熱傷後の複合免疫不全病態の解析とその対策

2012 年度 研究成果報告書

• 研究課題/領域番号: 22592027
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 救急医学
• 研究機関: 防衛医科大学校
• 研究代表者: 木下 学 防衛医科大学校, 医学教育部医学科専門課程, 准教授 (70531391)
• 研究分担者: 関 修司 防衛医科大学校, 医学教育部医学科専門課程, 教授 (80531392) ; 齋藤 大蔵 防衛医科大学校, 防衛医学研究センター, 教授 (90531632) ; 小野 聡 防衛医科大学校, 防衛医学研究センター, 准教授 (30531355) ; 宮崎 裕美 防衛医科大学校, 防衛医学研究センター, 助教 (30531636) ; 阪本 敏久 防衛医科大学校, 病院, 教授 (50178571) ; 西川 可穂子 防衛医科大学校, 病院, 助教 (20345416) ; 四ノ宮 成祥 防衛医科大学校, 医学教育部医学科専門課程, 教授 (40505260)
• 研究期間 (年度): 2010 – 2012
• キーワード: 熱傷 / 複合免疫不全 / 好中球 / クッパー細胞 / 熱傷後感染 / IL-18 / CD68陽性クッパー細胞 / CD11b陽性クッパー細胞

研究概要

熱傷後は細胞性免疫や液性免疫だけでなくKupffer細胞や好中球も機能不全に陥る複合免疫不全の病態を呈していた。IL-18は頻回投与で熱傷後のNK細胞機能を活性化し、Kupffer細胞や好中球の貪食能や殺菌活性も亢進させ、MRSAなどの熱傷後感染の予後を改善した。IL-18は肝で貪食能旺盛なCD68陽性Kupffer細胞の熱傷後の減少を改善し、炎症性サイトカインを主に産生するCD11b陽性Kupffer細胞の熱傷後の増加を逆に抑制、熱傷後感染時の肝での菌クリアランスを有利に導いた。

研究成果

• [雑誌論文] Immunoenhancing therapy with interleukin-18 against bacterial infection in immunocompromised hosts after severe surgical stress (2013)
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• [雑誌論文] Removal of increased circulating CD4+CD25+Foxp3+ regulatory T cells in patients with septic shock using hemoperfusion with polymyxin B-immobilized fibers (2013)
  • 著者名/発表者名: Ono S, Kimura A, Hiraki S, Takahata R, Tsujimoto H, Kinoshita M, Miyazaki H, Yamamoto J, Hase K, Saitoh D
  • 雑誌名: Surgery 巻: 153 ページ: 262-271
• [雑誌論文] Application of poly-L-lactic acid nanosheet as a material for wound dressing (2013)
  • 著者名/発表者名: Aoki S, Kinoshita M, Miyazaki H, Saito A, Fujie T, Iwaya K, Takeoka S, Saitoh D
  • 雑誌名: Plast Reconstr Surg 巻: 131 ページ: 236-240
• [雑誌論文] Activation of CD11b+ Kupffer cells/macrophages as a common cause for exacerbation of TNF/ Fas-ligand-dependent hepatitis in hypercholesterolemic mice (2013)
  • 著者名/発表者名: Nakashima H, Ogawa Y, Shono S, Kinoshita M, Nakashima M, Sato A, Ikarashi M, Seki S
  • 雑誌名: PLoS ONE
• [雑誌論文] Fragmentation of Poly(lactic acid) Nanosheets and Their Patchwork Treatment for Burn Wounds (2013)
  • 著者名/発表者名: Okamura, Y., Kabata, K., Kinoshita, M., iyazaki H, Saito A, Fujie T, Ohtsubo S, Saitoh, D., and Takeoka, S
  • 雑誌名: Adv. Mater 巻: 25 ページ: 545-551
• [雑誌論文] Novel therapeutic usage of polysaccharide nanosheets for aracinoid plasty and reinforcement of venous tensile strength in rat microneurosurgery (2013)
  • 著者名/発表者名: Otani N, Kinoshita M, Fujie T, Saito A, Takeoka S, Saitoh D, Hagisawa K, Nawashiro H, Shima K
  • 雑誌名: J. Clin. Neurosci 巻: 20 ページ: 301-305
• [雑誌論文] The Liver as a Pivotal Innate Immune Organ (2012)
  • 著者名/発表者名: Seki S, Nakashima H, Kinoshita M
  • 雑誌名: Immuno-gastroenterology 巻: 1 ページ: 76-89
• [雑誌論文] Insulin treatment directly restores neutrophil phagocytosis and bactericidal activity in diabetic mice, thereby improving surgical site infection with Staphylococcus aureus (2012)
  • 著者名/発表者名: Yano H, Kinoshita M, Fujino K, Nakashima M, Yamamoto Y, Miyazaki H, Hamada K, Iwaya K, Saitoh D, Seki S, Tanaka Y
  • 雑誌名: Infect Immun 巻: 80 ページ: 4409-4416
