Top

Intensive Care Medicine

Published in:

01-10-2010 | Review

The RAGE axis in systemic inflammation, acute lung injury and myocardial dysfunction: an important therapeutic target?

Authors: Benedict C. Creagh-Brown, Gregory J. Quinlan, Timothy W. Evans, Anne Burke-Gaffney

Published in: Intensive Care Medicine | Issue 10/2010

Abstract

Background

The sepsis syndromes, frequently complicated by pulmonary and cardiac dysfunction, remain a major cause of death amongst the critically ill. Targeted therapies aimed at ameliorating the systemic inflammation that characterises the sepsis syndromes have largely yielded disappointing results in clinical trials. Whilst there are many potential reasons for lack of success of clinical trials, one possibility is that the pathways targeted, to date, are only modifiable very early in the course of the illness. More recent approaches have therefore attempted to identify pathways that could offer a wider therapeutic window, such as the receptor for advanced glycation end-products (RAGE) and its ligands.

Purpose

The objectives of this study were to review the evidence supporting the role of the RAGE axis in systemic inflammation and associated acute lung injury and myocardial dysfunction, to explore some of the problems and conflicts that these RAGE studies have raised and to consider strategies by which they might be resolved.

Methods

MEDLINE was searched (1990–2010) and relevant literature collected and reviewed.

Results and conclusion

RAGE is an inflammation-perpetuating receptor with a diverse range of ligands. Evidence supporting a role of the RAGE axis in the pathogenesis of systemic inflammation, ALI and myocardial dysfunction is compelling with numerous animal experiments showing the beneficial effects of inhibiting the RAGE axis. Despite a number of unanswered questions that need to be further addressed, the potential for inhibiting RAGE-mediated inflammation in humans undoubtedly exists.

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 29:1303–1310PubMedCrossRef

Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S, Gruendling M, Huhle G, Jaschinski U, John S, Mayer K, Oppert M, Olthoff D, Quintel M, Ragaller M, Rossaint R, Stuber F, Weiler N, Welte T, Bogatsch H, Hartog C, Loeffler M, Reinhart K (2007) Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med 33:606–618PubMedCrossRef

Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D (2006) Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 34:344–353PubMedCrossRef

Brun-Buisson C (2000) The epidemiology of the systemic inflammatory response. Intensive Care Med 26(Suppl 1):S64–S74PubMedCrossRef

Dulhunty JM, Lipman J, Finfer S (2008) Does severe non-infectious SIRS differ from severe sepsis? Results from a multi-centre Australian and New Zealand intensive care unit study. Intensive Care Med 34:1654–1661PubMedCrossRef

Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med 342:1334–1349PubMedCrossRef

Vieillard-Baron A, Caille V, Charron C, Belliard G, Page B, Jardin F (2008) Actual incidence of global left ventricular hypokinesia in adult septic shock. Crit Care Med 36:1701–1706PubMedCrossRef

Williams TA, Dobb GJ, Finn JC, Knuiman MW, Geelhoed E, Lee KY, Webb SA (2008) Determinants of long-term survival after intensive care. Crit Care Med 36:1523–1530PubMedCrossRef

Webster NR, Galley HF (2009) Immunomodulation in the critically ill. Br J Anaesth 103:70–81PubMedCrossRef

10.

Schmidt AM, Yan SD, Yan SF, Stern DM (2000) The biology of the receptor for advanced glycation end products and its ligands. Biochim Biophys Acta 1498:99–111PubMedCrossRef

11.

Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A (1992) Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 267:14998–15004PubMed

12.

Yan SF, Ramasamy R, Schmidt AM (2010) Soluble RAGE: therapy and biomarker in unraveling the RAGE axis in chronic disease and aging. Biochem Pharmacol 79:1379–1386PubMedCrossRef

13.

Buckley ST, Ehrhardt C (2010) The receptor for advanced glycation end products (RAGE) and the lung. J Biomed Biotechnol 2010:917108PubMed

14.

Gefter JV, Shaufl AL, Fink MP, Delude RL (2009) Comparison of distinct protein isoforms of the receptor for advanced glycation end-products expressed in murine tissues and cell lines. Cell Tissue Res 337:79–89PubMedCrossRef

15.

