Mechanical analyses and treatment of immunodeficiency following burn injury

2012 Fiscal Year Final Research Report

• Project/Area Number: 22592027
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: National Defense Medical College
• Principal Investigator: KINOSHITA Manabu 防衛医科大学校, 医学教育部医学科専門課程, 准教授 (70531391)
• Co-Investigator(Kenkyū-buntansha): SEKI Shuhji 防衛医科大学校, 医学教育部医学科専門課程, 教授 (80531392) ; SAITOH Daizoh 防衛医科大学校, 防衛医学研究センター, 教授 (90531632) ; ONO Satoshi 防衛医科大学校, 防衛医学研究センター, 准教授 (30531355) ; MIYAZAKI Hiromi 防衛医科大学校, 防衛医学研究センター, 助教 (30531636) ; SAKAMOTO Toshihisa 防衛医科大学校, 病院, 教授 (50178571) ; NISHIKAWA Kahoko 防衛医科大学校, 病院, 助教 (20345416) ; SHINOMIYA Nariyoshi 防衛医科大学校, 医学教育部医学科専門課程, 教授 (40505260)
• Project Period (FY): 2010 – 2012
• Keywords: 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

Research Abstract

Severely burn-injured hosts are known to be highly susceptible to bacterial infections/sepsis, and their outcomes become extremely poor due to infectious complications. Their host defense systems against infections, such as Th1-mediated cellular immunity, Th2-mediated humoral immunity and neutrophil-mediated immunity, are severely and multifactorially impaired. Multiple IL-18 injections can effectively restore these impaired immune responses in the immunocompromised mice receiving severe burn injury, thus improving their survival after bacterial infections. IL-18 therapy also restored burn injury-induced phenotypic alteration of Kupffer cells, namely increasing CD68+ Kupffer cells but decreasing CD11b+ Kupffer cells.

Research Products

• [Journal Article] Immunoenhancing therapy with interleukin-18 against bacterial infection in immunocompromised hosts after severe surgical stress (2013)
  • Author(s): Kinoshita M, Miyazaki H, Ono S, Seki S
  • Journal Title: J. Leukocyte. Biol Volume: 93 Pages: 689-698
• [Journal Article] Removal of increased circulating CD4+CD25+Foxp3+ regulatory T cells in patients with septic shock using hemoperfusion with polymyxin B-immobilized fibers (2013)
  • Author(s): Ono S, Kimura A, Hiraki S, Takahata R, Tsujimoto H, Kinoshita M, Miyazaki H, Yamamoto J, Hase K, Saitoh D
  • Journal Title: Surgery Volume: 153 Pages: 262-271
• [Journal Article] Application of poly-L-lactic acid nanosheet as a material for wound dressing (2013)
  • Author(s): Aoki S, Kinoshita M, Miyazaki H, Saito A, Fujie T, Iwaya K, Takeoka S, Saitoh D
  • Journal Title: Plast Reconstr Surg Volume: 131 Pages: 236-240
• [Journal Article] Activation of CD11b+ Kupffer cells/macrophages as a common cause for exacerbation of TNF/ Fas-ligand-dependent hepatitis in hypercholesterolemic mice (2013)
  • Author(s): Nakashima H, Ogawa Y, Shono S, Kinoshita M, Nakashima M, Sato A, Ikarashi M, Seki S
  • Journal Title: PLoS ONE
• [Journal Article] Fragmentation of Poly(lactic acid) Nanosheets and Their Patchwork Treatment for Burn Wounds (2013)
  • Author(s): Okamura, Y., Kabata, K., Kinoshita, M., iyazaki H, Saito A, Fujie T, Ohtsubo S, Saitoh, D., and Takeoka, S
  • Journal Title: Adv. Mater Volume: 25 Pages: 545-551
• [Journal Article] Novel therapeutic usage of polysaccharide nanosheets for aracinoid plasty and reinforcement of venous tensile strength in rat microneurosurgery (2013)
  • Author(s): Otani N, Kinoshita M, Fujie T, Saito A, Takeoka S, Saitoh D, Hagisawa K, Nawashiro H, Shima K