• [雑誌論文] Fibrinogen γ-chain peptide-coated, adenosine diphosphate-encapsulated liposomes rescue thrombocytopenic rabbits from non-compressible liver hemorrhage (2012)
  • 著者名/発表者名: Nishikawa K, Hagisawa K, Kinoshita M, Shono S, Katsuno S, Doi M, Yanagawa R, Suzuki H, Iwaya K, Saitoh D, Sakamoto T, Seki S, Takeoka S, Handa M
  • 雑誌名: J Thromb Haemost 巻: 10 ページ: 2137-2148
• [雑誌論文] Photodynamic therapy can induce a protective innate immune response against murine bacterial arthritis via neutrophil accumulation (2012)
  • 著者名/発表者名: Tanaka M, Mroz P, Dai T, Huang L, Morimoto Y, Kinoshita M, Yoshihara Y, Nemoto K, Shinomiya N, Seki S, Hamblin M
  • 雑誌名: PLoS One
• [雑誌論文] Liposome-encapsulated hemoglobin attenuates cardiac dysfunction and sympathetic activity during hypohemoglobinemic shock (2012)
  • 著者名/発表者名: Nogami, Y., Takase, B., Kinoshita, M., Shono, S., Kaneda, S., Tanaka, Y., Kishimoto, S., Hattori, H., Ishihara, M
  • 雑誌名: SHOCK 巻: 38 ページ: 159-164
• [雑誌論文] Therapeutic efficacy of an antibiotic-loaded nanosheet in a murine burn-wound infection model (2012)
  • 著者名/発表者名: Saito A, Miyazaki H, Fujie T, Ohtsubo S, Kinoshita M, Saitoh D, Takeoka S
  • 雑誌名: Acta Biomater 巻: 8 ページ: 2932-2940
• [雑誌論文] An ultra-thin poly(L-lactic acid) nanosheet as a burn-wound dressing for protection against bacterial infection (2012)
  • 著者名/発表者名: Miyazaki H, Kinoshita M, Saito A, Fujie T, Kabata K, Hara E, Ono S, Takeoka S, Saitoh D
  • 雑誌名: Wound Repair Regen 巻: 20 ページ: 573-579
• [雑誌論文] The postoperative serum interleukin-15 concentration correlates with organ dysfunction and the prognosis of septic patients following emergency gastrointestinal surgery (2012)
  • 著者名/発表者名: Kimura A, Ono S, Hiraki S, Takahata R, Tsujimoto H, Miyazaki H, Kinoshita M, Hatsuse K, Saitoh D, Hase K, Yamamoto J
  • 雑誌名: J Surg Res 巻: 175 ページ: e83-e88
• [雑誌論文] Neutralization of IL-10 restores the down-regulation of IL-18 receptor on NK cells and IFN-γ production in septic mice, thus leading to an improved survival (2012)
  • 著者名/発表者名: Hiraki S, Ono S, Kinoshita M, Tsujimoto H, Takahata, R., Miyazaki H., Saitoh D, Seki S, Hase K
  • 雑誌名: SHOCK 巻: 37 ページ: 177-82
• [雑誌論文] Characterization of mouse liver phagocytic B cells in innate immunity (2012)
  • 著者名/発表者名: Nakashima M, Kinoshita M, Nakashima H, Habu Y, Miyazaki H, Hiroi S, Nakanishi K, Seki S
  • 雑誌名: J. Leukocyte. Biol 巻: 91 ページ: 537-546
• [雑誌論文] Neutralization of interleukin-10 or tumor growing factor-beta decreases the percentages of CD4+CD25+Foxp3+ regulatory T cells in septic mice, thus leading to an improved survival (2012)
  • 著者名/発表者名: Hiraki S, Ono S, Tsujimoto H, Kinoshita M, Takahata, R., Miyazaki H., Saitoh D, Hase K
  • 雑誌名: Surgery 巻: 151 ページ: 313-22
• [雑誌論文] Assessment of a Tissue-Engineered Gastric Wall Patch in a Rat Model (2012)
  • 著者名/発表者名: Maemura T, Kinoshita M, Shin M, Miyazaki H, Tsujimoto H, Ono S, Hase K, Saitoh D
  • 雑誌名: Artif. Organs 巻: 36 ページ: 409-17
• [雑誌論文] Optimal photosensitizers for photodynamic therapy of infections should kill bacteria but spare neutrophils (2012)