Galichet A, Weibel M, Heizmann CW (2008) Calcium-regulated intramembrane proteolysis of the RAGE receptor. Biochem Biophys Res Commun 370:1–5PubMedCrossRef

16.

Raucci A, Cugusi S, Antonelli A, Barabino SM, Monti L, Bierhaus A, Reiss K, Saftig P, Bianchi ME (2008) A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). FASEB J 22:3716–3727PubMedCrossRef

17.

Brown LF, Fraser CG (2008) Assay validation and biological variation of serum receptor for advanced glycation end-products. Ann Clin Biochem 45:518–519PubMedCrossRef

18.

Yamagishi S, Adachi H, Nakamura K, Matsui T, Jinnouchi Y, Takenaka K, Takeuchi M, Enomoto M, Furuki K, Hino A, Shigeto Y, Imaizumi T (2006) Positive association between serum levels of advanced glycation end products and the soluble form of receptor for advanced glycation end products in nondiabetic subjects. Metabolism 55:1227–1231PubMedCrossRef

19.

Santilli F, Vazzana N, Bucciarelli LG, Davi G (2009) Soluble forms of RAGE in human diseases: clinical and therapeutical implications. Curr Med Chem 16:940–952PubMedCrossRef

20.

Leclerc E, Fritz G, Vetter SW, Heizmann CW (2009) Binding of S100 proteins to RAGE: an update. Biochim Biophys Acta 1793:993–1007PubMedCrossRef

21.

Donato R (1999) Functional roles of S100 proteins, calcium-binding proteins of the EF-hand type. Biochim Biophys Acta 1450:191–231PubMedCrossRef

22.

Deloulme JC, Gentil BJ, Baudier J (2003) Monitoring of S100 homodimerization and heterodimeric interactions by the yeast two-hybrid system. Microsc Res Tech 60:560–568PubMedCrossRef

23.

Vogl T, Tenbrock K, Ludwig S, Leukert N, Ehrhardt C, van Zoelen MA, Nacken W, Foell D, van der Poll T, Sorg C, Roth J (2007) Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med 13:1042–1049PubMedCrossRef

24.

Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251PubMedCrossRef

25.

Fink MP (2007) Bench-to-bedside review: high-mobility group box 1 and critical illness. Crit Care 11:229PubMedCrossRef

26.

Kokkola R, Andersson A, Mullins G, Ostberg T, Treutiger CJ, Arnold B, Nawroth P, Andersson U, Harris RA, Harris HE (2005) RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages. Scand J Immunol 61:1–9PubMedCrossRef

27.

Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279:7370–7377PubMedCrossRef

28.

Lotze MT, Tracey KJ (2005) High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 5:331–342PubMedCrossRef

29.

Bianchi ME (2009) HMGB1 loves company. J Leukoc Biol 86:573–576PubMedCrossRef

30.

Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, Parroche P, Drabic S, Golenbock D, Sirois C, Hua J, An LL, Audoly L, La Rosa G, Bierhaus A, Naworth P, Marshak-Rothstein A, Crow MK, Fitzgerald KA, Latz E, Kiener PA, Coyle AJ (2007) Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 8:487–496PubMedCrossRef

31.

Rauvala H (2007) Interview with Dr. Heikki Rauvala regarding pivotal advance: analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 (amphoterin). Interview by Marco E Bianchi. J Leukoc Biol 81:46–48PubMed

32.

Tsan MF, Baochong G (2007) Pathogen-associated molecular pattern contamination as putative endogenous ligands of Toll-like receptors. J Endotoxin Res 13:6–14PubMedCrossRef

33.

Smit AJ, Lutgers HL (2004) The clinical relevance of advanced glycation endproducts (AGE) and recent developments in pharmaceutics to reduce AGE accumulation. Curr Med Chem 11:2767–2784PubMed

34.

Anderson MM, Requena JR, Crowley JR, Thorpe SR, Heinecke JW (1999) The myeloperoxidase system of human phagocytes generates Nepsilon-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation. J Clin Invest 104:103–113PubMedCrossRef

35.

Yan SF, Ramasamy R, Schmidt AM (2008) Mechanisms of disease: advanced glycation end-products and their receptor in inflammation and diabetes complications. Nat Clin Pract Endocrinol Metab 4:285–293PubMedCrossRef

36.

