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Erschienen in: Inflammation Research 11/2012

01.11.2012 | Original Research Paper

The effect of sRAGE-Fc fusion protein attenuates inflammation and decreases mortality in a murine cecal ligation and puncture model

verfasst von: Su Jin Jeong, Beom Jin Lim, Sungha Park, Donghoon Choi, Hye Won Kim, Nam Su Ku, Sang Hoon Han, Chang Oh Kim, Jun Yong Choi, Young Goo Song, June Myung Kim

Erschienen in: Inflammation Research | Ausgabe 11/2012

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Abstract

Objective

Inhibition of the receptor for advanced glycation end products (RAGE) may attenuate the systemic inflammatory response and ensuing severe sepsis. We report an investigation into the effect of soluble RAGE (sRAGE)-Fc fusion protein in severe sepsis induced by a cecal ligation and puncture (CLP) procedure.

Materials and methods

The experiment was performed using CLP control mice, mice treated with 0.5 or 1.0 μg sRAGE-Fc fusion protein, and sham surgery mice.

Results

Survival benefits over the CLP control group were evident (P = 0.036) in mice given 1.0 μg sRAGE-Fc fusion protein. In addition, the pulmonary inflammation score in the sRAGE-Fc fusion protein-treated group was significantly lower than that in the CLP control group (P < 0.05). Lung tissue in the sRAGE-Fc fusion protein-treated group revealed a significant decrease in the expression of inflammatory cytokines. Furthermore, levels of interleukin (IL)-1β and tumor necrosis factor-α were significantly lower in sRAGE-Fc fusion protein treated groups (P < 0.001). Moreover, IL-6 levels showed a significant difference between CLP control and sRAGE-Fc fusion protein treated groups (P < 0.01).

