Intensive Care Medicine

, Volume 30, Issue 5, pp 748–756

Stress-hyperglycemia, insulin and immunomodulation in sepsis

Review

Abstract

Stress-hyperglycemia and insulin resistance are exceedingly common in critically ill patients, particularly those with sepsis. Multiple pathogenetic mechanisms are responsible for this metabolic syndrome; however, increased release of pro-inflammatory mediators and counter-regulatory hormones may play a pivotal role. Recent data suggests that hyperglycemia may potentiate the pro-inflammatory response while insulin has the opposite effect. Furthermore, emerging evidence suggests that tight glycemic control will improve the outcome of critically ill patients. This paper reviews the pathophysiology of stress hyperglycemia in the critically ill septic patient and outlines a treatment strategy for the management of this disorder.

Keywords

Insulin Glucose Sepsis Sepsis syndrome Critical illness Insulin resistance Hyperglycemia 

References

  1. 1.
    Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the nited States from 1979 through 2000. N Engl J Med 348:1546–1554CrossRefPubMedGoogle Scholar
  2. 2.
    Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome and associated costs of care. Crit Care Med 29:1303–1310PubMedGoogle Scholar
  3. 3.
    Friedman G, Silva E, Vincent JL (1998) Has the mortality of septic shock changed with time? Crit Care Med 26:2078–2086PubMedGoogle Scholar
  4. 4.
    Marik PE, Varon J (2001) Sepsis: state of the art. Dis Mon 47:463–532Google Scholar
  5. 5.
    Bone RC (1996) Sir Isaac Newton, sepsis, SIRS and CARS. Crit Care Med 24:1125–1128PubMedGoogle Scholar
  6. 6.
    Bone RC, Sibbald WJ, Sprung CL (1992) The ACCP-SCCM Consensus Conference on sepsis and organ failure. Chest 101:1481–1483PubMedGoogle Scholar
  7. 7.
    Bone RC, Grodzin CJ, Balk RA (1997) Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 112:235–243PubMedGoogle Scholar
  8. 8.
    Natanson C, Esposito CJ, Banks SM (1998) The sirens’ songs of confirmatory sepsis trials: selection bias and sampling error. Crit Care Med 26:1927–1931PubMedGoogle Scholar
  9. 9.
    Eichacker PQ, Parent C, Kalil A, Esposito C, Cui X, Banks SM, Gerstenberger EP, Fitz Y, Danner RL, Natanson C (2002) Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 166:1197–1205CrossRefPubMedGoogle Scholar
  10. 10.
    Dellinger RP (1999) Severe sepsis trials: Why have they failed? Minerva Anestesiol 65:340–345PubMedGoogle Scholar
  11. 11.
    van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R (2001) Intensive insulin therapy in critically ill patients. N Engl J Med 345:1359–1367PubMedGoogle Scholar
  12. 12.
    van den Berghe G, Wouters PJ, Bouillon R, Weekers F, Verwaest C, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P (2003) Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 31:359–366PubMedGoogle Scholar
  13. 13.
    Marik PE, Zaloga GP (2002) Adrenal insufficiency in the critically ill: a new look at an old problem. Chest 122:1784–1796CrossRefPubMedGoogle Scholar
  14. 14.
    Hart BB, Stanford GG, Ziegler MG, Lake CR, Chernow B (1989) Catecholamines: study of interspecies variation. Crit Care Med 17:1203–1218PubMedGoogle Scholar
  15. 15.
    van den Berghe G (2002) Neuroendocrine pathobiology of chronic illness. Crit Care Clin 18:509–528PubMedGoogle Scholar
  16. 16.
    Siegel JH, Cerra FB, Coleman B, Giovannini I, Shetye M, Border JR, McMenamy RH (1979) Physiological and metabolic correlations in human sepsis. Invited commentary. Surgery 86:163–193PubMedGoogle Scholar
  17. 17.