  • Journal Title: J. Clin. Neurosci Volume: 20 Pages: 301-305
• [Journal Article] The Liver as a Pivotal Innate Immune Organ (2012)
  • Author(s): Seki S, Nakashima H, Kinoshita M
  • Journal Title: Immuno-gastroenterology Volume: 1 Pages: 76-89
• [Journal Article] Insulin treatment directly restores neutrophil phagocytosis and bactericidal activity in diabetic mice, thereby improving surgical site infection with Staphylococcus aureus (2012)
  • Author(s): Yano H, Kinoshita M, Fujino K, Nakashima M, Yamamoto Y, Miyazaki H, Hamada K, Iwaya K, Saitoh D, Seki S, Tanaka Y
  • Journal Title: Infect Immun Volume: 80 Pages: 4409-4416
• [Journal Article] Fibrinogen γ-chain peptide-coated, adenosine diphosphate-encapsulated liposomes rescue thrombocytopenic rabbits from non-compressible liver hemorrhage (2012)
  • Author(s): 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
  • Journal Title: J Thromb Haemost Volume: 10 Pages: 2137-2148
• [Journal Article] Photodynamic therapy can induce a protective innate immune response against murine bacterial arthritis via neutrophil accumulation (2012)
  • Author(s): Tanaka M, Mroz P, Dai T, Huang L, Morimoto Y, Kinoshita M, Yoshihara Y, Nemoto K, Shinomiya N, Seki S, Hamblin M
  • Journal Title: PLoS One
• [Journal Article] Liposome-encapsulated hemoglobin attenuates cardiac dysfunction and sympathetic activity during hypohemoglobinemic shock (2012)
  • Author(s): Nogami, Y., Takase, B., Kinoshita, M., Shono, S., Kaneda, S., Tanaka, Y., Kishimoto, S., Hattori, H., Ishihara, M
  • Journal Title: SHOCK Volume: 38 Pages: 159-164
• [Journal Article] Therapeutic efficacy of an antibiotic-loaded nanosheet in a murine burn-wound infection model (2012)
  • Author(s): Saito A, Miyazaki H, Fujie T, Ohtsubo S, Kinoshita M, Saitoh D, Takeoka S
  • Journal Title: Acta Biomater Volume: 8 Pages: 2932-2940
• [Journal Article] An ultra-thin poly(L-lactic acid) nanosheet as a burn-wound dressing for protection against bacterial infection (2012)
  • Author(s): Miyazaki H, Kinoshita M, Saito A, Fujie T, Kabata K, Hara E, Ono S, Takeoka S, Saitoh D
  • Journal Title: Wound Repair Regen Volume: 20 Pages: 573-579
• [Journal Article] The postoperative serum interleukin-15 concentration correlates with organ dysfunction and the prognosis of septic patients following emergency gastrointestinal surgery (2012)
  • Author(s): Kimura A, Ono S, Hiraki S, Takahata R, Tsujimoto H, Miyazaki H, Kinoshita M, Hatsuse K, Saitoh D, Hase K, Yamamoto J
  • Journal Title: J Surg Res Volume: 175 Pages: e83-e88
• [Journal Article] 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)
  • Author(s): Hiraki S, Ono S, Kinoshita M, Tsujimoto H, Takahata, R., Miyazaki H., Saitoh D, Seki S, Hase K
  • Journal Title: SHOCK Volume: 37 Pages: 177-82
• [Journal Article] Characterization of mouse liver phagocytic B cells in innate immunity (2012)
  • Author(s): Nakashima M, Kinoshita M, Nakashima H, Habu Y, Miyazaki H, Hiroi S, Nakanishi K, Seki S
  • Journal Title: J. Leukocyte. Biol Volume: 91 Pages: 537-546
• [Journal Article] 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)
  • Author(s): Hiraki S, Ono S, Tsujimoto H, Kinoshita M, Takahata, R., Miyazaki H., Saitoh D, Hase K
  • Journal Title: Surgery Volume: 151 Pages: 313-22
