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The Gut

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Mechanisms of Sepsis-Induced Organ Dysfunction and Recovery

Part of the book series: Update in Intensive Care and Emergency Medicine ((UICMSOFT,volume 44))

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References

  1. Langkamp-Henken B, Donovan TB, Pate LM, Maull CD, Kudsk KA (1995) Increased intestinal permeability following blunt and penetrating trauma. Crit Care Med 23:660–664

    Article  PubMed  CAS  Google Scholar 

  2. Pape H-C, Dwenger A, Regel G, et al (1994) Increased gut permeability aftermultiple trauma. Br J Surg 81:850–852

    Article  PubMed  CAS  Google Scholar 

  3. Kompan L, Kremzar B, Gadzijev E, Prosek M (1999) Effects of early enteral nutrition on intestinal permeability and the development of multiple organ failure after multiple injury. Intensive Care Med 25:157–161

    Article  PubMed  CAS  Google Scholar 

  4. Faries PL, Simon RJ, Martella AT, Lee MJ, Machiedo GW (1998) Intestinal permeability correlates with severity of injury in trauma patients. J Trauma 44:1031–1036

    Article  PubMed  CAS  Google Scholar 

  5. Penalva JC, Martinez J, Laveda R, et al (2004) A study of intestinal permeability in relation to the inflammatory response and plasma endocab IgM levels in patients with acute pancreatitis. J Clin Gastroenterol 38:512–517

    Article  PubMed  CAS  Google Scholar 

  6. Ammori BJ, Fitzgerald P, Hawkey P, McMahon MJ (2003) The early increase in intestinal permeability and systemic endotoxin exposure in patients with severe acute pancreatitis is not associated with systemic bacterial translocation: molecular investigation of microbial DNA in the blood. Pancreas 26:18–22

    Article  PubMed  CAS  Google Scholar 

  7. Ammori BJ, Leeder PC, King RFGJ, et al (1999) Early increase in intestinal permeability in patients with severe acute pancreatitis: correlation with endotoxemia, organ failure, and mortality. J Gastrointest Surg 3:252–262

    Article  PubMed  CAS  Google Scholar 

  8. Doig CJ, Sutherland LR, Sandham JD, Fick GH, Verhoef M, Meddings JB (1998) Increased intestinal permeability is associated with the development of multiple organ dysfunction syndrome in critically ill ICU patients. Am J Respir Crit Care Med 158:444–451

    PubMed  CAS  Google Scholar 

  9. Oudemans-van Straaten HM, Jansen PG, Hoek FJ, et al (1996) Intestinal permeability, circulating endotoxin, and postoperative systemic responses in cardiac surgery patients. J Cardiothorac Vasc Anesth 10:187–194

    Article  PubMed  CAS  Google Scholar 

  10. Carrico CJ, Meakins JL, Marshall JC, Fry D, Maier RV (1985) Multiple-organ-failure syndrome. Arch Surg 121:196–208

    Google Scholar 

  11. Fink MP, Delude RL (2005) Epithelial barrier dysfunction: a unifying theme to explain the pathogenesis of multiple organ dysfunction at the cellular level. Crit Care Clin 21:177–196

    Article  PubMed  CAS  Google Scholar 

  12. Stevenson BR (1999) Understanding tight junction clinical physiology at themolecular level. J Clin Invest 104:3–4

    Article  PubMed  CAS  Google Scholar 

  13. Tsukita S, Furuse M, Itoh M (2001) Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2:285–293

    Article  PubMed  CAS  Google Scholar 

  14. Tsukita S, Furuse M (2000) The structure and function of claudins, cell adhesion molecules at tight junctions. Ann NY Acad Sci 915:129–135

    Article  PubMed  CAS  Google Scholar 

  15. Furuse M, Itoh M, Hirase T, Nagafuchi A, Yonemura S, Tsukita S (1994) Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin in tight junctions. J Cell Biol 127:1617–1626

    Article  PubMed  CAS  Google Scholar 

  16. Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM (1998) The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem 273:29745–29753

    Article  PubMed  CAS  Google Scholar 

  17. Itoh M, Nagafuchi A, Moroi S, Tsukita S (1997) Involvement of ZO-1 in cadherin-based cell adhesion through its direct binding to alpha catenin and actin filaments. J Cell Biol 138:181–192

    Article  PubMed  CAS  Google Scholar 

  18. Sheth B, Fesenko I, Collins JE, et al (1997) Tight junction assembly during mouse blastocyst formation is regulated by late expression of ZO-1 alpha+ isoform. Development 124:2027–2937