    Clowes GH, Martin H, Walji S, Hirsch E, Gazitua R, Goodfellow R (1978) Blood insulin responses to blood glucose levels in high output sepsis and spetic shock. Am J Surg 135:577–583PubMedGoogle Scholar
  18. 18.
    Dahn MS, Jacobs LA, Smith S, Hans B, Lange MP, Mitchell RA, Kirkpatrick JR (1985) The relationship of insulin production to glucose metabolism in severe sepsis. Arch Surg 120:166–172PubMedGoogle Scholar
  19. 19.
    Mizock BA (2001) Alterations in fuel metabolism in critical illness hyperglycemia. Best Pract Res Clin Endocrinol Metab 15:533–551Google Scholar
  20. 20.
    Mehta VK, Hao W, Brooks-Worrell BM, Palmer JP (1994) Low-dose interleukin 1 and tumor necrosis factor individually stimulate insulin release but in combination cause suppression. Eur J Endocrinol 130:208–214Google Scholar
  21. 21.
    Shepard PR, Kahn BB (1999) Glucose transporters and insulin action. Implications for insulin resistance and diabetes mellitus. N Engl J Med 341:248–257PubMedGoogle Scholar
  22. 22.
    Pessin JE, Saltiel AR (2000) Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest 106:165–169PubMedGoogle Scholar
  23. 23.
    McCowen KC, Malhotra A, Bistrian BR (2001) Stress-induced hyperglycemia. Crit Care Clin 17:107–124PubMedGoogle Scholar
  24. 24.
    Frankenfield DC, Omert LA, Badellino MM, Wiles CE, III, Bagley SM, Goodarzi S, Siegel JH (1994) Correlation between measured energy expenditure and clinically obtained variables in trauma and sepsis patients. J Parenter Enteral Nutr 18:398–403Google Scholar
  25. 25.
    Agwunobi AO, Reid C, Maycock P, Little RA, Carlson GL (2000) Insulin resistance and substrate utilization in human endotoxemia. J Clin Endocrinol Metab 85:3770–3778PubMedGoogle Scholar
  26. 26.
    Gelb AW, Bayona NA, Wilson JX, Cechetto DF (2002) Propofol anesthesia compared to awake reduces infarct size in rats. Anesthesiol 96:1183–1190CrossRefGoogle Scholar
  27. 27.
    Sakurai Y, Zhang XJ, Wolfe RR (1996) TNF directly stimulates glucose uptake and leucine oxidation and inhibits FFA flux in conscious dogs. Am J Physiol 270:E864–E872PubMedGoogle Scholar
  28. 28.
    Lang CH, Dobrescu C (1991) Gram-negative infection increases noninsulin-mediated glucose disposal. Endocrinology 128:645–653Google Scholar
  29. 29.
    Meszaros K, Lang CH, Bagby GJ, Spitzer JJ (1987) Tumor necrosis factor increases in vivo glucose utilization of macrophage-rich tissues. Biochem Biophys Res Commun 149:1–6PubMedGoogle Scholar
  30. 30.
    Bird TA, Davies A, Baldwin SA, Saklatvala J (1990) Interleukin 1 stimulates hexose transport in fibroblasts by increasing the expression of glucose transporters. J Biol Chem 265:13578–13583PubMedGoogle Scholar
  31. 31.
    Green CJ, Campbell IT, O’Sullivan E, Underhill S, McLaren DP, Hipkin LJ, MacDonald IA, Russell J (1995) Septic patients in multiple organ failure can oxidize infused glucose, but non-oxidative disposal (storage) is impaired. Clin Sci 89:601–609PubMedGoogle Scholar
  32. 32.
    Saeed M, Carlson GL, Little RA, Irving MH (1999) Selective impairment of glucose storage in human sepsis. Br J Surg 86:813–821CrossRefPubMedGoogle Scholar
  33. 33.