• [Journal Article] Assessment of a Tissue-Engineered Gastric Wall Patch in a Rat Model (2012)
  • Author(s): Maemura T, Kinoshita M, Shin M, Miyazaki H, Tsujimoto H, Ono S, Hase K, Saitoh D
  • Journal Title: Artif. Organs Volume: 36 Pages: 409-17
• [Journal Article] Optimal photosensitizers for photodynamic therapy of infections should kill bacteria but spare neutrophils (2012)
  • Author(s): Tanaka M, Kinoshita M, Yoshihara Y, Shinomiya N, Seki S, Nemoto K, Hamblin M, Dai T, Huang L, Morimoto Y
  • Journal Title: Photochem. Photobiol Volume: 88 Pages: 227-32
• [Journal Article] Antitumor immunity produced by the liver Kupffer cells, NK cells, NKT cells and CD8+ CD122+ T cells (2011)
  • Author(s): Seki S, Nakashima H, Nakashima M, Kinoshita M
  • Journal Title: Clin. Dev. Immunol. 2011 Volume: 2011 Pages: 864385
• [Journal Article] The immunologic outcome of enhanced function of mouse liver lymphocytes and Kupffer cells by high-fat-cholesterol diet (2011)
  • Author(s): Shono S, Habu Y, Nakashima M, Sato A, Nakashima H, Miyazaki H, Kinoshita M, Tsumatori G, Shinomiya N, Seki S
  • Journal Title: SHOCK Volume: 36 Pages: 484-93
• [Journal Article] Enhancement of neutrophil function by IL-18 therapy protects burn-injured mice from MRSA infection. (2011)
  • Author(s): Kinoshita M, Miyazaki H., Ono S, Inatsu, A., Nakashima, H., Tsujimoto, H., Shinomiya, N., Saitoh, D., Seki, S
  • Journal Title: Infect Immun Volume: 79 Pages: 2670-80
• [Journal Article] 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)
  • Author(s): Fujino K, Kinoshita M, Saitoh A, Yano H, Nishikawa K, Fujie T, Iwaya K, Kakihara M, Takeoka S, Saitoh D, Tanaka Y
  • Journal Title: Surg Endosc Volume: 25 Pages: 3428-36
• [Journal Article] Augmented bacterial elimination by Kupffer cells after IL-18 pretreatment via IFN-gamma produced from NK cells in burn-injured mice (2011)
  • Author(s): Miyazaki H., Kinoshita M, Ono S, Nakashima M, Hara E, Ohno H, Seki S, Saitoh D
  • Journal Title: BURNS Volume: 37 Pages: 1208-1215
• [Journal Article] Postoperative serum concentrations of High Mortality Group Box chromosomal protein-1 correlates to the duration of SIRS and pulmonary dysfunction following gastrointestinal surgery (2011)
  • Author(s): Takahata, R., Ono S, Tsujimoto H, Hiraki S, Kimura A, Kinoshita M, Miyazaki H., Saitoh D, Hase K
  • Journal Title: J. Surg. Res. Volume: 170 Pages: e135-40
• [Journal Article] Photodynamic therapy using intra-articular photofrin for murine MRSA arthritis: biphasic light dose response for neutrophil-mediated antibacterial effect (2011)
  • Author(s): Tanaka M, Kinoshita M, Yoshihara Y, Shinomiya S, Seki S, Nemoto K, Hamblin M, Morimoto Y
  • Journal Title: Laser Surg Med Volume: 43 Pages: 221-229
• [Journal Article] Preoperative Toll-like receptor expression in monocytes is associated with host immunological responses following gastrointestinal surgery (2011)
  • Author(s): Ono S, Tsujimoto H, Hiraki S, Kinoshita M, Hase K
  • Journal Title: World J. Surg Volume: 35 Pages: 365-371
• [Journal Article] Intraosseous transfusion with liposome-encapsulated hemoglobin improves mouse survival after hypohemoglobinemic shock without scavenging nitric oxide (2011)
  • Author(s): Shono, S., Kinoshita, M., Takase, B., Nogami, Y., Kaneda, S., Ishihara, M., Saitoh, D., Kikuchi, M. and Seki, S
  • Journal Title: SHOCK Volume: 35 Pages: 45-52
