参考文献
1）Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20: 864–74.
2）Matsuda N, Hattori Y. Systemic inflammatory response syndrome (SIRS): molecular pathophysiology and gene therapy. J Pharmacol Sci 2006;101: 189-98.
3）Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-10.
4）Vincent JL, Taccone F, Schmit X. Classification, incidence, and outcomes of sepsis and multiple organ failure. Contrib Nephrol 2007;156:64-74.
5）Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858–73.
6）Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296-327.
7）柴田恵三, 舟田 久. 我が国におけるSIRS・sepsisの疫学. 日本臨牀 2004;62:2184-8.
8）Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996; 86:973-83.
9）Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci 2008;1143:1-20.
10）O'Neill LA. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol Rev 2008;226:10-8.
11）Frantz S, Ertl G, Bauersachs J. Mechanisms of disease: Toll-like receptors in cardiovascular disease. Nat Clin Pract Cardiovasc Med. 2007;4:444-54.
12）松田直之. 全身性炎症反応症候群とToll-like受容体シグナル -Alert Cell Strategy-. 循環制御2004; 25:276-84.
13）Matsuda N, Hattori Y. Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction. J Smooth Muscle Res 2007;43:117-37.
14）Cartwright N, Murch O, McMaster SK, Paul-Clark MJ, van Heel DA, Ryffel B, et al. Selective NOD1 agonists cause shock and organ injury/dysfunction in vivo. Am J Respir Crit Care Med 2007; 175:595-603.
15）Becker CE, O'neill LA. Inflammasomes in inflammatory disorders: the role of TLRs and their interactions with NLRs. Semin Immunopathol 2007; 29:239-48.
16）Shen HM, Pervaiz S. TNF receptor superfamily-induced cell death: redox-dependent execution. FASEB J 2006; 20:1589-98.
17）Boraschi D, Tagliabue A. The interleukin-1 receptor family. Vitam Horm 2006; 74:229-54.
18）Kishimoto T. IL-6: from laboratory to bedside. Clin Rev Allergy Immunol 2005;28:177-86.
19）Kanazawa N. Dendritic cell immunoreceptors: C-type lectin receptors for pattern-recognition and signaling on antigen-presenting cells. J Dermatol Sci 2007; 45:77-86.
20）Lutterloh EC, Opal SM. Antibodies against RAGE in sepsis and inflammation: implications for therapy. Expert Opin Pharmacother 2007; 8:1193-6.
21）Leger AJ, Covic L, Kuliopulos A. Protease-activated receptors in cardiovascular diseases. Circulation 2006; 114:1070-7.
22）Jesmin S, Gando S, Matsuda N, Sakuma I, Kobayashi S, Sakuraya F, et al. Temporal changes in pulmonary expression of key procoagulant molecules in rabbits with endotoxin-induced acute lung injury: elevated expression levels of protease-activated receptors. Thromb Haemost 2004;92:966-79.
23）Matsuda N, Hattori Y, Takahashi Y, Nishihira J, Jesmin S, Kobayashi M, et al. Therapeutic effect of in vivo transfection of transcription factor decoy to NF-κB on septic lung in mice. Am J Physiol Lung Cell Mol Physiol 2004;287: L1248-55.
24）Matsuda N, Hattori Y, Takahashi Y, Jesmin S, Gando S. Nuclear Factor-κB decoy oligonucleotides prevent acute lung injury in mice with cecal ligation and puncture-induced sepsis. Mol Pharmacol 2005;67:1018-25.
25）Matsuda N, Yamazaki H, Takano KI, Matsui K, Takano Y, Kemmotsu O, et al. Priming by lipopolysaccharide exaggerates acute lung injury and mortality in responses to peptidoglycan through up-regulation of Toll-like receptor-2 expression in mice. Biochem Pharmacol 2008;75:1065-75.
26）Matsuda N, Yamamoto S, Yokoo H, Tobe K, Hattori Y. Nuclear factor-κB decoy oligodeoxynucleotides ameliorate impaired glucose tolerance and insulin resistance in mice with cecal ligation and puncture-induced sepsis. Crit Care Med 2009 in press.
27）Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein NF-κB by a posttranslational mechanism. Cell 1986;47:921-8.
28）Chen LF, Greene WC. Shaping the nuclear action of NF-κB. Nat Rev Mol Cell Biol 2004;5:392-401.
29）Gross S, Piwnica-Worms D. Real-time imaging of ligand-induced IKK activation in intact cells and in living mice. Nat Methods 2005;2:607-14.
30）Bates PW, Miyamoto S. Expanded nuclear roles for IκBzeta. Sci STKE 2004;254:48.