    Mizock BA (1997) Alterations in fuel metabolism in critical illness. Hyperglycemia. In: Ober KP (ed) Endocrinology of critical disease. Humana Press, Totawa, New Jersey, pp 197–297Google Scholar
  34. 34.
    Mesotten D, Delhanty PJ, Vanderhoydonc F, Hardman KV, Weekers F, Baxter RC, Van den BG (2002) Regulation of insulin-like growth factor binding protein-1 during protracted critical illness. J Clin Endocrinol Metab 87:5516–5523CrossRefPubMedGoogle Scholar
  35. 35.
    Jeevanandam M, Young DH, Schiller WR (1990) Glucose turnover, oxidation, and indices of recycling in severely traumatized patients. J Trauma 30:582–589PubMedGoogle Scholar
  36. 36.
    Cerra FB (1987) Hypermetabolism, organ failure, and metabolic support. Surgery 101:1–14PubMedGoogle Scholar
  37. 37.
    Wolfe RR (1997) Substrate utilization/insulin resistance in sepsis/trauma. Baillieres Clin Endocrinol Metab 11:645–657PubMedGoogle Scholar
  38. 38.
    Petit F, Bagby GJ, Lang CH (1995) Tumor necrosis factor mediates zymosan-induced increase in glucose flux and insulin resistance. Am J Physiol 268:E219–E228PubMedGoogle Scholar
  39. 39.
    Roh MS, Moldawer LL, Ekman LG, Dinarello CA, Bistrian BR, Jeevanandam M, Brennan MF (1986) Stimulatory effect of interleukin-1 upon hepatic metabolism. Metabolism 35:419–424PubMedGoogle Scholar
  40. 40.
    Lang CH (1992) Sepsis-induced insulin resistance in rats is mediated by a beta-adrenergic mechanism. Am J Physiol 263:E703–E711PubMedGoogle Scholar
  41. 41.
    Chambrier C, Laville M, Rhzioual BK, Odeon M, Bouletreau P, Beylot M (2000) Insulin sensitivity of glucose and fat metabolism in severe sepsis. Clin Sci 99:321–328CrossRefPubMedGoogle Scholar
  42. 42.
    Aljada A, Ghanim H, Assian E, Dandona P (2002) Tumor necrosis factor-alpha inhibits insulin-induced increase in endothelial nitric oxide synthase and reduces insulin receptor content and phosphorylation in human aortic endothelial cells. Metabolism 51:487–491CrossRefPubMedGoogle Scholar
  43. 43.
    Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271:665–668PubMedGoogle Scholar
  44. 44.
    Kanety H, Feinstein R, Papa MZ, Hemi R, Karasik A (1995) Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. J Biol Chem 270:23780–23784CrossRefPubMedGoogle Scholar
  45. 45.
    Paz K, Hemi R, LeRoith D, Karasik A, Elhanany E, Kanety H, Zick Y (1997) A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J Biol Chem 272:29911–29918CrossRefPubMedGoogle Scholar
  46. 46.
    Nunes AL, Carvalheira JB, Carvalho CR, Brenelli SL, Saad MJ (2001) Tissue-specific regulation of early steps in insulin action in septic rats. Life Sci 69:2103–2112CrossRefPubMedGoogle Scholar
  47. 47.
    Hotamisligil GS, Budavari A, Murray D, Spiegelman BM (1994) Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest 94:1543–9PubMedGoogle Scholar
  48. 48.
    Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM (1994) Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci USA 91:4854–4858PubMedGoogle Scholar
  49. 49.
    Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J (2002) Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 277:48115–48121CrossRefPubMedGoogle Scholar
  50. 50.
    Gay NJ, Keith FJ (1991) Drosophila Toll and IL-1 receptor. Nature 351:355–356CrossRefPubMedGoogle Scholar
  51. 51.
    Belvin MP, Anderson KV (1996) A conserved signaling pathway: the Drosophila toll-dorsal pathway. Annu Rev Cell Develop Biol 12:393–416CrossRefGoogle Scholar
  52. 52.
    Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S (1999) Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162:3749–3752PubMedGoogle Scholar
  53. 53.
    Barnes PJ, Karin M (1997) Nuclear factor-kB-A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336:1066–1071PubMedGoogle Scholar
  54. 54.
    Chiasson JL, Shikama H, Chu DT, Exton JH (1981) Inhibitory effect of epinephrine on insulin-stimulated glucose uptake by rat skeletal muscle. J Clin Invest 68:706–713PubMedGoogle Scholar
  55. 55.
    Haring H, Kirsch D, Obermaier B, Ermel B, Machicao F (1986) Decreased tyrosine kinase activity of insulin receptor isolated from rat adipocytes rendered insulin-resistant by catecholamine treatment in vitro. Biochem J 234:59–66PubMedGoogle Scholar
  56. 56.
    Dimitriadis G, Leighton B, Parry-Billings M, Sasson S, Young M, Krause U, Bevan S, Piva T, Wegener G, Newsholme EA (1997) Effects of glucocorticoid excess on the sensitivity of glucose transport and metabolism to insulin in rat skeletal muscle. Biochem J 321:707–712PubMedGoogle Scholar
  57. 57.
    Smith TR, Elmendorf JS, David TS, Turinsky J (1997) Growth hormone-induced insulin resistance: role of the insulin receptor, IRS-1, GLUT-1, and GLUT-4. Am J Physiol 272:E1071–E1079PubMedGoogle Scholar
  58. 58.
    Dominici FP, Cifone D, Bartke A, Turyn D (1999) Alterations in the early steps of the insulin-signaling system in skeletal muscle of GH-transgenic mice. Am J Physiol 277:E447–E454PubMedGoogle Scholar
  59. 59.
    Khaodhiar L, McCowen K, Bistrian B (1999) Perioperative hyperglycemia, infection or risk? Curr Opin Clin Nutr Metab Care 2:79–82CrossRefPubMedGoogle Scholar
  60. 60.
    Norhammar AM, Ryden L, Malmberg K (1999) Admission plasma glucose. Independent risk factor for long-term prognosis after myocardial infarction even in nondiabetic patients. Diabetes Care 22:1827–1831PubMedGoogle Scholar
  61. 61.
    Zindrou D, Taylor KM, Bagger JP (2001) Admission plasma glucose: an independent risk factor in nondiabetic women after coronary artery bypass grafting. Diabetes Care 24:1634–1639PubMedGoogle Scholar
  62. 62.
    Malmberg K, Norhammar A, Wedel H, Ryden L (1999) Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 99:2626–26232PubMedGoogle Scholar
  63. 63.
    Malmberg K (1997) Prospective randomised study of intensive insulin treatment on long-term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. Br Med J 314:1512–1515Google Scholar
  64. 64.
    Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin L (1995) Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol 26:57–65PubMedGoogle Scholar
  65. 65.
    Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC (2001) Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 32:2426–2432PubMedGoogle Scholar
  66. 66.
    Woo J, Lam CW, Kay R, Wong AH, Teoh R, Nicholls MG (1990) The influence of hyperglycemia and diabetes mellitus on immediate and 3-month morbidity and mortality after acute stroke. Arch Neurol 47:1174–1177PubMedGoogle Scholar
  67. 67.
    Dandona P, Aljada A, Bandyopadhyay A (2003) The potential therapeutic role of insulin in acute myocardial infarction in patients admitted to intensive care and in those with unspecified hyperglycemia. Diabetes Care 26:516–519PubMedGoogle Scholar
  68. 68.
    Hansen TK, Thiel S, Wouters PJ, Christiansen JS, van den Berghe G (2003) Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab 88:1082–1088CrossRefPubMedGoogle Scholar
  69. 69.
    Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P (2000) Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab 85:2970–2973Google Scholar
  70. 70.
    Straczkowski M, Dzienis-Straczkowska S, Stepien A, Kowalska I, Szelachowska M, Kinalska I (2002) Plasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-alpha system. J Clin Endocrinol Metab 87:4602–4606CrossRefPubMedGoogle Scholar
  71. 71.