• [Journal Article] Characteristic changes in heart rate variability induces during hemorrhagic shock, and effect of liposome-encapsulated hemoglobin in rats (2010)
  • Author(s): Nogami, Y., Takase, B., Kinoshita, M., Shono, S., Kaneda, S., Ishihara, M., Kikuchi, M., Maehara, T
  • Journal Title: J Arrhythmia Volume: 26 Pages: 189-198
• [Journal Article] Voltage gated potassium channel Kv1.3 blocker as apotential treatment for rat anti-glomerular basement membrane glomerulonephritis (2010)
  • Author(s): 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
  • Journal Title: Am. J. Physiol-Renal Volume: 299 Pages: 1258-1269
• [Journal Article] Characteriation of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice (2010)
  • Author(s): Kinoshita, M., Uchida, T., Sato, A., Nakashima, M., Nakashima H., Shono S., Habu, Y., Miyazaki, H., Hiroi, S., Seki, S
  • Journal Title: J. Hepatol Volume: 53 Pages: 903-910
• [Journal Article] The effect of ketamine anesthesia on the immune function of mice with postoperative septicemia (2010)
  • Author(s): Takahashi, T., Kinoshita, M., Shono, S., Habu, Y., Ogura, T., Seki S., Kazama, T
  • Journal Title: Anesth Analg Volume: 111 Pages: 1051-1058
• [Journal Article] Dual therapeutic action of antibiotic-loaded nanosheets for the treatment of gastrointestinal tissue defects (2010)
  • Author(s): Fujie, T., Saito, A., Kinoshita, M., Ohtsubo, S., Saitoh, D., and Takeoka, S
  • Journal Title: Biomaterials Volume: 31 Pages: 6269-6278
• [Journal Article] 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)
  • Author(s): Nogami, Y., Kinoshita, M., Takase, B., Inatsu, A., Ishihara, M., Seki, S., and Maehara, T
  • Journal Title: J. Thorac. Cardiovasc. Surg. Volume: 140 Pages: 624-632
• [Journal Article] Influence of Intraarticular Neutrophils on the Effects of Photodynamic Therapy for Murine MRSA Arthritis (2010)
  • Author(s): Tanaka, M., Kinoshita, M., Yoshihara, Y., Shinomiya, N., Seki, S., Nemoto, K., Morimoto, Y
  • Journal Title: Photochem. Photobiol Volume: 86 Pages: 403-409
• [Journal Article] Immunosuppression in the livers of mice with obstructive jaundice participates in their susceptibility to bacterial infection and tumor metastasis (2010)
  • Author(s): Kawarabayashi, N., Seki, S., Hatsuse, K., Kinoshita, M., Takigawa, T., Tsujimoto, H., Kawabata, T., Nakashima, H., Shono, S., and Mochizuki, H
  • Journal Title: SHOCK Volume: 33 Pages: 500-506
• [Journal Article] Pretreatment with ascorbic acid prevents lethal gastrointestinal syndrome in mice receiving a massive amount of radiation (2010)
  • Author(s): Yamamoto, T., Kinoshita, M., Shinomiya, N., Hiroi, S., Sugasawa, H., Matsushita, Y., Majima, T., Saitoh, D., Seki, S
  • Journal Title: J. Radiat. Res. Volume: 51 Pages: 145-156
• [Journal Article] Sealing effect of a polysaccharide nanosheet for murine cecal puncture (2010)
  • Author(s): Fujie, T., Kinoshita, M., Shono, S., Saito, A., Okamura, Y., Saitoh, D., Takeoka, S
  • Journal Title: Surgery Volume: 148 Pages: 48-58
• [Journal Article] Effective control of massive venous bleeding by "multi-overlapping therapy" using polysaccharide nanosheets in rabbit inferior vena cava injury model
  • Author(s): Hagisawa K, Saito A, Kinoshita M, Fujie T, Otani N, Shono S, Park YK, Takeoka S
  • Journal Title: J. Vasc. Surg.