Conclusions

sRAGE-Fc fusion protein has beneficial effects in a standard murine model of polymicrobial, intra-abdominal severe sepsis.
Literatur
1.
Zurück zum Zitat Rice TW, Bernard GR. Therapeutic intervention and targets for sepsis. Annu Rev Med. 2005;56:225–8.PubMedCrossRef Rice TW, Bernard GR. Therapeutic intervention and targets for sepsis. Annu Rev Med. 2005;56:225–8.PubMedCrossRef
2.
Zurück zum Zitat Cross AS, Opal SM. A new paradigm for the treatment of sepsis: is it time to consider combination therapy? Ann Intern Med. 2003;138:502–5.PubMed Cross AS, Opal SM. A new paradigm for the treatment of sepsis: is it time to consider combination therapy? Ann Intern Med. 2003;138:502–5.PubMed
3.
Zurück zum Zitat Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem. 1992;267:14998–5004.PubMed Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem. 1992;267:14998–5004.PubMed
4.
Zurück zum Zitat Schmidt AM, Vianna M, Gerlach M, Brett J, Ryan J, Kao J, Esposito C, Hegarty H, Hurley W, Clauss M. Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. J Biol Chem. 1992;267:14987–97.PubMed Schmidt AM, Vianna M, Gerlach M, Brett J, Ryan J, Kao J, Esposito C, Hegarty H, Hurley W, Clauss M. Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. J Biol Chem. 1992;267:14987–97.PubMed
5.
Zurück zum Zitat Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, Nagashima M, Lundh ER, Vijay S, Nitecki D. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem. 1995;270:25752–61.PubMedCrossRef Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, Nagashima M, Lundh ER, Vijay S, Nitecki D. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem. 1995;270:25752–61.PubMedCrossRef
6.
Zurück zum Zitat Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999;97:889–901.PubMedCrossRef Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999;97:889–901.PubMedCrossRef
7.
Zurück zum Zitat Chavakis T, Bierhaus A, Al Fakhri N, Schneider D, Witte S, Linn T, Nagashima M, Morser J, Arnold B, Preissner KT, Nawroth P. The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med. 2003;198:1507–15.PubMedCrossRef Chavakis T, Bierhaus A, Al Fakhri N, Schneider D, Witte S, Linn T, Nagashima M, Morser J, Arnold B, Preissner KT, Nawroth P. The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med. 2003;198:1507–15.PubMedCrossRef
8.
Zurück zum Zitat Basta G, Lazzerini G, Massaro M, Simoncini T, Tanganelli P, Fu C, Kislinger T, Stern DM, Schmidt AM, De Caterina R. Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses. Circulation. 2002;105:816–22.PubMedCrossRef Basta G, Lazzerini G, Massaro M, Simoncini T, Tanganelli P, Fu C, Kislinger T, Stern DM, Schmidt AM, De Caterina R. Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses. Circulation. 2002;105:816–22.PubMedCrossRef
9.
Zurück zum Zitat Li J, Schmidt AM. Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J Biol Chem. 1997;272:16498–506.PubMedCrossRef Li J, Schmidt AM. Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J Biol Chem. 1997;272:16498–506.PubMedCrossRef
10.
Zurück zum Zitat Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM. Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem. 1997;272:17810–4.PubMedCrossRef Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM. Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem. 1997;272:17810–4.PubMedCrossRef
11.
Zurück zum Zitat Schmidt AM, Yan SD, Stern DM. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Investig. 2001;108:949–55.PubMed Schmidt AM, Yan SD, Stern DM. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Investig. 2001;108:949–55.PubMed
12.
Zurück zum Zitat Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, Stern D, Schmidt AM, D’Agati VD. Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol. 2000;11:1656–66.PubMed Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, Stern D, Schmidt AM, D’Agati VD. Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol. 2000;11:1656–66.PubMed
13.
Zurück zum Zitat Liliensiek B, Weigand MA, Bierhaus A, Nicklas W, Kasper M, Hofer S, Plachky J, Grne H, Kurschus FC, Schmidt AM, Du Yan S, Martin E, Schleicher E, Stern DM, Hämmerling GG, Nawroth P, Arnold B. Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. J Clin Investig. 2004;113:1641–50.PubMed Liliensiek B, Weigand MA, Bierhaus A, Nicklas W, Kasper M, Hofer S, Plachky J, Grne H, Kurschus FC, Schmidt AM, Du Yan S, Martin E, Schleicher E, Stern DM, Hämmerling GG, Nawroth P, Arnold B. Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. J Clin Investig. 2004;113:1641–50.PubMed
14.
