Model / HMGB1 antagonist (reference) / Result
Arthritis / Anti-HMGB1 antibodies (S41–S44)
Recombinant HMGB1 A box (S41,S43)
Blockade of RAGE-signaling (S45)
Thrombomodulin (S46) / Reduced inflammation and tissue destruction
Neuropathic pain / Anti-HMGB1 antibodies (S47,S48) / Alleviation of pain.
Endotoxemia / Anti-HMGB1 antibodies (S49) Thrombomodulin (S50, S51) / Protection from lethality.
Sepsis / Anti-HMGB1 antibodies (S49,S52)
Recombinant HMGB1 A box (S53)
Blockade of RAGE-signaling (S54) / Improved survival (even after administration 24h after onset of disease) representing a uniquely wide therapeutic window.
Pancreatitis / Anti-HMGB1 antibodies (S55)
Recombinant HMGB1 A box (S56) / Decreased severity of pancreatitis.
Colitis / Anti-HMGB1 antibodies (S57,S58) / Reduced inflammation and tumor incidence
Hemorrhagic shock / Anti-HMGB1 antibodies (S59,S60) / Improved survival and reduced organ dysfunction.
Stroke / Anti-HMGB1 antibodies (S61,S62)
Recombinant HMGB1 A box (S62) / Marked neuroprotection and reduced magnitude of cell death.
Epilepsy / Recombinant HMGB1 A box (S63) / Anticonvulsant effects.
Ischemia-reperfusion injury / Anti-HMGB1 antibodies (S64)
Recombinant HMGB1 A box (S65) / Attenuation of shock and tissue damage and reduced cytokine release.
Atherosclerosis / Anti-HMGB1 antibodies (S66) / Prevention of disease development
Myocardial infarction / Anti-HMGB1 antibodies (S67) / Increased infarcts.
Recombinant HMGB1 A box (S65) / Attenuation of tissue damage.
Transplantation / Anti-HMGB1 antibodies (S68) / Enhances allograft survival.
Recombinant HMGB1 A box (S69) / Enhances allograft survival.
Respiratory disorders / Anti-HMGB1 antibodies (S70–S72)
Recombinant HMGB1 A box (S73) / Reduced inflammation and development of pulmonary fibrosis.
Acetaminophen-induced liver damage / Anti-HMGB1 antibodies (S74) / Improved survival.
Reduced hepatotoxicity.
Abbreviation: RAGE, receptor for advanced glycation end products.
S41.Kokkola, R. etal. Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis Rheum.48, 2052–2058 (2003).
S42.Hamada, T. etal. Extracellular high mobility group box chromosomal protein 1 is a coupling factor for hypoxia and inflammation in arthritis. Arthritis Rheum.58, 2675–2685 (2008).
S43.Östberg, T. etal. Protective targeting of high mobility group box chromosomal protein 1 in a spontaneous arthritis model. Arthritis Rheum.62, 2963–2972 (2010).
S44.Schierbeck, H. etal. Monoclonal anti-HMGB1.antibody protection in two experimental arthritis models. Mol. Med.17, 1039–1044 (2011).
S45.Hofmann, M.A. etal. RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response. Genes Immun.3, 123–135 (2002).
S46.Van de Wouwer, M. etal. The lectin-like domain of thrombomodulin interferes with complement activation and protects against arthritis. J.Thromb. Haemost.4, 1813–1824 (2006).
S47.Otoshi, K., Kikuchi, S., Kato, K., Sekiguchi, M., Konno, S. Anti-HMGB1 neutralization antibody improves pain-related behavior induced by application of autologous nucleus pulposus onto nerve roots in rats. Spine (PhilaPa 1976) 36, E692E698 (2011).
S48.Shibasaki, M. etal. Induction of high mobility group box1 in dorsal root ganglion contributes to pain hypersensitivity after peripheral nerve injury. Pain 149, 514–521 (2010).
S49.Wang, H. etal. HMG1 as a late mediator of endotoxin lethality in mice. Science285, 248–251 (1999).
S50.Abeyama, K. etal. The Nterminal domain of thrombomodulin sequesters high-mobility groupB1 protein, a novel antiinflammatory mechanism. J.Clin. Investig.115, 1267–1274 (2005).