    PubMed  CAS  Google Scholar 

  19. Sheth B, Moran B, Anderson JM, Fleming TP (2000) Post-translational control of occluding membrane assembly in mouse trophectoderm: a mechanism to regulate timing of tight junction biogenesis and blastocyst formation. Development 127:831–840

    PubMed  CAS  Google Scholar 

  20. Unno N, Hodin RA, Fink MP (1999) Acidic conditions exacerbate interferon-gamma-induced intestinal epithelial hyperpermeability: role of peroxynitrous acid. Crit Care Med 27:1429–1436

    Article  PubMed  CAS  Google Scholar 

  21. Unno N, Menconi MJ, Smith M, Fink MP (1995) Nitric oxide mediates interferon-gammainduced hyperpermeability in cultured human intestinal epithelial monolayers. Crit Care Med 23:1170–1176

    Article  PubMed  CAS  Google Scholar 

  22. Han X, Fink MP, Delude RL (2003) Proinflammatory cytokines cause NO.-dependent and independent changes in expression and localization of tight junction proteins in intestinal epithelial cells. Shock 19:229–237

    Article  PubMed  CAS  Google Scholar 

  23. Adams RB, Planchon SM, Roche JK (1993) IFN-y modulation of epithelial barrier function: time course, reversibility, and site of cytokine binding. J Immunol 150:2356–2363

    PubMed  CAS  Google Scholar 

  24. Planchon SM, Martins CAP, Guerrant RL, Roche JK (1994) Regulation of intestinal epithelial barrier function by TGF-b1. Evidence for its role in abrogating the effects of T cell cytokine. J Immunol 153:5730–5739

    PubMed  CAS  Google Scholar 

  25. Madara JL, Stafford J (1989) Interferon-y directly affectsbarrier functionof cultured intestinal epithelial monolayers. J Clin Invest 83:724–727

    Article  PubMed  CAS  Google Scholar 

  26. Salzman AL, Menconi MJ, Unno N, et al (1995) Nitric oxide dilates tight junctions and depletes ATP in cultured Caco-2BBe intestinal epithelialmonolayers. Am J Physiol 268:G361–G373

    PubMed  CAS  Google Scholar 

  27. Menconi MJ, Unno N, Smith M, Aguirre DE, Fink MP (1998) The effect of nitric oxide donors on the permeability of cultured intestinal epithelial monolayers: role of superoxide, hydroxyl radical, and peroxynitrite. Biochem Biophys Acta 1425:189–203

    PubMed  CAS  Google Scholar 

  28. Chavez A, Morin MJ, Unno N, Fink MP, Hodin RA (1999) Acquired interferon-y responsiveness during Caco-2 cell differentiation: effects on iNOS gene expression. Gut 44:659–665

    Article  PubMed  CAS  Google Scholar 

  29. Chavez A, Menconi MJ, Hodin RA, Fink MP (1999) Cytokine-induced epithelial hyperpermeability: role of nitric oxide. Crit Care Med 27:2246–2251

    Article  PubMed  CAS  Google Scholar 

  30. Han X, Fink MP, Uchiyama T, Delude RL (2004) Increased iNOS activity is essential for the development of pulmonary epithelial tight junction dysfunction in endotoxemic mice. Am J Physiol Lung Cell Mol Physiol 286:L259–L267

    Article  PubMed  CAS  Google Scholar 

  31. Wink DA, Mitchell JB (1998) Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radical Biol Med 25:434–456

    Article  CAS  Google Scholar 

  32. Pryor WA, Squadrito GL (1995) The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am J Physiol 268:L699–L722

    PubMed  CAS  Google Scholar 

  33. Unno N, Menconi MJ, Smith M, Aguirre DG, Fink MP (1997) Hyperpermeability of intestinal epithelial monolayers is induced by NO: effect of low extracellular pH. Am J Physiol 272:G923–G934

    PubMed  CAS  Google Scholar 

  34. Sugi K, Musch MW, Field M, Chang EB (2001) Inhibition of Na+, K+-ATPase by interferon gammadown-regulates intestinal epithelial transport andbarrier function. Gastroenterology 120:1393–1403

    Article  PubMed  CAS  Google Scholar 

  35. Qayyum I, Zubrow AB, Ashraf QM, Kubin J, Delivoria-Papadopoulos M, Mishra OP (2001) Nitration as a mechanism of Na+, K+-ATPase modification during hypoxia in the cerebral cortex of the guinea pig fetus. Neurochem Res 26:1163–1169

