Analysis of reactive oxygen species, NO, CO and H_2S as therapeutic targets in the immune complex diseases

• Project/Area Number: 20591349
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: Nagasaki University
• Principal Investigator: SHIMIZU Kazuhiro Nagasaki University, 大学院・医歯薬学総合研究科, 准教授 (80170968)
• Co-Investigator(Kenkyū-buntansha): SATO Shinichi 東京大学, 医学部附属病院, 教授 (20215792)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: アルサス反応 / 活性酸素種 / 一酸化窒素 / 一酸化炭素 / 硫化水素 / Arthus reaction / Carbon monoxide / Nitric oxide / Hydrogen sulfide / Immune complex disease

Research Abstract

To assess the roles of H_2S in the IC induced diseases, reverse passive cutaneous Arthus reaction was conducted using NaHS as an H_2S donor. Furthermore, we conducted similar experiments using selectin-deficient (selectin^<-/->) mice to determine the involvement of selectin molecules in the H_2S mediated pathway. Exogenous application of H_2S dramatically attenuated inflammatory reactions in wild type (WT) mice associated with Arthus reaction. Namely, mRNA expressions of tumor necrosis factor-α, interferon-γ and neutrophil numbers were significantly reduced in the lesional skins of NaHS treated WT mice relative to untreated ones. NaHS treatment significantly reduced these three parameters in the lesional skins of E- and P-selectin^<-/-> mice, but not in those of L- selectin^<-/-> mice. Quite similar results were obtained in the blocking study using WT mice injected with monoclonal antibodies to E-, P- and L-selectin. Our results indicated that exogenous application of H_2S attenuates inflammatory responses in reverse passive Arthus reaction through L-selectin involved pathways, but not through E- or P-selectin pathways.

Research Products

• [Journal Article] Platelets control leukocyte recruitment in a murine model of cutaneous arthus reaction. (2010)
  • Author(s): Hara T, Shimizu K, Ogawa F, Yanaba K, Iwata Y, Muroi E, Takenaka M, Komura K, Hasegawa M, Fujimoto M, Sato S
  • Journal Title: Am J Pathol. 176(1) Pages: 259-269
• [Journal Article] Establishment of experimental eosinophilic vasculitis by IgE-mediated cutaneous reverse passive arthus reaction. (2009)
  • Author(s): Ishii T, Fujita T, Matsushita T, Yanaba K, Hasegawa M, Nakashima H, Ogawa F, Shimizu K, Takehara K, Tedder TF, Sato S, Fujimoto M
  • Journal Title: Am J Pathol. 174(6) Pages: 2225-2233
• [Journal Article] Involvement of gaseous low molecular monoxides in the cutaneous reverse passive Arthus reaction : cytoprotective action of carbon monoxide. (2008)
  • Author(s): Shimizu K, Bae SJ, Hara T, Iwata Y, Yamaoka T, Komura K, Muroi E, Takenaka M, Ogawa F, Sato S
  • Journal Title: Clin Exp Immunol. 153(2) Pages: 245-257
  • NAID: 120006983393
• [Journal Article] Involvement of gaseous low molecular monoxides in the cutaneous reverse passive Arthus reaction : cytoprotective action of carbon monoxide (2008)
  • Author(s): Shimizu K., et al
  • Journal Title: Clinical and Experimental Immunology 153 Pages: 245-257
  • NAID: 120006983393
  • Peer Reviewed
• [Journal Article] Involvement of gaseous low molecular monoxides in the cutaneous reverse passive Arthus reaction : cytoprotective action of carbon monoxide. (2008)
  • Author(s): Shimizu K, Bae SJ, Hara T, Iwata Komura K, Muroi E, Takenaka M Sato S
  • Journal Title: Clin Exp Immunol 153 Pages: 245-257
  • NAID: 120006983393
  • Peer Reviewed
• [Journal Article] Increased levels of urinary nitrite and nitrotyrosine in Yusho victims 40 year after accidental poisoning with polychlorinated biphenyls in Nagasaki, Japan (2008)
  • Author(s): Shimizu K, Ogawa F, Thile JJ, Lee JB, Bae SJ, Sato S
  • Journal Title: J Appl Toxicol. 28(8) Pages: 1040-1044
  • Peer Reviewed
• [Journal Article] Increased Serum Levels of N(epsilon)-(hexanoyl)lysine, A New Marker of Oxidative Stress, in Systemic Sclerosis. (2008)
  • Author(s): Shimizu K, Ogawa F, Akiyama Yoshizaki A, Iwata Y, Komura K, Bae S, Sato S
  • Journal Title: J Rheumatol 35(11) Pages: 2214-2219
  • Peer Reviewed
• [Presentation] Hydrogen sulfide attenuates the inflammatory reaction in the cutaneous reverse passive Arthus reaction (2009)
  • Author(s): Shimizu K, et al
  • Organizer: The 34^<th> Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: JAL Resort Sea Hawk Hotel(Fukuoka)
  • Year and Date: 2009-12-05
• [Presentation] Hydrogen sulfide attenuates the inflammatory reactions in the cutaneous reverse passive Arthus reaction. (2009)
  • Author(s): Shimizu K, et al.
  • Organizer: 日本研究皮膚科学会第34回年次学術大会・総会
  • Place of Presentation: 福岡市・JALリゾートシーホークホテル福岡
• [Presentation] Involvement of gaseous low molecular monoxides in the cutaneous reverse passive Arthus reaction (2008)
  • Author(s): Kazuhiro Shimizu, SangJae Bae, Toshihide Hara, Fumihide Ogawa, Eiji Muroi, Shinichi Sato
  • Organizer: 2^<nd> International Conference on Cutaneous Lupus Erythematosus
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2008-05-12
• [Presentation] Involvement of gaseous low molecular monoxides in the cutaneous reverse passive Arthus reaction (2008)
  • Author(s): Shimizu K., et al
  • Organizer: 2^<nd> International Conference on Cutaneous Lupus Erythematosus
  • Place of Presentation: Shiran Kaikan(Kyoto)