S51.Nagato, M., Okamoto, K., Abe, Y., Higure, A., Yamaguchi, K. Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia. Crit. Care. Med.37, 2181–2186 (2009).
S52.Qin, S. etal. Role of HMGB1 in apoptosis-mediated sepsis lethality. J.Exp. Med.203, 1637–1642 (2006).
S53.Yang, H. etal. Reversing established sepsis with antagonists of endogenous high-mobility group Box1. Proc. Natl. Acad. Sci. USA101, 296–301 (2004).
S54.Lutterloh, E.C. etal. Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection. Crit. Care11, R122 (2007).
S55.Sawa, H. etal. Blockade of high mobility group box1 protein attenuates experimental severe acute pancreatitis. World J.Gastroenterol.12, 7666–7670 (2006).
S56.Yuan, H. etal. Protective effect of HMGB1 A box on organ injury of acute pancreatitis in mice. Pancreas38, 143–48 (2009).
S57.Maeda, S. etal. Essential roles of high-mobility group Box1 in the development of murine colitis and colitis-associated cancer. Biochem. Biophys. Res. Commun.360, 394–400 (2007).
S58.Yang, R. etal. Bile high-mobility group Box1 contributes to gut barrier dysfunction in experimental endotoxemia. Am. J.Physiol. Regul. Integr. Comp. Physiol.297, R362–R369(2009).
S59.Yang, R. etal. Anti-HMGB1 neutralizing antibody ameliorates gut barrier dysfunction and improves survival after hemorrhagic shock. Mol. Med.12, 105–114 (2006).
S60.Kim, J.Y. etal. HMGB1 contributes to the development of acute lung injury after hemorrhage. Am. J.Physiol. Lung Cell Mol. Physiol.288, L958L965 (2005).
S61.Liu, K. etal. Anti-high mobility group Box1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. FASEB J.21, 3904–3916 (2007).
S62.Muhammad, S. etal. The HMGB1 receptor RAGE mediates ischemic brain damage. J.Neurosci.28, 12023–12031 (2008).
S63.Maroso M.etal. Toll-like receptor 4 and high-mobility group box1 are involved in ictogenesis and can be targeted to reduce seizures. Nat. Med. 16, 413–419 (2010).
S64.Tsung, A. etal. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J.Exp. Med.201, 1135–1143 (2005).
S65.Andrassy, M. etal. High-mobility group box1 in ischemia-reperfusion injury of the heart. Circulation117, 3216–3226 (2008).
S66.Kanellakis, P. etal. High-mobility group box protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein edeficient mice. Arterioscler. Thromb. Vasc. Biol.31, 313–319 (2011).
S67.Oozawa, S. etal. Effects of HMGB1 on ischemia-reperfusion injury in the rat heart. Circ. J.72, 1178–1184 (2008).
S68.Gao, Q. etal. TLR4 mediates early graft failure after intraportal islet transplantation. Am. J.Transplant.10, 1588–1596 (2010).
S69.Huang Y.etal. Extracellular HMGB1 functions as an innate immune-mediator implicated in murine cardiac allograft acute rejection. Am. J.Transplant.7, 799–808 (2007).
S70.Abraham, E., Arcaroli, J., Carmody, A., Wang, H., Tracey, K.J. HMG1 as a mediator of acute lung inflammation. J.Immunol.165, 2950–2954 (2000).
S71.Ogawa, E.N. etal. Contribution of high-mobility group box1 to the development of ventilator-induced lung injury. Am. J.Respir. Crit. Care Med.174, 400–407 (2006).
S72.Ueno, H. etal. Contributions of high mobility group box protein in experimental and clinical acute lung injury. Am. J.Respir. Crit. Care Med.170, 1310–1316 (2004).
S73.Gong, Q. etal. Protective effect of antagonist of high-mobility group Box1 on lipopolysaccharide-induced acute lung injury in mice. Scand. J.Immunol.69, 29–35 (2009).
S74.Antoine, D.J., Williams, D.P., Kipar, A., Laverty, H., Park, B.K. Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatotoxicity. Mol. Med.16, 479–490 (2010).
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