Collison KS, Parhar RS, Saleh SS, Meyer BF, Kwaasi AA, Hammami MM, Schmidt AM, Stern DM, Al-Mohanna FA (2002) RAGE-mediated neutrophil dysfunction is evoked by advanced glycation end products (AGEs). J Leukoc Biol 71:433–444PubMed

37.

Takahashi HK, Mori S, Wake H, Liu K, Yoshino T, Ohashi K, Tanaka N, Shikata K, Makino H, Nishibori M (2009) Advanced glycation end products subspecies-selectively induce adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells. J Pharmacol Exp Ther 330:89–98PubMedCrossRef

38.

Buetler TM, Leclerc E, Baumeyer A, Latado H, Newell J, Adolfsson O, Parisod V, Richoz J, Maurer S, Foata F, Piguet D, Junod S, Heizmann CW, Delatour T (2008) N(epsilon)-carboxymethyllysine-modified proteins are unable to bind to RAGE and activate an inflammatory response. Mol Nutr Food Res 52:370–378PubMedCrossRef

39.

Valencia JV, Mone M, Koehne C, Rediske J, Hughes TE (2004) Binding of receptor for advanced glycation end products (RAGE) ligands is not sufficient to induce inflammatory signals: lack of activity of endotoxin-free albumin-derived advanced glycation end products. Diabetologia 47:844–852PubMedCrossRef

40.

Thornalley PJ, Battah S, Ahmed N, Karachalias N, Agalou S, Babaei-Jadidi R, Dawnay A (2003) Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry. Biochem J 375:581–592PubMedCrossRef

41.

Yan SD, Zhu H, Zhu A, Golabek A, Du H, Roher A, Yu J, Soto C, Schmidt AM, Stern D, Kindy M (2000) Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat Med 6:643–651PubMedCrossRef

42.

Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691PubMedCrossRef

43.

Chavakis T, Bierhaus A, Al-Fakhri N, Schneider D, Witte S, Linn T, Nagashima M, Morser J, Arnold B, Preissner KT, Nawroth PP (2003) The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med 198:1507–1515PubMedCrossRef

44.

Aleshin A, Ananthakrishnan R, Li Q, Rosario R, Lu Y, Qu W, Song F, Bakr S, Szabolcs M, D’Agati V, Liu R, Homma S, Schmidt AM, Yan SF, Ramasamy R (2008) RAGE modulates myocardial injury consequent to LAD infarction via impact on JNK and STAT signaling in a murine model. Am J Physiol Heart Circ Physiol 294:H1823–H1832PubMedCrossRef

45.

Ghavami S, Rashedi I, Dattilo BM, Eshraghi M, Chazin WJ, Hashemi M, Wesselborg S, Kerkhoff C, Los M (2008) S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J Leukoc Biol 83:1484–1492PubMedCrossRef

46.

Yeh CH, Sturgis L, Haidacher J, Zhang XN, Sherwood SJ, Bjercke RJ, Juhasz O, Crow MT, Tilton RG, Denner L (2001) Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. Diabetes 50:1495–1504PubMedCrossRef

47.

Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Kloting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt A-M, Stern DM, Haring H-U, Schleicher E, Nawroth PP (2001) Diabetes-associated sustained activation of the transcription factor nuclear factor κB. Diabetes 50:2792–2808PubMedCrossRef

48.

Liliensiek B, Weigand MA, Bierhaus A, Nicklas W, Kasper M, Hofer S, Plachky J, Grone HJ, Kurschus FC, Schmidt AM, Yan SD, Martin E, Schleicher E, Stern DM, Hammerling GG, Nawroth PP, Arnold B (2004) Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. J Clin Invest 113:1641–1650PubMed

49.

Lutterloh EC, Opal SM, Pittman DD, Keith JC Jr, Tan XY, Clancy BM, Palmer H, Milarski K, Sun Y, Palardy JE, Parejo NA, Kessimian N (2007) Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection. Crit Care 11:R122PubMedCrossRef

50.