    Article  PubMed  CAS  Google Scholar 

  36. Mishra OP, Delivoria-Papadopoulos M, Cahillane G, Wagerle LC (1989) Lipid peroxidation as the mechanism of modification of the affinity of the Na+, K+-ATPase active sites for ATP, K+, Na+, and strophanthidin in vitro. Neurochem Res 14:845–851

    Article  PubMed  CAS  Google Scholar 

  37. Unno N, Wang H, Menconi MJ, et al (1997) Inhibition of inducible nitric oxide synthase ameliorates lipopolysaccharide-induced gut mucosal barrier dysfunction in rats. Gastroenterology 113:1246–1257

    Article  PubMed  CAS  Google Scholar 

  38. Han X, Fink MP, Yang R, Delude RL (2004) Increased iNOS activity is essential for intestinal epithelial tight junction dysfunction in endotoxemic mice. Shock 21:261–270

    Article  PubMed  CAS  Google Scholar 

  39. Moore WM, Webber RK, Jerome GM, Tjong FS, Misko TP, Currie MG (1994) L-N6-(1-iminoethyl)lysine: A selective inhibitor of inducible nitric oxide synthase. J Med Chem 37:3886–3888

    Article  PubMed  CAS  Google Scholar 

  40. Kubes P (1993) Ischemia-reperfusion in the feline small intestine: a role for nitric oxide. Am J Physiol 264:G143–G149

    PubMed  CAS  Google Scholar 

  41. Kubes P (1992) Nitric oxide modulates epithelial permeability in the feline small intestine. Am J Physiol 262:G1138–G1142

    PubMed  CAS  Google Scholar 

  42. Sakakibara A, Furuse M, Saitou M, Ando-Akatsuka Y, Tsukita S (1997) Possible involvement of phosphorylation of occludin in tight junction formation. J Cell Biol 137:1393–1401

    Article  PubMed  CAS  Google Scholar 

  43. Ravin HA, Rowley D, Jenkins C, Fine J (1960) On the absorption of bacterial endotoxin from the gastro-intestinal tract of the normal and shocked animal. J Exp Med 112:783–792

    Article  PubMed  CAS  Google Scholar 

  44. Fine J, Frank ED, Rutenberg SH, Schweinburg FB (1959) The bacterial factor in traumatic shock. N Engl J Med 260:214–216

    Article  PubMed  CAS  Google Scholar 

  45. Moore FA, Moore EE, Poggetti R, et al (1991) Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma. J Trauma 31:629–638

    Article  PubMed  CAS  Google Scholar 

  46. Luyer MD, Buurman WA, Hadfoune M, et al (2004) Pretreatment with high-fat enteral nutrition reduces endotoxin and tumor necrosis factor-alpha and preserves gut barrier function early after hemorrhagic shock. Shock 21:65–71

    Article  PubMed  Google Scholar 

  47. Wan S, LeClerc JL, Huynh CH, et al (1999) Does steroid pretreatment increase endotoxin release during clinical cardiopulmonary bypass? J Thorac Cardiovasc Surg 117:1004–1008

    Article  PubMed  CAS  Google Scholar 

  48. Martinez-Pellus AE, Merino P, Bru M, et al (1993) Can selective digestive decontamination avoid the endotoxemia and cytokine activation promoted by cardiopulmonary bypass. Crit Care Med 21:1684–1691

    Article  PubMed  CAS  Google Scholar 

  49. Yates SP, Jorgensen R, Andersen GR, Merrill AR (2006) Stealth and mimicry by deadly bacterial toxins. Trends Biochem Sci 31:123–133

    Article  PubMed  CAS  Google Scholar 

  50. Wu L, Estrada O, Zaborina O, et al (2005) Recognition of host immune activation by Pseudomonas aeruginosa. Science 309:774–747

    Article  PubMed  CAS  Google Scholar 

  51. Kohler JE, Zaborina O, Wu L, et al (2005) Components of intestinal epithelial hypoxia activate the virulence circuitry of Pseudomonas. Am J Physiol Gastrointest Liver Physiol 288:G1084–G1054

    Article  CAS  Google Scholar 

  52. Alverdy J, Holbrook C, Rocha F, et al (2000) Gut-derivedsepsis occurswhen the right pathogen with the right virulence genes meets the right host: evidence for In vivo virulence expression in pseudomonas aeruginosa. Ann Surg 232:480–489