    Chettab K, Zibara K, Belaiba SR, McGregor JL (2002) Acute hyperglycaemia induces changes in the transcription levels of 4 major genes in human endothelial cells: macroarrays-based expression analysis. Thromb Haemost 87:141–148PubMedGoogle Scholar
  72. 72.
    Standiford TJ, Kunkel SL, Greenberger MJ, Laichalk LL, Strieter RM (1996) Expression and regulation of chemokines in bacterial pneumonia. J Leukoc Biol 59:24–28PubMedGoogle Scholar
  73. 73.
    Hack CE, Aarden LA, Thijs LG (1997) Role of cytokines in sepsis. Adv Immunol 66:101–195PubMedGoogle Scholar
  74. 74.
    Multz AS, Cohen R (2003) Systemic response to pneumonia in the critically ill patient. Semin Resp Infect 18:68–71Google Scholar
  75. 75.
    Aljada A, Ghanim H, Mohanty P, Hofmeyer D, Tripathy D, Dandona P (2002) Glucose activates nuclear factor kappa B pathway in mononuclear cells (MNC) and induces an increase in p47phox. subunit in MNC membranes [Abstract]. Diabetes 51 (Suppl 2):A537Google Scholar
  76. 76.
    Yorek MA, Dunlap JA (2002) Effect of increased concentration of D-glucose or L-fucose on monocyte adhesion to endothelial cell monolayers and activation of nuclear factor-kappaB. Metabolism 51:225–234CrossRefPubMedGoogle Scholar
  77. 77.
    Guha M, Bai W, Nadler JL, Natarajan R (2000) Molecular mechanisms of tumor necrosis factor alpha gene expression in monocytic cells via hyperglycemia-induced oxidant stress-dependent and -independent pathways. J Biol Chem 275:17728–17739CrossRefPubMedGoogle Scholar
  78. 78.
    Ceriello A, Bortolotti N, Motz E, Pieri C, Marra M, Tonutti L, Lizzio S, Feletto F, Catone B, Taboga C (1999) Meal-induced oxidative stress and low-density lipoprotein oxidation in diabetes: the possible role of hyperglycemia. Metabolism 48:1503–1508PubMedGoogle Scholar
  79. 79.
    Ceriello A (1993) Coagulation activation in diabetes mellitus: the role of hyperglycaemia and therapeutic prospects. Diabetologia 36:1119–1125Google Scholar
  80. 80.
    Aljada A, Ghanim H, Mohanty P, Syed T, Dandona P (2003) Glucose intake induces an increase in AP-1 and Egr-1 in mononuclear cells and plasma matrix metalloproteinases and tissue factor (TF) concentrations. J Clin Endocrinol MetabGoogle Scholar
  81. 81.
    Giugliano D, Marfella R, Coppola L, Verrazzo G, Acampora R, Giunta R, Nappo F, Lucarelli C, D’Onofrio F (1997) Vascular effects of acute hyperglycemia in humans are reversed by L-arginine. Evidence for reduced availability of nitric oxide during hyperglycemia. Circulation 95:1783–1790PubMedGoogle Scholar
  82. 82.
    Pozzilli P, Leslie RD (1994) Infections and diabetes: mechanisms and prospects for prevention. Diabet Med 11:935–941PubMedGoogle Scholar
  83. 83.
    Mowlavi A, Andrews K, Milner S, Herndon DN, Heggers JP (2000) The effects of hyperglycemia on skin graft survival in the burn patient. Ann Plast Surg 45:629–632PubMedGoogle Scholar
  84. 84.
    Furnary AP, Zerr KJ, Grunkemeier GL, Starr A (1999) Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg 67:352–360CrossRefPubMedGoogle Scholar
  85. 85.