Zhu S, Ashok M, Li J, Li W, Yang H, Wang P, Tracey KJ, Sama AE, Wang H (2009) Spermine protects mice against lethal sepsis partly by attenuating surrogate inflammatory markers. Mol Med 15:275–282PubMed

51.

Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, Susarla SM, Ulloa L, Wang H, DiRaimo R, Czura CJ, Roth J, Warren HS, Fink MP, Fenton MJ, Andersson U, Tracey KJ (2004) Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A 101:296–301PubMedCrossRef

52.

Ulloa L, Ochani M, Yang H, Tanovic M, Halperin D, Yang R, Czura CJ, Fink MP, Tracey KJ (2002) Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci U S A 99:12351–12356PubMedCrossRef

53.

van Zoelen MA, Schouten M, de Vos AF, Florquin S, Meijers JC, Nawroth PP, Bierhaus A, van der Poll T (2009) The receptor for advanced glycation end products impairs host defense in pneumococcal pneumonia. J Immunol 182:4349–4356PubMedCrossRef

54.

van Zoelen MA, van der Sluijs KF, Achouiti A, Florquin S, Braun-Pater JM, Yang H, Nawroth PP, Tracey KJ, Bierhaus A, van der Poll T (2009) Receptor for advanced glycation end products is detrimental during influenza A virus pneumonia. Virology 391:265–273PubMedCrossRef

55.

Raman KG, Sappington PL, Yang R, Levy RM, Prince JM, Liu S, Watkins SK, Schmidt AM, Billiar TR, Fink MP (2006) The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock. Am J Physiol Gastrointest Liver Physiol 291:556–565CrossRef

56.

van Zoelen MA, Vogl T, Foell D, Van Veen SQ, van Till JW, Florquin S, Tanck MW, Wittebole X, Laterre PF, Boermeester MA, Roth J, van der Poll T (2009) Expression and role of myeloid-related protein-14 in clinical and experimental sepsis. Am J Respir Crit Care Med 180:1098–1106PubMedCrossRef

57.

Levy RM, Mollen KP, Prince JM, Kaczorowski DJ, Vallabhaneni R, Liu S, Tracey KJ, Lotze MT, Hackam DJ, Fink MP, Vodovotz Y, Billiar TR (2007) Systemic inflammation and remote organ injury following trauma require HMGB1. Am J Physiol Regul Integr Comp Physiol 293:R1538–R1544PubMed

58.

Sawa H, Ueda T, Takeyama Y, Yasuda T, Shinzeki M, Nakajima T, Kuroda Y (2006) Blockade of high mobility group box-1 protein attenuates experimental severe acute pancreatitis. World J Gastroenterol 12:7666–7670PubMed

59.

Yang R, Harada T, Mollen KP, Prince JM, Levy RM, Englert JA, Gallowitsch-Puerta M, Yang L, Yang H, Tracey KJ, Harbrecht BG, Billiar TR, Fink MP (2006) Anti-HMGB1 neutralizing antibody ameliorates gut barrier dysfunction and improves survival after hemorrhagic shock. Mol Med 12:105–114PubMedCrossRef

60.

Wang H, Ward MF, Sama AE (2009) Novel HMGB1-inhibiting therapeutic agents for experimental sepsis. Shock 32:348–357PubMedCrossRef

61.

Cai B, Chen F, Lin X, Miller E, Szabo C, Deitch EA, Ulloa L (2009) Anti-inflammatory adjuvant in resuscitation fluids improves survival in hemorrhage. Crit Care Med 37:860–868PubMedCrossRef

62.

Yang ZY, Ling Y, Yin T, Tao J, Xiong JX, Wu HS, Wang CY (2008) Delayed ethyl pyruvate therapy attenuates experimental severe acute pancreatitis via reduced serum high mobility group box 1 levels in rats. World J Gastroenterol 14:4546–4550PubMedCrossRef

63.

Humpert PM, Lukic IK, Thorpe SR, Hofer S, Awad EM, Andrassy M, Deemer EK, Kasper M, Schleicher E, Schwaninger M, Weigand MA, Nawroth PP, Bierhaus A (2009) AGE-modified albumin containing infusion solutions boosts septicaemia and inflammation in experimental peritonitis. J Leukoc Biol 86:589–597PubMedCrossRef

64.