31）Kamiyama K, Matsuda N, Yamamoto S, Takano K, Takano Y, Yamazaki H, et al. Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea-pig lungs using methylprednisolone. Am J Physiol Lung Cell Mol Physiol 2008;295:L998-1006.
32）Matsuda N，Takano Y，Kageyama S，Hatakeyama N，Shakunaga K，Kitajima I，et al. Silencing of caspase-8 and caspase-3 by RNA interference prevents vascular endothelial cell injury in mice with endotoxic shock. Cardiovasc Res 2007;76:132-40.
33）Matsuda N, Yamamoto S, Takano KI, Kageyama SI, Kurobe Y, Yoshiwara Y, et al. Silencing of Fas-associated Death Domain Protects Mice from Septic Lung Inflammation and Apoptosis. Am J Respir Crit Care Med 2009;79:806-15.
34）Ye X, Ding J, Zhou X, Chen G, Liu SF. Divergent roles of endothelial NF-κB in multiple organ injury and bacterial clearance in mouse models of sepsis. J Exp Med 2008;205:1303-15.
図 NF-κB活性化の古典的経路
Nuclear factor-κB（NF-κB）は，5種類のサブタイプからなるRel/ NF-κBファミリーの総称であり，非炎症病態ではI-κB（inhibitory κB）と結合し，核内移行が阻止され，細胞質内に存在する。敗血症などの全身性炎症病態では，Toll-like受容体，IL-1受容体，TNF受容体などの炎症性受容体の各リガンドとの反応により，IRAK（Interleukin-1 receptor-associated kinase），TRAF（tumor necrosis factor receptor –associated factor），TAK1（TGF-βactivated kinase 1）などのリン酸化酵素が活性化し，さらに細胞質内でIKK（inhibitory κB kinase）が活性化される。これにより，IKKのターゲット分子であるI-κBがリン酸化されると，I-κBは細胞質内でマルチユビキチン化を受け，細胞質内消化を受け，ペッドキャップ構造のとれた2量体NF-κBが核内へ移行し，DNA上のκB領域と結合することで炎症性分子の転写が高まる。NF-κBデコイ核酸を用いた遺伝子治療は，2量体NF-κBを補綴する2本鎖オリゴヌクレオチドとして作用し，細胞質内でDNA上のκB領域と競合し，NF-κB活性化を抑制する。
1）Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20: 864–74.
2）Matsuda N, Hattori Y. Systemic inflammatory response syndrome (SIRS): molecular pathophysiology and gene therapy. J Pharmacol Sci 2006;101: 189-98.
3）Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-10.
4）Vincent JL, Taccone F, Schmit X. Classification, incidence, and outcomes of sepsis and multiple organ failure. Contrib Nephrol 2007;156:64-74.
5）Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858–73.
6）Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296-327.
7）柴田恵三, 舟田 久. 我が国におけるSIRS・sepsisの疫学. 日本臨牀 2004;62:2184-8.
8）Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996; 86:973-83.
9）Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci 2008;1143:1-20.
10）O'Neill LA. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol Rev 2008;226:10-8.
11）Frantz S, Ertl G, Bauersachs J. Mechanisms of disease: Toll-like receptors in cardiovascular disease. Nat Clin Pract Cardiovasc Med. 2007;4:444-54.
12）松田直之. 全身性炎症反応症候群とToll-like受容体シグナル -Alert Cell Strategy-. 循環制御2004; 25:276-84.
13）Matsuda N, Hattori Y. Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction. J Smooth Muscle Res 2007;43:117-37.
14）Cartwright N, Murch O, McMaster SK, Paul-Clark MJ, van Heel DA, Ryffel B, et al. Selective NOD1 agonists cause shock and organ injury/dysfunction in vivo. Am J Respir Crit Care Med 2007; 175:595-603.
15）Becker CE, O'neill LA. Inflammasomes in inflammatory disorders: the role of TLRs and their interactions with NLRs. Semin Immunopathol 2007; 29:239-48.
16）Shen HM, Pervaiz S. TNF receptor superfamily-induced cell death: redox-dependent execution. FASEB J 2006; 20:1589-98.
17）Boraschi D, Tagliabue A. The interleukin-1 receptor family. Vitam Horm 2006; 74:229-54.
18）Kishimoto T. IL-6: from laboratory to bedside. Clin Rev Allergy Immunol 2005;28:177-86.
19）Kanazawa N. Dendritic cell immunoreceptors: C-type lectin receptors for pattern-recognition and signaling on antigen-presenting cells. J Dermatol Sci 2007; 45:77-86.