    Zerr KJ, Furnary AP, Grunkemeier GL, Bookin S, Kanhere V, Starr A (1997) Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg 63:356–361PubMedGoogle Scholar
  86. 86.
    McManus LM, Bloodworth RC, Prihoda TJ, Blodgett JL, Pinckard RN (2001) Agonist-dependent failure of neutrophil function in diabetes correlates with extent of hyperglycemia. J Leukoc Biol 70:395–404PubMedGoogle Scholar
  87. 87.
    Evans TW (2001) Hemodynamic and metabolic therapy in critically ill patients. N Engl J Med 345:1417–1418CrossRefPubMedGoogle Scholar
  88. 88.
    Rassias AJ, Marrin CA, Arruda J, Whalen PK, Beach M, Yeager MP (1999) Insulin infusion improves neutrophil function in diabetic cardiac surgery patients. Anesth Analg 88:1011–1016PubMedGoogle Scholar
  89. 89.
    Nielson CP, Hindson DA (1989) Inhibition of polymorphonuclear leukocyte respiratory burst by elevated glucose concentrations in vitro. Diabetes 38:1031–1035Google Scholar
  90. 90.
    Kwoun MO, Ling PR, Lydon E, Imrich A, Qu Z, Palombo J, Bistrian BR (1997) Immunologic effects of acute hyperglycemia in nondiabetic rats. J Parenter Enteral Nutr 21:91–95Google Scholar
  91. 91.
    Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, Ahmad S (2001) Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 86:3257–3265PubMedGoogle Scholar
  92. 92.
    Aljada A, Ghanim H, Mohanty P, Kapur N, Dandona P (2002) Insulin inhibits the pro-inflammatory transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations. J Clin Endocrinol Metab 87:1419–1422PubMedGoogle Scholar
  93. 93.
    Aljada A, Dandona P (2000) Effect of insulin on human aortic endothelial nitric oxide synthase. Metabolism 49:147–150PubMedGoogle Scholar
  94. 94.
    Peng HB, Spiecker M, Liao JK (1998) Inducible nitric oxide: an autoregulatory feedback inhibitor of vascular inflammation. J Immunol 161:1970–1976PubMedGoogle Scholar
  95. 95.
    Spiecker M, Darius H, Kaboth K, Hubner F, Liao JK (1998) Differential regulation of endothelial cell adhesion molecule expression by nitric oxide donors and antioxidants. J Leukoc Biol 63:732–739PubMedGoogle Scholar
  96. 96.
    Spiecker M, Peng HB, Liao JK (1997) Inhibition of endothelial vascular cell adhesion molecule-1 expression by nitric oxide involves the induction and nuclear translocation of IkappaBalpha. J Biol Chem 272:30969–30974PubMedGoogle Scholar
  97. 97.
    Meldrum DR, McIntyre RC, Sheridan BC, Cleveland JC Jr, Fullerton DA, Harken AH (1997) L-arginine decreases alveolar macrophage proinflammatory monokine production during acute lung injury by a nitric oxide synthase-dependent mechanism. J Trauma 43:888–893PubMedGoogle Scholar
  98. 98.
    Laroux FS, Lefer DJ, Kawachi S, Scalia R, Cockrell AS, Gray L, van der Heyde H, Hoffman JM, Grisham MB (2000) Role of nitric oxide in the regulation of acute and chronic inflammation. Antioxidants Redox Signaling 2:391–396CrossRefGoogle Scholar
  99. 99.
    Torre A de la, Schroeder RA, Punzalan C, Kuo PC (1999) Endotoxin-mediated S-nitrosylation of p50 alters NF-kappa B-dependent gene transcription in ANA-1 murine macrophages. J Immunol 162:4101–4108PubMedGoogle Scholar
  100. 100.
    Walley KR, McDonald TE, Higashimoto Y, Hayashi S (1999) Modulation of proinflammatory cytokines by nitric oxide in murine acute lung injury. Am J Respir Crit Care Med 160:698–704PubMedGoogle Scholar
  101. 101.