Soop A, Sunden-Cullberg J, Albert J, Hallstrom L, Treutiger CJ, Sollevi A (2009) Adenosine infusion attenuates sRAGE in endotoxin-induced inflammation in human volunteers. Acta Physiol (Oxf) 197:47–53CrossRef

65.

Bopp C, Hofer S, Weitz J, Bierhaus A, Nawroth PP, Martin E, Buchler MW, Weigand MA (2008) sRAGE is elevated in septic patients and associated with patients outcome. J Surg Res 147:79–83PubMedCrossRef

66.

Kocsis AK, Szabolcs A, Hofner P, Takacs T, Farkas G, Boda K, Mandi Y (2009) Plasma concentrations of high-mobility group box protein 1, soluble receptor for advanced glycation end-products and circulating DNA in patients with acute pancreatitis. Pancreatology 9:383–391PubMedCrossRef

67.

Calfee CS, Ware LB, Eisner MD, Parsons PE, Thompson BT, Wickersham N, Matthay MA (2008) Plasma receptor for advanced glycation end-products and clinical outcomes in acute lung injury. Thorax 63:1083–1089PubMedCrossRef

68.

Determann RM, Wolthuis EK, Choi G, Bresser P, Bernard A, Lutter R, Schultz MJ (2008) Lung epithelial injury markers are not influenced by use of lower tidal volumes during elective surgery in patients without preexisting lung injury. Am J Physiol Lung Cell Mol Physiol 294:L344–L350PubMedCrossRef

69.

Creagh-Brown B, Hector L, Lagan A, Burke-Gaffney A, Quinlan G, Evans T (2009) RAGE ligands are implicated in the development of sirs after surgery necessitating cardiopulmonary bypass. Am J Respir Crit Care Med 179:A1163

70.

Makam M, Diaz D, Laval J, Gernez Y, Conrad CK, Dunn CE, Davies ZA, Moss RB, Herzenberg LA, Tirouvanziam R (2009) Activation of critical, host-induced, metabolic and stress pathways marks neutrophil entry into cystic fibrosis lungs. Proc Natl Acad Sci U S A 106:5779–5783PubMedCrossRef

71.

Angus DC, Yang L, Kong L, Kellum JA, Delude RL, Tracey KJ, Weissfeld L (2007) Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis. Crit Care Med 35:1061–1067PubMedCrossRef

72.

Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G, Tracey KJ, Lee ML, Andersson J, Tokics L, Treutiger CJ (2005) Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med 33:564–573PubMedCrossRef

73.

Peltz E, Moore E, Eckels PC, Damle SS, Tsuruta Y, Johnson JL, Sauaia A, Silliman CC, Banerjee A, Abraham E (2009) HMGB1 is markedly elevated within six hours of mechanical trauma in humans. Shock 32:17–22PubMedCrossRef

74.

Gaini S, Pedersen SS, Koldkjaer OG, Pedersen C, Moller HJ (2007) High mobility group box-1 protein in patients with suspected community-acquired infections and sepsis: a prospective study. Crit Care 11:R32PubMedCrossRef

75.

Gibot S, Massin F, Cravoisy A, Barraud D, Nace L, Levy B, Bollaert PE (2007) High-mobility group box 1 protein plasma concentrations during septic shock. Intensive Care Med 33:1347–1353PubMedCrossRef

76.

Karlsson S, Pettila V, Tenhunen J, Laru-Sompa R, Hynninen M, Ruokonen E (2008) HMGB1 as a predictor of organ dysfunction and outcome in patients with severe sepsis. Intensive Care Med 34:1046–1053PubMedCrossRef

77.

Alleva LM, Yang H, Tracey KJ, Clark IA (2005) High mobility group box 1 (HMGB1) protein: possible amplification signal in the pathogenesis of falciparum malaria. Trans R Soc Trop Med Hyg 99:171–174PubMedCrossRef

78.

Ombrellino M, Wang H, Ajemian MS, Talhouk A, Scher LA, Friedman SG, Tracey KJ (1999) Increased serum concentrations of high-mobility-group protein 1 in haemorrhagic shock. Lancet 354:1446–1447PubMedCrossRef

79.