Zurück zum Zitat Lutterloh EC, Opal SM, Pittman D, Keith JC, Tan X, Clancy BM, Palmer H, Milarski K, Sun Y, Palardy JE, Parejo NA, Kessimian N. Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection. Crit Care. 2007;11:R122–R. Lutterloh EC, Opal SM, Pittman D, Keith JC, Tan X, Clancy BM, Palmer H, Milarski K, Sun Y, Palardy JE, Parejo NA, Kessimian N. Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection. Crit Care. 2007;11:R122–R.
15.
Zurück zum Zitat Goldenberg MM. Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis. Clin Ther. 1999;21:75–87.PubMedCrossRef Goldenberg MM. Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis. Clin Ther. 1999;21:75–87.PubMedCrossRef
16.
Zurück zum Zitat Rittirsch D, HuberLang MS, Flierl MA, Ward PA. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protocol. 2009;4:31–6.PubMedCrossRef Rittirsch D, HuberLang MS, Flierl MA, Ward PA. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protocol. 2009;4:31–6.PubMedCrossRef
17.
Zurück zum Zitat Oliveira GP, Oliveira MB, Santos RS, Lima LD, Dias CM, Ab’ Saber AM, Teodoro WR, Capelozzi VL, Gomes RN, Bozza PT, Pelosi P, Rocco PR. Intravenous glutamine decreases lung and distal organ injury in an experimental model of abdominal sepsis. Crit Care. 2009;13:R74. Oliveira GP, Oliveira MB, Santos RS, Lima LD, Dias CM, Ab’ Saber AM, Teodoro WR, Capelozzi VL, Gomes RN, Bozza PT, Pelosi P, Rocco PR. Intravenous glutamine decreases lung and distal organ injury in an experimental model of abdominal sepsis. Crit Care. 2009;13:R74.
18.
Zurück zum Zitat Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. Nat Rev Drug Discov. 2005;4:854–65.PubMedCrossRef Buras JA, Holzmann B, Sitkovsky M. Animal models of sepsis: setting the stage. Nat Rev Drug Discov. 2005;4:854–65.PubMedCrossRef
19.
Zurück zum Zitat Orfanos SE, Mavrommati I, Korovesi I, Roussos C. Pulmonary endothelium in acute lung injury: from basic science to the critically ill. Intensive Care Med. 2004;30:1702–14.PubMedCrossRef Orfanos SE, Mavrommati I, Korovesi I, Roussos C. Pulmonary endothelium in acute lung injury: from basic science to the critically ill. Intensive Care Med. 2004;30:1702–14.PubMedCrossRef
20.
Zurück zum Zitat Huttunen HJ, Fages C, Rauvala H. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem. 1999;274:19919–24.PubMedCrossRef Huttunen HJ, Fages C, Rauvala H. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem. 1999;274:19919–24.PubMedCrossRef
21.
Zurück zum Zitat Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Klting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt AM, Stern DM, Hring HU, Schleicher E, Nawroth PP. Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. Diabetes. 2001;50:2792–808.PubMedCrossRef Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Klting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt AM, Stern DM, Hring HU, Schleicher E, Nawroth PP. Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB. Diabetes. 2001;50:2792–808.PubMedCrossRef
22.
Zurück zum Zitat Zen K, Chen CX, Chen Y, Wilton R, Liu Y. Receptor for advanced glycation endproducts mediates neutrophil migration across intestinal epithelium. J Immunol. 2007;178:2483–90.PubMed Zen K, Chen CX, Chen Y, Wilton R, Liu Y. Receptor for advanced glycation endproducts mediates neutrophil migration across intestinal epithelium. J Immunol. 2007;178:2483–90.PubMed
23.
Zurück zum Zitat Rasaiah VP, Malloy JL, Lewis JF, Veldhuizen RA. Early surfactant administration protects against lung dysfunction in a mouse model of ARDS. Am J Physiol. Lung Cell Mol Physiol. 2003;284:L783–L90. Rasaiah VP, Malloy JL, Lewis JF, Veldhuizen RA. Early surfactant administration protects against lung dysfunction in a mouse model of ARDS. Am J Physiol. Lung Cell Mol Physiol. 2003;284:L783–L90.
24.
Zurück zum Zitat Slutsky AS, Tremblay LN. Multiple system organ failure. Is mechanical ventilation a contributing factor? Am J Respir Crit Care Med. 1998;157:1721–5.PubMed Slutsky AS, Tremblay LN. Multiple system organ failure. Is mechanical ventilation a contributing factor? Am J Respir Crit Care Med. 1998;157:1721–5.PubMed
25.
Zurück zum Zitat van Zoelen MA, Schouten M, de Vos AF, Florquin S, Meijers JC, Nawroth P, Bierhaus A, van der Poll T. The receptor for advanced glycation end products impairs host defense in pneumococcal pneumonia. J Immunol. 2009;182:4349–56.PubMedCrossRef van Zoelen MA, Schouten M, de Vos AF, Florquin S, Meijers JC, Nawroth P, Bierhaus A, van der Poll T. The receptor for advanced glycation end products impairs host defense in pneumococcal pneumonia. J Immunol. 2009;182:4349–56.PubMedCrossRef