    Pahl HL (1999) Activators and target genes of rel/NF-kappaB transcription factors. Oncogene 18:6853–6866PubMedGoogle Scholar
  102. 102.
    Bohrer H, Qiu F, Zimmermann T, Zhang Y, Jllmer T, Mannel D, Bottiger BW, Stern DM, Waldherr R, Saeger HD, Ziegler R, Bierhaus A, Martin E, Nawroth PP (1997) Role of NFkappaB in the mortality of sepsis. J Clin Invest 100:972–985PubMedGoogle Scholar
  103. 103.
    Arnalich F, Garcia-Palomero E, Lopez J, Jimenez M, Madero R, Renart J, Vazquez JJ, Montiel C (2000) Predictive value of nuclear factor kappaB activity and plasma cytokine levels in patients with sepsis. Infect Immunol 68:1942–1945CrossRefGoogle Scholar
  104. 104.
    Paterson RL, Galley HF, Dhillon JK, Webster NR (2000) Increased nuclear factor kappa B activation in critically ill patients who die. Crit Care Med 28:1047–1051Google Scholar
  105. 105.
    Marik PE (2002) Nuclear factor-kappaB inhibition in sepsis: steroids versus specific nuclear factor-kappaB inhibitors? Crit Care Med 30:2393–2394CrossRefPubMedGoogle Scholar
  106. 106.
    Christman JW, Lancaster LH, Blackwell TS (1998) Nuclear factor kappa B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy. Intensive Care Med 24:1131–1138CrossRefPubMedGoogle Scholar
  107. 107.
    Fink MP (2003) Nulcear factor-kB: Is it a therapeutic target for the adjuvant treatment of sepsis. Crit Care Med 31:2400–2402CrossRefPubMedGoogle Scholar
  108. 108.
    Liu SF, Ye X, Malik AB (1999) Inhibition of NF-kappaB activation by pyrrolidine dithiocarbamate prevents In vivo expression of proinflammatory genes. Circulation 100:1330–1337PubMedGoogle Scholar
  109. 109.
    Marik PE, Zaloga G (2003) Gastric vs post-pyloric feeding? A systematic review. Intensive Care MedGoogle Scholar
  110. 110.
    Marik PE, Zaloga GP (2001) Early enteral nutrition in acutely ill patients: a systematic review. Crit Care Med 29:2264–2270PubMedGoogle Scholar
  111. 111.
    Marik PE, Pinsky MR (2003) Death by total parenteral nutrition. Intensive Care Med 29:867–869PubMedGoogle Scholar
  112. 112.
    Ghanim H, Garg R, Aljada A, Mohanty P, Kumbkarni Y, Assian E, Hamouda W, Dandona P (2001) Suppression of nuclear factor-kappaB and stimulation of inhibitor kappaB by troglitazone: evidence for an anti-inflammatory effect and a potential antiatherosclerotic effect in the obese. J Clin Endocrinol Metab 86:1306–1312PubMedGoogle Scholar
  113. 113.
    Aljada A, Garg R, Ghanim H, Mohanty P, Hamouda W, Assian E, Dandona P (2001) Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action? J Clin Endocrinol Metab 86:3250–3256PubMedGoogle Scholar
  114. 114.
    Yue Tl TL, Chen J, Bao W, Narayanan PK, Bril A, Jiang W, Lysko PG, Gu JL, Boyce R, Zimmerman DM, Hart TK, Buckingham RE, Ohlstein EH (2001) In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation 104:2588–2594PubMedGoogle Scholar
  115. 115.
    Wayman NS, Hattori Y, McDonald MC, Mota-Filipe H, Cuzzocrea S, Pisano B, Chatterjee PK, Thiemermann C (2002) Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J 16:1027–1040CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Department of Critical Care MedicineUniversity of Pittsburgh Medical CenterPittsburghUSA
  2. 2.Conemaugh Memorial Medical CenterJohnstownUSA

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