Lantos J, Foldi V, Roth E, Weber G, Bogar L, Csontos C (2009) Burn trauma induces early Hmgb1 release in patients: its correlation with cytokines. Shock 33:562–567

80.

Hatada T, Wada H, Nobori T, Okabayashi K, Maruyama K, Abe Y, Uemoto S, Yamada S, Maruyama I (2005) Plasma concentrations and importance of high mobility group box protein in the prognosis of organ failure in patients with disseminated intravascular coagulation. Thromb Haemost 94:975–979PubMed

81.

van Zoelen MA, Laterre PF, van Veen SQ, van Till JW, Wittebole X, Bresser P, Tanck MW, Dugernier T, Ishizaka A, Boermeester MA, van der Poll T (2007) Systemic and local high mobility group box 1 concentrations during severe infection. Crit Care Med 35:2799–2804PubMedCrossRef

82.

Nguyen D, Spapen H, Schiettecatte J, Delvaux R, Hubloue I, Huyghens L (2007) S100B protein: a biomarker of organ dysfunction in patients with severe sepsis and septic shock? In: Proceedings of American Thoracic Society, San Francisco (abstract A441)

83.

Nguyen DN, Spapen H, Su F, Schiettecatte J, Shi L, Hachimi-Idrissi S, Huyghens L (2006) Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock. Crit Care Med 34:1967–1974PubMedCrossRef

84.

Unden J, Bellner J, Eneroth M, Alling C, Ingebrigtsen T, Romner B (2005) Raised serum S100B levels after acute bone fractures without cerebral injury. J Trauma 58:59–61PubMedCrossRef

85.

Rasmussen LS, Christiansen M, Eliasen K, Sander-Jensen K, Moller JT (2002) Biochemical markers for brain damage after cardiac surgery—time profile and correlation with cognitive dysfunction. Acta Anaesthesiol Scand 46:547–551PubMedCrossRef

86.

Mazzini GS, Schaf DV, Vinade ER, Horowitz E, Bruch RS, Brunm LM, Goncalves CA, Bacal F, Souza DO, Portela LV, Bordignon S (2007) Increased S100B serum levels in dilated cardiomyopathy patients. J Card Fail 13:850–854PubMedCrossRef

87.

Leonard S, Watts A, Parmar K, Wendon J, Hunt B (1999) Serum S100 as a marker of cerebral injury in acute liver failure (ALF) and during orthotopic liver transplantation (OLT). Crit Care 3:P223

88.

Foell D, Roth J (2004) Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum 50:3762–3771PubMedCrossRef

89.

Sander J, Fagerhol MK, Bakken JS, Dale I (1984) Plasma levels of the leucocyte L1 protein in febrile conditions: relation to aetiology, number of leucocytes in blood, blood sedimentation reaction and C-reactive protein. Scand J Clin Lab Invest 44:357–362PubMedCrossRef

90.

Boelke E, Storck M, Buttenschoen K, Berger D, Hannekum A (2000) Endotoxemia and mediator release during cardiac surgery. Angiology 51:743–749PubMedCrossRef

91.

Payen D, Lukaszewicz AC, Belikova I, Faivre V, Gelin C, Russwurm S, Launay JM, Sevenet N (2008) Gene profiling in human blood leucocytes during recovery from septic shock. Intensive Care Med 34:1371–1376PubMedCrossRef

92.

Hofmann MA, Drury S, Hudson BI, Gleason MR, Qu W, Lu Y, Lalla E, Chitnis S, Monteiro J, Stickland MH, Bucciarelli LG, Moser B, Moxley G, Itescu S, Grant PJ, Gregersen PK, Stern DM, Schmidt AM (2002) RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response. Genes Immun 3:123–135PubMedCrossRef

93.

Kornblit B, Munthe-Fog L, Madsen HO, Strom J, Vindelov L, Garred P (2008) Association of HMGB1 polymorphisms with outcome in patients with systemic inflammatory response syndrome. Crit Care 12:R83PubMedCrossRef

94.

Uchida T, Shirasawa M, Ware LB, Kojima K, Hata Y, Makita K, Mednick G, Matthay ZA, Matthay MA (2006) Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med 173:1008–1015PubMedCrossRef

95.