20）Lutterloh EC, Opal SM. Antibodies against RAGE in sepsis and inflammation: implications for therapy. Expert Opin Pharmacother 2007; 8:1193-6.
21）Leger AJ, Covic L, Kuliopulos A. Protease-activated receptors in cardiovascular diseases. Circulation 2006; 114:1070-7.
22）Jesmin S, Gando S, Matsuda N, Sakuma I, Kobayashi S, Sakuraya F, et al. Temporal changes in pulmonary expression of key procoagulant molecules in rabbits with endotoxin-induced acute lung injury: elevated expression levels of protease-activated receptors. Thromb Haemost 2004;92:966-79.
23）Matsuda N, Hattori Y, Takahashi Y, Nishihira J, Jesmin S, Kobayashi M, et al. Therapeutic effect of in vivo transfection of transcription factor decoy to NF-κB on septic lung in mice. Am J Physiol Lung Cell Mol Physiol 2004;287: L1248-55.
24）Matsuda N, Hattori Y, Takahashi Y, Jesmin S, Gando S. Nuclear Factor-κB decoy oligonucleotides prevent acute lung injury in mice with cecal ligation and puncture-induced sepsis. Mol Pharmacol 2005;67:1018-25.
25）Matsuda N, Yamazaki H, Takano KI, Matsui K, Takano Y, Kemmotsu O, et al. Priming by lipopolysaccharide exaggerates acute lung injury and mortality in responses to peptidoglycan through up-regulation of Toll-like receptor-2 expression in mice. Biochem Pharmacol 2008;75:1065-75.
26）Matsuda N, Yamamoto S, Yokoo H, Tobe K, Hattori Y. Nuclear factor-κB decoy oligodeoxynucleotides ameliorate impaired glucose tolerance and insulin resistance in mice with cecal ligation and puncture-induced sepsis. Crit Care Med 2009 in press.
27）Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein NF-κB by a posttranslational mechanism. Cell 1986;47:921-8.
28）Chen LF, Greene WC. Shaping the nuclear action of NF-κB. Nat Rev Mol Cell Biol 2004;5:392-401.
29）Gross S, Piwnica-Worms D. Real-time imaging of ligand-induced IKK activation in intact cells and in living mice. Nat Methods 2005;2:607-14.
30）Bates PW, Miyamoto S. Expanded nuclear roles for IκBzeta. Sci STKE 2004;254:48.
31）Kamiyama K, Matsuda N, Yamamoto S, Takano K, Takano Y, Yamazaki H, et al. Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea-pig lungs using methylprednisolone. Am J Physiol Lung Cell Mol Physiol 2008;295:L998-1006.
32）Matsuda N，Takano Y，Kageyama S，Hatakeyama N，Shakunaga K，Kitajima I，et al. Silencing of caspase-8 and caspase-3 by RNA interference prevents vascular endothelial cell injury in mice with endotoxic shock. Cardiovasc Res 2007;76:132-40.
33）Matsuda N, Yamamoto S, Takano KI, Kageyama SI, Kurobe Y, Yoshiwara Y, et al. Silencing of Fas-associated Death Domain Protects Mice from Septic Lung Inflammation and Apoptosis. Am J Respir Crit Care Med 2009;79:806-15.
34）Ye X, Ding J, Zhou X, Chen G, Liu SF. Divergent roles of endothelial NF-κB in multiple organ injury and bacterial clearance in mouse models of sepsis. J Exp Med 2008;205:1303-15.
図 NF-κB活性化の古典的経路
Nuclear factor-κB（NF-κB）は，5種類のサブタイプからなるRel/ NF-κBファミリーの総称であり，非炎症病態ではI-κB（inhibitory κB）と結合し，核内移行が阻止され，細胞質内に存在する。敗血症などの全身性炎症病態では，Toll-like受容体，IL-1受容体，TNF受容体などの炎症性受容体の各リガンドとの反応により，IRAK（Interleukin-1 receptor-associated kinase），TRAF（tumor necrosis factor receptor –associated factor），TAK1（TGF-βactivated kinase 1）などのリン酸化酵素が活性化し，さらに細胞質内でIKK（inhibitory κB kinase）が活性化される。これにより，IKKのターゲット分子であるI-κBがリン酸化されると，I-κBは細胞質内でマルチユビキチン化を受け，細胞質内消化を受け，ペッドキャップ構造のとれた2量体NF-κBが核内へ移行し，DNA上のκB領域と結合することで炎症性分子の転写が高まる。NF-κBデコイ核酸を用いた遺伝子治療は，2量体NF-κBを補綴する2本鎖オリゴヌクレオチドとして作用し，細胞質内でDNA上のκB領域と競合し，NF-κB活性化を抑制する。
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