985) Role of free oxygen radicals in the development of gastro-intestinal mucosal damage in Escherichia coli sepsis. Circ Shock 16:383–393PubMedGoogle Scholar
  56. 56.
    Klebanoff SJ, Vadas MA, Harlan JM et al. (1986) Stimulation of neutrophils by tumor necrosis factor. J Immunol 136:4220–4225PubMedGoogle Scholar
  57. 57.
    Shalaby MR, Aggarwal BB, Rinderknecht E et al. (1985) Activation of human polymorpho-nuclear neutrophil functions by interferon-gamma and tumor necrosis factors. J Immunol 135:2069–2073PubMedGoogle Scholar
  58. 58.
    Moore FD Jr, Socher SH, Davis C (1991) Tumor necrosis factor and endotoxin can cause neutrophil activation through separate pathways. Arch Surg 126:70–73PubMedCrossRefGoogle Scholar
  59. 59.
    Guthrie LA, McPhail LC, Henson PM, Johnston RB (1985) Priming of neutrophils for enhanced release of oxygen metabolites by bacterial lipopolysaccharides. J Exp Med 160:1656–1671CrossRefGoogle Scholar
  60. 60.
    Vercellotti GM, Yin HQ, Gustafson KS, Nelson RD, Jacob HS (1988) Platelet-activating factor primes neutrophil responses to agonists: Role in promoting neutrophil-mediated endothe-lial damage. Blood 71:1100–1107PubMedGoogle Scholar
  61. 61.
    Carlos TM, Harlan JM (1990) Membrane proteins involved in phagocyte adherence to endo-thelium. Immunol Rev 114:5–28PubMedCrossRefGoogle Scholar
  62. 62.
    Nash S, Stafford J, Madara JL (1987) Effects of polymorphonuclear leukocyte transmigration on the barrier function of cultured intestinal epithelial monolayers. J Clin Invest 80:1104–1113PubMedCrossRefGoogle Scholar
  63. 63.
    Nash S, Stafford J, Madara JL (1988) The selective and superoxide-independent disruption of intestinal epithelial tight junctions during leukocyte transmigration. Lab Invest 59:531–537PubMedGoogle Scholar
  64. 64.
    Souba WW, Klimberg VS, Plumley DA et al. (1990) Current Research Review: The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection. J Surg Res 48:383–391PubMedCrossRefGoogle Scholar
  65. 65.
    Souba WW, Herskowitz K, Klimberg VS et al. (1990) The effects of sepsis and endotoxemia on gut glutamine metabolism. Ann Surg 211:543–551PubMedCrossRefGoogle Scholar
  66. 66.
    Salloum RM, Copeland EM, Souba WW (1991) Brush border transport of glutamine and other substrates during sepsis and endotoxemia. Ann Surg 213:401–410PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1992

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  • M. P. Fink

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