• [Journal Article] Tissue Engineering of the Stomach
  • Author(s): Maemura T, Shin M, Kinoshita M
  • Journal Title: J. Surg. Res.
• [Journal Article] The effect of synthetic C-reactive protein on the in vitro immune response of human PBMCs stimulated with bacterial reagents
  • Author(s): Sato A, Nakashima H, Kinoshita M, Nakashima M, Ogawa Y, Shono S, Ikarashi M, Seki S
  • Journal Title: Inflammation
• [Journal Article] Linezolid and vancomycin decrease the therapeutic effect of methylene blue-photodynamic therapy in a mouse model of MRSA bacterial arthritis
  • Author(s): Tanaka M, Mroz P, Dai T, Huang L, Morimoto Y, Kinoshita M, Yoshihara Y, Shinomiya N, Seki S, Nemoto K, Hamblin M
  • Journal Title: Photochem. Photobiol
• [Presentation] Pioglitazone Improves Mouse Survival After Post-Burn Bacterial Infection Via Restoration of Kupffer Cell Function (2011)
  • Author(s): Miyazaki H, Kinoshita M, Ono S, Seki S, Saitoh D
  • Organizer: 18th Annual Meeting of Society for Free Radical Biology and Medicine
  • Place of Presentation: Atlanta, USA
  • Year and Date: 20111100
• [Presentation] Interleukin-18 therapy enhances Kupffer cell-mediated bacterial elimination in post-burn infection models via the activation of NK cell function (2010)
  • Author(s): Kinoshita M, Shinomiya N, Miyazaki H, Ono S, Saitoh D, Seki S
  • Organizer: Chemical and Biological Defense Science and Technology (CBD S&T) 2010
  • Place of Presentation: Orland, USA
  • Year and Date: 20101100
• [Presentation] CpG-oligodeoxynucleotides challenge induces severe multi-organ damage and lethality via TNF and FasL-mediated NKT cell activation in aged mice (2010)
  • Author(s): Kinoshita M, Shinomiya N, Kawabata T, Seki S
  • Organizer: Chemical and Biological Defense Science and Technology (CBD S&T) 2010
  • Place of Presentation: Orland, USA
  • Year and Date: 20101100
• [Presentation] Activation of NK cells by IL-18 augments bacterial elimination by Kupffer cells in the burn-injured mice (2010)
  • Author(s): Miyazaki H, Kinoshita M, Ono S, Nakashima M, Hara E, Ohno H, Seki S, Daizoh D
  • Organizer: Society for Free Radical Biology and Medicine 17th Annual Meeting
  • Place of Presentation: Orlando, USA
  • Year and Date: 20101100
• [Presentation] Characterization of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice (2010)
  • Author(s): Kinoshita M, Uchida T, Sato A, Nakashima M, Nakashima H, Shono S, Habu Y, Miyazaki H, Seki S
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe Japan
  • Year and Date: 20100800
• [Presentation] Interleukin-18 treatment following burn injury activates Kupffer cell phagocytosis in mice (2010)
  • Author(s): Miyazaki H, Kinoshita M, Ono S, Hara E, Takagi T, Seki S, Saitoh D
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe Japan
  • Year and Date: 20100800
• [Book] 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)
  • Author(s): 木下学,関修司,阿保徹編
  • Total Pages: 55-66, 78-92, 208-213
  • Publisher: 医学書院