    Article  PubMed  CAS  Google Scholar 

  53. Gaines JM, Carty NL, Colmer-Hamood JA, Hamood AN (2005) Effect of static growth and different levels of environmental oxygen on toxA and ptxR expression in the Pseudomonas aeruginosa strain PAO1. Microbiology 151:2263–2275

    Article  PubMed  CAS  Google Scholar 

  54. Peitzman AB, Udekwu AO, Ochoa J, Smith S (1991) Bacterial translocation in traumapatients. J Trauma 31:1083–1087

    PubMed  CAS  Google Scholar 

  55. Magnotti LJ, Upperman JS, Xu D-Z, Lu Q, Deitch EA (1998) Gut-derived mesenteric lymph but not portal blood increases endothelial cell permeability and promotes lung injury after hemorrhagic shock. Ann Surg 228:518–527

    Article  PubMed  CAS  Google Scholar 

  56. Zallen G, Moore EE, Johnson JL, Tamura DY, Ciesla DJ, Silliman CC (2006) Posthemorrhagic shockmesenteric lymph primes circulating neutrophils and provokes lung injury. J Surg Res 83:83–88

    Article  Google Scholar 

  57. Upperman JS, Deitch EA, Guo W, Lu Q, Xu D (1998) Post-hemorrhagic shock mesenteric lymph is cytotoxic to endothelial cells and activates neutrophils. Shock 10:407–414

    Article  PubMed  CAS  Google Scholar 

  58. Magnotti LJ, Xu DZ, Lu Q, Deitch EA (1999) Gut-derived mesenteric lymph: a link between burn and lung injury. Arch Surg 134:1333–1340

    Article  PubMed  CAS  Google Scholar 

  59. Gonzalez RJ, Moore EE, Ciesla DJ, Meng X, Biffl WL, Silliman CC (2001) Post-hemorrhagic shock mesenteric lymph lipids prime neutrophils for enhanced cytotoxicity via phospholipase A2. Shock 16:218–222

    Article  PubMed  CAS  Google Scholar 

  60. Gonzalez RJ, Moore EE, Ciesla DJ, Biffl WL, Offner PJ, Silliman CC (2001) Phospholipase A(2)-derived neutral lipids from posthemorrhagic shock mesenteric lymph prime the neutrophil oxidative burst. Surgery 130:198–203

    Article  PubMed  CAS  Google Scholar 

  61. Kaiser VL, Sifri ZC, Dikdan GS, et al (2005) Trauma-hemorrhagic shock mesenteric lymph from rat contains a modified form of albumin that is implicated in endothelial cell toxicity. Shock 23:417–425

    Article  PubMed  CAS  Google Scholar 

  62. Dayal SD, Hauser CJ, Feketeova E, et al (2002) Shockmesenteric lymph-induced rat polymorphonuclear neutrophil activation and endothelial cell injury is mediated by aqueous factors. J Trauma 52:1048–1055

    Article  PubMed  Google Scholar 

  63. Deitch EA, Shi HP, Lu Q, Feketeova E, Xu DZ (2003) Serine proteases are involved in the pathogenesis of trauma-hemorrhagic shock-induced gut and lung injury. Shock 19:452–456

    Article  PubMed  CAS  Google Scholar 

  64. Eckmann L, Jung HC, Schurer-Maly C, Panja A, Morzycka-Wroblewska E, Kagnoff MF (1993) Differential cytokine expression by human intestinal epithelial cell lines. Gastroenterology 105:1689–1697.

    PubMed  CAS  Google Scholar 

  65. Kim JM, Kim JS, Jun HC, Oh YK, Song IS, Kim CY (2002) Differential expression and polarized secretion of CXC and CC chemokines by human intestinal epithelial cancer cell lines in response to Clostridium difficile toxin A. Microbiol Immunol 46:333–342

    PubMed  CAS  Google Scholar 

  66. Taylor CT, Fueki N, Agah A, Hershberg RM, Colgan SP (1999) Critical role of cAMP response element binding protein expression in hypoxia-elicited induction of epithelial tumor necrosis factor-alpha. J Biol Chem 274:19447–19454

    Article  PubMed  CAS  Google Scholar 

  67. Jung HC, Eckmann L, Yang SK, et al (1995) A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J Clin Invest 95:55–65

    Article  PubMed  CAS  Google Scholar 

  68. Eckmann L, Stenson WF, Savidge TC, et al (1997) Role of intestinal epithelial cells in the host secretory response to infection by invasive bacteria. Bacterial entry induces epithelial prostagl and in Hsynthase-2 expression and prostaglandin E2 and F2 production. JClin Invest 100:296–309