Su X, Looney MR, Gupta N, Matthay MA (2009) Receptor for advanced glycation end-products (RAGE) is an indicator of direct lung injury in models of experimental lung injury. Am J Physiol Lung Cell Mol Physiol 297:L1–L5PubMedCrossRef

96.

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

97.

Zhang H, Tasaka S, Shiraishi Y, Fukunaga K, Yamada W, Seki H, Ogawa Y, Miyamoto K, Nakano Y, Hasegawa N, Miyasho T, Maruyama I, Ishizaka A (2008) Role of soluble receptor for advanced glycation end products on endotoxin-induced lung injury. Am J Respir Crit Care Med 178:356–362PubMedCrossRef

98.

Hagiwara S, Iwasaka H, Hasegawa A, Koga H, Noguchi T (2008) Effects of hyperglycemia and insulin therapy on high mobility group box 1 in endotoxin-induced acute lung injury in a rat model. Crit Care Med 36:2407–2413PubMedCrossRef

99.

Sternberg DI, Gowda R, Mehra D, Qu W, Weinberg A, Twaddell W, Sarkar J, Wallace A, Hudson B, D’Ovidio F, Arcasoy S, Ramasamy R, D’Armiento J, Schmidt AM, Sonett JR (2008) Blockade of receptor for advanced glycation end product attenuates pulmonary reperfusion injury in mice. J Thorac Cardiovasc Surg 136:1576–1585PubMedCrossRef

100.

Ogawa EN, Ishizaka A, Tasaka S, Koh H, Ueno H, Amaya F, Ebina M, Yamada S, Funakoshi Y, Soejima J, Moriyama K, Kotani T, Hashimoto S, Morisaki H, Abraham E, Takeda J (2006) Contribution of high-mobility group box-1 to the development of ventilator-induced lung injury. Am J Respir Crit Care Med 174:400–407PubMedCrossRef

101.

Calfee CS, Budev MM, Matthay MA, Church G, Brady S, Uchida T, Ishizaka A, Lara A, Ranes JL, deCamp MM, Arroliga AC (2007) Plasma receptor for advanced glycation end-products predicts duration of ICU stay and mechanical ventilation in patients after lung transplantation. J Heart Lung Transplant 26:675–680PubMedCrossRef

102.

Briot R, Frank JA, Uchida T, Lee JW, Calfee CS, Matthay MA (2009) Elevated levels of the receptor for advanced glycation end products, a marker of alveolar epithelial type I cell injury, predict impaired alveolar fluid clearance in isolated perfused human lungs. Chest 135:269–275PubMedCrossRef

103.

Wittkowski H, Sturrock A, van Zoelen MA, Viemann D, van der Poll T, Hoidal JR, Roth J, Foell D (2007) Neutrophil-derived S100A12 in acute lung injury and respiratory distress syndrome. Crit Care Med 35:1369–1375PubMedCrossRef

104.

Lorenz E, Muhlebach MS, Tessier PA, Alexis NE, Duncan Hite R, Seeds MC, Peden DB, Meredith W (2008) Different expression ratio of S100A8/A9 and S100A12 in acute and chronic lung diseases. Respir Med 102:567–573PubMedCrossRef

105.

van Zoelen MA, Ishizaka A, Wolthuls EK, Choi G, van der Poll T, Schultz MJ (2008) Pulmonary levels of high-mobility group box 1 during mechanical ventilation and ventilator-associated pneumonia. Shock 29:441–445PubMed

106.

Boyd JH, Kan B, Roberts H, Wang Y, Walley KR (2008) S100A8 and S100A9 mediate endotoxin-induced cardiomyocyte dysfunction via the receptor for advanced glycation end products. Circ Res 102:1239–1246PubMedCrossRef

107.

Tzeng H-P, Fan J, Vallejo JG, Dong JW, Chen X, Houser SR, Mann DL (2008) Negative inotropic effects of high-mobility group box 1 protein in isolated contracting cardiac myocytes. Am J Physiol Heart Circ Physiol 294:H1490–H1496PubMedCrossRef

108.