  • 著者名/発表者名: Tanaka M, Kinoshita M, Yoshihara Y, Shinomiya N, Seki S, Nemoto K, Hamblin M, Dai T, Huang L, Morimoto Y
  • 雑誌名: Photochem. Photobiol 巻: 88 ページ: 227-32
• [雑誌論文] Antitumor immunity produced by the liver Kupffer cells, NK cells, NKT cells and CD8+ CD122+ T cells (2011)
  • 著者名/発表者名: Seki S, Nakashima H, Nakashima M, Kinoshita M
  • 雑誌名: Clin. Dev. Immunol. 2011 巻: 2011 ページ: 864385
• [雑誌論文] The immunologic outcome of enhanced function of mouse liver lymphocytes and Kupffer cells by high-fat-cholesterol diet (2011)
  • 著者名/発表者名: Shono S, Habu Y, Nakashima M, Sato A, Nakashima H, Miyazaki H, Kinoshita M, Tsumatori G, Shinomiya N, Seki S
  • 雑誌名: SHOCK 巻: 36 ページ: 484-93
• [雑誌論文] Enhancement of neutrophil function by IL-18 therapy protects burn-injured mice from MRSA infection. (2011)
  • 著者名/発表者名: Kinoshita M, Miyazaki H., Ono S, Inatsu, A., Nakashima, H., Tsujimoto, H., Shinomiya, N., Saitoh, D., Seki, S
  • 雑誌名: Infect Immun 巻: 79 ページ: 2670-80
• [雑誌論文] Novel overlaying technique of poly L-lactic acid (PLLA) nanosheet for adhesion prophylaxis and fixation of intraperitoneal onlay polypropylene mesh in a rabbit model (2011)
  • 著者名/発表者名: Fujino K, Kinoshita M, Saitoh A, Yano H, Nishikawa K, Fujie T, Iwaya K, Kakihara M, Takeoka S, Saitoh D, Tanaka Y
  • 雑誌名: Surg Endosc 巻: 25 ページ: 3428-36
• [雑誌論文] Augmented bacterial elimination by Kupffer cells after IL-18 pretreatment via IFN-gamma produced from NK cells in burn-injured mice (2011)
  • 著者名/発表者名: Miyazaki H., Kinoshita M, Ono S, Nakashima M, Hara E, Ohno H, Seki S, Saitoh D
  • 雑誌名: BURNS 巻: 37 ページ: 1208-1215
• [雑誌論文] Postoperative serum concentrations of High Mortality Group Box chromosomal protein-1 correlates to the duration of SIRS and pulmonary dysfunction following gastrointestinal surgery (2011)
  • 著者名/発表者名: Takahata, R., Ono S, Tsujimoto H, Hiraki S, Kimura A, Kinoshita M, Miyazaki H., Saitoh D, Hase K
  • 雑誌名: J. Surg. Res. 巻: 170 ページ: e135-40
• [雑誌論文] Photodynamic therapy using intra-articular photofrin for murine MRSA arthritis: biphasic light dose response for neutrophil-mediated antibacterial effect (2011)
  • 著者名/発表者名: Tanaka M, Kinoshita M, Yoshihara Y, Shinomiya S, Seki S, Nemoto K, Hamblin M, Morimoto Y
  • 雑誌名: Laser Surg Med 巻: 43 ページ: 221-229
• [雑誌論文] Preoperative Toll-like receptor expression in monocytes is associated with host immunological responses following gastrointestinal surgery (2011)
  • 著者名/発表者名: Ono S, Tsujimoto H, Hiraki S, Kinoshita M, Hase K
  • 雑誌名: World J. Surg 巻: 35 ページ: 365-371
• [雑誌論文] Intraosseous transfusion with liposome-encapsulated hemoglobin improves mouse survival after hypohemoglobinemic shock without scavenging nitric oxide (2011)
  • 著者名/発表者名: Shono, S., Kinoshita, M., Takase, B., Nogami, Y., Kaneda, S., Ishihara, M., Saitoh, D., Kikuchi, M. and Seki, S
  • 雑誌名: SHOCK 巻: 35 ページ: 45-52
• [雑誌論文] Characteristic changes in heart rate variability induces during hemorrhagic shock, and effect of liposome-encapsulated hemoglobin in rats (2010)