    Article  CAS  Google Scholar 

  69. Bustin M, Lehn DA, Landsman D (1990) Structural features of the HMG chromosomal proteins and their genes. Biochim Biophys Acta 1049:231–243

    PubMed  CAS  Google Scholar 

  70. Wang H, Bloom O, Zhang M, et al (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251

    Article  PubMed  CAS  Google Scholar 

  71. Yang H, Ochani M, Li J, et al (2004) Reversing established sepsis with antagonists of endogenous HMGB1. Proc Natl Acad Sci USA 101:296–301

    Article  PubMed  CAS  Google Scholar 

  72. Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ (2000) HMG-1 as a mediator of acute lung inflammation. J Immunol 165:2950–2954

    PubMed  CAS  Google Scholar 

  73. Kim JY, Park JS, Strassheim D, et al (2005) HMGB1 contributes to the development of acute lung injury after hemorrhage. Am J Physiol Lung Cell Mol Physiol 288:L958–L965

    Article  PubMed  CAS  Google Scholar 

  74. Sappington PL, Yang R, Yang H, Tracey KJ, Delude RL, Fink MP (2002) HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology 123:790–802

    Article  PubMed  CAS  Google Scholar 

  75. Andersson U, Wang H, Palmblad K, et al (2001) High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 192:565–570

    Article  Google Scholar 

  76. Ombrellino M, Wang H, Ajemian MS, et al (1999) Increased serum concentrations of highmobility-group protein 1 in haemorrhagic shock. Lancet 354:1446–1447

    Article  PubMed  CAS  Google Scholar 

  77. Pachot A, Monneret G, Voirin N, et al (2005) Longitudinal study of cytokine and immune transcription factor mRNA expression in septic shock. Clin Immunol 114:61–69

    Article  PubMed  CAS  Google Scholar 

  78. Sunden-Cullberg J, Norrby-Teglund A, Rouhianen A, et al (2005) Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med 33:564–573

    Article  PubMed  CAS  Google Scholar 

  79. Rendon-Mitchell B, Ochani M, Li J, et al (2003) IFN-gamma induces highmobility group box 1 protein release partly through a TNF-dependent mechanism. J Immunol 170:3890–3897

    PubMed  CAS  Google Scholar 

  80. Gardella S, Andrei C, Ferrera D, et al (2002) The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep 3:995–1001

    Article  PubMed  CAS  Google Scholar 

  81. Bonaldi T, Talamo F, Scaffidi P, et al (2003)Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J 22:5551–5560

    Article  PubMed  CAS  Google Scholar 

  82. Semino C, Angelini G, Poggi A, Rubartelli A (2005) NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood 106:609–616

    Article  PubMed  CAS  Google Scholar 

  83. Wang H, Vishnubhakat JM, Bloom O, et al (2002) Proinflammatory cytokines (tumor necrosis factor and interleukin 1) stimulate release of high mobility group protein-1 by pituicytes. Surgery 126:389–392

    Google Scholar 

  84. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195

    Article  PubMed  CAS  Google Scholar 

  85. Liu S, Stolz DB, Sappington PL, et al (2006) HMGB1 is secreted by immunostimulated enterocytes and contributes to cytomix-induced hyperpermeability of Caco-2 monolayers. Am J Physiol Cell Physiol 290:C990–999

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Departments of Critical Care Medicine, Surgery, Pharmacology and Pathology, University of Pittsburgh School of Medicine, Room 616 Scaife Hall 3550 Terrace Street, Pittsburgh, PA, 15261, USA

    M. P. Fink

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  1. M. P. Fink
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Editors and Affiliations

  1. Health Sciences Center, Division Pulmonary & Critical Care Medicine, University of Colorado, E. Ninth Avenue 4200, 80262, Denver, CO, USA

    Edward Abraham MD

  2. Bloomsbury Institute of Intensive Care, Division Medicine, University College Hospital, Gower Street, WC1E 6BT, London, UK

    Mervyn Singer MD

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Fink, M.P. (2007). The Gut. In: Abraham, E., Singer, M. (eds) Mechanisms of Sepsis-Induced Organ Dysfunction and Recovery. Update in Intensive Care and Emergency Medicine, vol 44. Springer, Berlin, Heidelberg . https://doi.org/10.1007/3-540-30328-6_26

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  • DOI: https://doi.org/10.1007/3-540-30328-6_26

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-30157-8

  • Online ISBN: 978-3-540-30328-2

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