Xu H, Su Z, Wu J, Yang M, Penninger JM, Martin CM, Kvietys PR, Rui T (2010) The alarmin cytokine, high mobility group box 1, is produced by viable cardiomyocytes and mediates the lipopolysaccharide-induced myocardial dysfunction via a TLR4/phosphatidylinositol 3-kinase gamma pathway. J Immunol 184:1492–1498PubMedCrossRef

109.

Hagiwara S, Iwasaka H, Hasegawa A, Asai N, Noguchi T (2009) Hyperglycemia contributes to cardiac dysfunction in a lipopolysaccharide-induced systemic inflammation model. Crit Care Med 37:2223–2227PubMedCrossRef

110.

Ince CP, Sinaasappel MP (1999) Microcirculatory oxygenation and shunting in sepsis and shock. Crit Care Med 27:1369–1377PubMedCrossRef

111.

Andrassy M, Volz HC, Igwe JC, Funke B, Eichberger SN, Kaya Z, Buss S, Autschbach F, Pleger ST, Lukic IK, Bea F, Hardt SE, Humpert PM, Bianchi ME, Mairbaurl H, Nawroth PP, Remppis A, Katus HA, Bierhaus A (2008) High-mobility group box-1 in ischemia-reperfusion injury of the heart. Circulation 117:3216–3226PubMedCrossRef

112.

Bucciarelli LG, Ananthakrishnan R, Hwang YC, Kaneko M, Song F, Sell DR, Strauch C, Monnier VM, Yan SF, Schmidt AM, Ramasamy R (2008) RAGE and modulation of ischemic injury in the diabetic myocardium. Diabetes 57:1941–1951PubMedCrossRef

113.

Rittirsch D, Hoesel LM, Ward PA (2007) The disconnect between animal models of sepsis and human sepsis. J Leukoc Biol 81:137–143PubMedCrossRef

114.

van Zoelen MA, Schmidt AM, Florquin S, Meijers JC, de Beer R, de Vos AF, Nawroth PP, Bierhaus A, van der Poll T (2009) Receptor for advanced glycation end products facilitates host defense during Escherichia coli-induced abdominal sepsis in mice. J Infect Dis 200:765–773PubMedCrossRef

115.

Pullerits R, Brisslert M, Jonsson IM, Tarkowski A (2006) Soluble receptor for advanced glycation end products triggers a proinflammatory cytokine cascade via beta2 integrin Mac-1. Arthritis Rheum 54:3898–3907PubMedCrossRef

116.

Unsinger J, McDonough JS, Shultz LD, Ferguson TA, Hotchkiss RS (2009) Sepsis-induced human lymphocyte apoptosis and cytokine production in “humanized” mice. J Leukoc Biol 86:219–227PubMedCrossRef

117.

Su J, Li X, Cui X, Li Y, Fitz Y, Hsu L, Mani H, Quezado M, Eichacker PQ (2008) Ethyl pyruvate decreased early nuclear factor-kappaB levels but worsened survival in lipopolysaccharide-challenged mice. Crit Care Med 36:1059–1067PubMedCrossRef

Title: The RAGE axis in systemic inflammation, acute lung injury and myocardial dysfunction: an important therapeutic target?
Authors: Benedict C. Creagh-Brown
Gregory J. Quinlan
Timothy W. Evans
Anne Burke-Gaffney
Publication date: 01-10-2010
Publisher: Springer-Verlag
Published in: Intensive Care Medicine / Issue 10/2010
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-010-1952-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The RAGE axis in systemic inflammation, acute lung injury and myocardial dysfunction: an important therapeutic target?

Abstract

Background

Purpose

Methods

Results and conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Purpose

Methods

Results and conclusion

Please log in to get access to this content

Other articles of this Issue 10/2010

Intensive care reimbursement practices: results from the ICUFUND survey

Selective decontamination of the digestive tract: selectivity is not required

Development and validation of a questionnaire for quantitative assessment of perceived discomforts in critically ill patients

Erratum to: A critical appraisal of the quality of critical care pharmacotherapy clinical practice guidelines and their strength of recommendations

Macrolide combination antibiotic therapy should be prudently considered in complicated CAP cases and in regions with low macrolide susceptibility

Do hypooncotic fluids for shock increase the risk of late-onset acute respiratory distress syndrome?