  • 著者名/発表者名: Nogami, Y., Takase, B., Kinoshita, M., Shono, S., Kaneda, S., Ishihara, M., Kikuchi, M., Maehara, T
  • 雑誌名: J Arrhythmia 巻: 26 ページ: 189-198
• [雑誌論文] Voltage gated potassium channel Kv1.3 blocker as apotential treatment for rat anti-glomerular basement membrane glomerulonephritis (2010)
  • 著者名/発表者名: Hyodo T, Oda T, Kikuchi Y, Higashi K, Kushiyama T, Yamamoto K, Yamada M, Suzuki S, Hokari Y, Kinoshita M, Seki S, Fujinaka F, Yamamoto T, Miura S, Kumagai H
  • 雑誌名: Am. J. Physiol-Renal 巻: 299 ページ: 1258-1269
• [雑誌論文] Characteriation of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice (2010)
  • 著者名/発表者名: Kinoshita, M., Uchida, T., Sato, A., Nakashima, M., Nakashima H., Shono S., Habu, Y., Miyazaki, H., Hiroi, S., Seki, S
  • 雑誌名: J. Hepatol 巻: 53 ページ: 903-910
• [雑誌論文] The effect of ketamine anesthesia on the immune function of mice with postoperative septicemia (2010)
  • 著者名/発表者名: Takahashi, T., Kinoshita, M., Shono, S., Habu, Y., Ogura, T., Seki S., Kazama, T
  • 雑誌名: Anesth Analg 巻: 111 ページ: 1051-1058
• [雑誌論文] Dual therapeutic action of antibiotic-loaded nanosheets for the treatment of gastrointestinal tissue defects (2010)
  • 著者名/発表者名: Fujie, T., Saito, A., Kinoshita, M., Ohtsubo, S., Saitoh, D., and Takeoka, S
  • 雑誌名: Biomaterials 巻: 31 ページ: 6269-6278
• [雑誌論文] Cardiac dysfunction induced by experimental myocardial infarction impairs the host defense response to bacterial infection in mice due to reduced phagocytosis of Kupffer cells (2010)
  • 著者名/発表者名: Nogami, Y., Kinoshita, M., Takase, B., Inatsu, A., Ishihara, M., Seki, S., and Maehara, T
  • 雑誌名: J. Thorac. Cardiovasc. Surg. 巻: 140 ページ: 624-632
• [雑誌論文] Influence of Intraarticular Neutrophils on the Effects of Photodynamic Therapy for Murine MRSA Arthritis (2010)
  • 著者名/発表者名: Tanaka, M., Kinoshita, M., Yoshihara, Y., Shinomiya, N., Seki, S., Nemoto, K., Morimoto, Y
  • 雑誌名: Photochem. Photobiol 巻: 86 ページ: 403-409
• [雑誌論文] Immunosuppression in the livers of mice with obstructive jaundice participates in their susceptibility to bacterial infection and tumor metastasis (2010)
  • 著者名/発表者名: Kawarabayashi, N., Seki, S., Hatsuse, K., Kinoshita, M., Takigawa, T., Tsujimoto, H., Kawabata, T., Nakashima, H., Shono, S., and Mochizuki, H
  • 雑誌名: SHOCK 巻: 33 ページ: 500-506
• [雑誌論文] Pretreatment with ascorbic acid prevents lethal gastrointestinal syndrome in mice receiving a massive amount of radiation (2010)
  • 著者名/発表者名: Yamamoto, T., Kinoshita, M., Shinomiya, N., Hiroi, S., Sugasawa, H., Matsushita, Y., Majima, T., Saitoh, D., Seki, S
  • 雑誌名: J. Radiat. Res. 巻: 51 ページ: 145-156
• [雑誌論文] Sealing effect of a polysaccharide nanosheet for murine cecal puncture (2010)
  • 著者名/発表者名: Fujie, T., Kinoshita, M., Shono, S., Saito, A., Okamura, Y., Saitoh, D., Takeoka, S
  • 雑誌名: Surgery 巻: 148 ページ: 48-58
• [雑誌論文] Effective control of massive venous bleeding by "multi-overlapping therapy" using polysaccharide nanosheets in rabbit inferior vena cava injury model
  • 著者名/発表者名: Hagisawa K, Saito A, Kinoshita M, Fujie T, Otani N, Shono S, Park YK, Takeoka S
  • 雑誌名: J. Vasc. Surg.