26.
Zurück zum Zitat van Zoelen MA, Schmidt A, Florquin S, Meijers JC, de Beer R, de Vos AF, Nawroth P, Bierhaus A, van der Poll T. Receptor for advanced glycation end products facilitates host defense during Escherichia coli-induced abdominal sepsis in mice. J Infect Dis. 2009;200:765–73.PubMedCrossRef van Zoelen MA, Schmidt A, Florquin S, Meijers JC, de Beer R, de Vos AF, Nawroth P, Bierhaus A, van der Poll T. Receptor for advanced glycation end products facilitates host defense during Escherichia coli-induced abdominal sepsis in mice. J Infect Dis. 2009;200:765–73.PubMedCrossRef
27.
Zurück zum Zitat Jo D, Liu D, Yao S, Collins RD, Hawiger J. Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis. Nat Med. 2005;11:892–8.PubMedCrossRef Jo D, Liu D, Yao S, Collins RD, Hawiger J. Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis. Nat Med. 2005;11:892–8.PubMedCrossRef
28.
Zurück zum Zitat Coornaert B, Carpentier I, Beyaert R. A20: central gatekeeper in inflammation and immunity. J Biol Chem. 2009;284:8217–21.PubMedCrossRef Coornaert B, Carpentier I, Beyaert R. A20: central gatekeeper in inflammation and immunity. J Biol Chem. 2009;284:8217–21.PubMedCrossRef
29.
Zurück zum Zitat Kang N, Yoon H, Lee Y, Won M, Chung MJ, Park J, Hur GM, Lee H, Park B. A20 attenuates allergic airway inflammation in mice. J Immunol. 2009;183:1488–95.PubMedCrossRef Kang N, Yoon H, Lee Y, Won M, Chung MJ, Park J, Hur GM, Lee H, Park B. A20 attenuates allergic airway inflammation in mice. J Immunol. 2009;183:1488–95.PubMedCrossRef
30.
Zurück zum Zitat Bopp C, Bierhaus A, Hofer S, Bouchon A, Nawroth P, Martin E, Weigand MA. Bench-to-bedside review: the inflammation-perpetuating pattern-recognition receptor RAGE as a therapeutic target in sepsis. Crit Care. 2008;12:201. Bopp C, Bierhaus A, Hofer S, Bouchon A, Nawroth P, Martin E, Weigand MA. Bench-to-bedside review: the inflammation-perpetuating pattern-recognition receptor RAGE as a therapeutic target in sepsis. Crit Care. 2008;12:201.
31.
Zurück zum Zitat Sorci G, Riuzzi F, Arcuri C, Giambanco I, Donato R. Amphoterin stimulates myogenesis and counteracts the antimyogenic factors basic fibroblast growth factor and S100B via RAGE binding. Mol Cell Biol. 2004;24:4880–94.PubMedCrossRef Sorci G, Riuzzi F, Arcuri C, Giambanco I, Donato R. Amphoterin stimulates myogenesis and counteracts the antimyogenic factors basic fibroblast growth factor and S100B via RAGE binding. Mol Cell Biol. 2004;24:4880–94.PubMedCrossRef
32.
Zurück zum Zitat van Zoelen MA, van der Poll T. Targeting RAGE in sepsis. Crit Care. 2008;12:103. van Zoelen MA, van der Poll T. Targeting RAGE in sepsis. Crit Care. 2008;12:103.
33.
Zurück zum Zitat Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ. HMG-1 as a mediator of acute lung inflammation. J Immunol. 2000;165:2950–4.PubMed Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ. HMG-1 as a mediator of acute lung inflammation. J Immunol. 2000;165:2950–4.PubMed
34.
Zurück zum Zitat Ueno H, Matsuda T, Hashimoto S, Amaya F, Kitamura Y, Tanaka M, Kobayashi A, Maruyama I, Yamada S, Hasegawa N, Soejima J, Koh H, Ishizaka A. Contributions of high mobility group box protein in experimental and clinical acute lung injury. Am J Respir Crit Care Med. 2004;170:1310–6.PubMedCrossRef Ueno H, Matsuda T, Hashimoto S, Amaya F, Kitamura Y, Tanaka M, Kobayashi A, Maruyama I, Yamada S, Hasegawa N, Soejima J, Koh H, Ishizaka A. Contributions of high mobility group box protein in experimental and clinical acute lung injury. Am J Respir Crit Care Med. 2004;170:1310–6.PubMedCrossRef
35.
Zurück zum Zitat 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. Role of soluble receptor for advanced glycation end products on endotoxin-induced lung injury. Am J Respir Crit Care Med. 2008;178:356–62.PubMedCrossRef 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. Role of soluble receptor for advanced glycation end products on endotoxin-induced lung injury. Am J Respir Crit Care Med. 2008;178:356–62.PubMedCrossRef
Metadaten
Titel
The effect of sRAGE-Fc fusion protein attenuates inflammation and decreases mortality in a murine cecal ligation and puncture model
verfasst von
Su Jin Jeong
Beom Jin Lim
Sungha Park
Donghoon Choi
Hye Won Kim
Nam Su Ku
Sang Hoon Han
Chang Oh Kim
Jun Yong Choi
Young Goo Song
June Myung Kim
Publikationsdatum
01.11.2012
Verlag
SP Birkhäuser Verlag Basel
Erschienen in
Inflammation Research / Ausgabe 11/2012
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-012-0518-7

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