• [雑誌論文] Tissue Engineering of the Stomach
  • 著者名/発表者名: Maemura T, Shin M, Kinoshita M
  • 雑誌名: J. Surg. Res.
• [雑誌論文] The effect of synthetic C-reactive protein on the in vitro immune response of human PBMCs stimulated with bacterial reagents
  • 著者名/発表者名: Sato A, Nakashima H, Kinoshita M, Nakashima M, Ogawa Y, Shono S, Ikarashi M, Seki S
  • 雑誌名: Inflammation
• [雑誌論文] Linezolid and vancomycin decrease the therapeutic effect of methylene blue-photodynamic therapy in a mouse model of MRSA bacterial arthritis
  • 著者名/発表者名: Tanaka M, Mroz P, Dai T, Huang L, Morimoto Y, Kinoshita M, Yoshihara Y, Shinomiya N, Seki S, Nemoto K, Hamblin M
  • 雑誌名: Photochem. Photobiol
• [学会発表] Pioglitazone Improves Mouse Survival After Post-Burn Bacterial Infection Via Restoration of Kupffer Cell Function (2011)
  • 著者名/発表者名: Miyazaki H, Kinoshita M, Ono S, Seki S, Saitoh D
  • 学会等名: 18th Annual Meeting of Society for Free Radical Biology and Medicine
  • 発表場所: Atlanta, USA
  • 年月日: 20111100
• [学会発表] Interleukin-18 therapy enhances Kupffer cell-mediated bacterial elimination in post-burn infection models via the activation of NK cell function (2010)
  • 著者名/発表者名: Kinoshita M, Shinomiya N, Miyazaki H, Ono S, Saitoh D, Seki S
  • 学会等名: Chemical and Biological Defense Science and Technology (CBD S&T) 2010
  • 発表場所: Orland, USA
  • 年月日: 20101100
• [学会発表] CpG-oligodeoxynucleotides challenge induces severe multi-organ damage and lethality via TNF and FasL-mediated NKT cell activation in aged mice (2010)
  • 著者名/発表者名: Kinoshita M, Shinomiya N, Kawabata T, Seki S
  • 学会等名: Chemical and Biological Defense Science and Technology (CBD S&T) 2010
  • 発表場所: Orland, USA
  • 年月日: 20101100
• [学会発表] Activation of NK cells by IL-18 augments bacterial elimination by Kupffer cells in the burn-injured mice (2010)
  • 著者名/発表者名: Miyazaki H, Kinoshita M, Ono S, Nakashima M, Hara E, Ohno H, Seki S, Daizoh D
  • 学会等名: Society for Free Radical Biology and Medicine 17th Annual Meeting
  • 発表場所: Orlando, USA
  • 年月日: 20101100
• [学会発表] Characterization of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice (2010)
  • 著者名/発表者名: Kinoshita M, Uchida T, Sato A, Nakashima M, Nakashima H, Shono S, Habu Y, Miyazaki H, Seki S
  • 学会等名: 14th International Congress of Immunology
  • 発表場所: Kobe Japan
  • 年月日: 20100800
• [学会発表] Interleukin-18 treatment following burn injury activates Kupffer cell phagocytosis in mice (2010)
  • 著者名/発表者名: Miyazaki H, Kinoshita M, Ono S, Hara E, Takagi T, Seki S, Saitoh D
  • 学会等名: 14th International Congress of Immunology
  • 発表場所: Kobe Japan
  • 年月日: 20100800
• [図書] Th1とTh2, サイトカインとケモカイン, 組織傷害と免疫,病態のしくみがわかる免疫学 (2010)
  • 著者名/発表者名: 木下学,関修司,阿保徹編
  • 総ページ数: 55-66, 78-92, 208-213
  • 出版者: 医学書院