start-ver=1.4 cd-journal=joma no-vol=41 cd-vols= no-issue=1 article-no= start-page=171 end-page=181 dt-received= dt-revised= dt-accepted= dt-pub-year=2013 dt-pub=201301 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Redox-Active Protein Thioredoxin-1 Administration Ameliorates Influenza A Virus (H1N1)-Induced Acute Lung Injury in Mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objectives: Influenza virus infections can cause severe acute lung injury leading to significant morbidity and mortality. Thioredoxin-1 is a redox-active defensive protein induced in response to stress conditions. Animal experiments have revealed that thioredoxin-1 has protective effects against various severe disorders. This study was undertaken to evaluate the protective effects of recombinant human thioredoxin-1 administration on influenza A virus (H1N1)-induced acute lung injury in mice. Design: Prospective animal trial. Setting: Research laboratory. Subjects: Nine-week-old male C57BL/6 mice inoculated with H1N1. Intervention: The mice were divided into a vehicle-treated group and recombinant human thioredoxin-1-treated group. For survival rate analysis, the vehicle or recombinant human thioredoxin-1 was administered intraperitoneally every second day from day -1 to day 13. For lung lavage and pathological analyses, vehicle or recombinant human thioredoxin-1 was administered intraperitoneally on days 1, 1, and 3. Measurements and Main Results: Lung lavage and pathological analyses were performed at 24, 72, and 120 hrs after inoculation. The recombinant human thioredoxin-1 treatment significantly improved the survival rate of H1N1-inoculated mice, although the treatment did not affect virus propagation in the lung. The treatment significantly attenuated the histological changes and neutrophil infiltration in the lung of H1N1-inoculated mice. The treatment significantly attenuated the production of tumor necrosis factor-a and chemokine (C-X-C motif) ligand 1 in the lung and oxidative stress enhancement, which were observed in H1N1-inoculated mice. H1N1 induced expressions of tumor necrosis factor-a and chemokine (C-X-C motif) ligand 1 in murine lung epithelial cells MLE-12, which were inhibited by the addition of recombinant human thioredoxin-1. The recombinant human thioredoxin-1 treatment started 30 mins after H1N1 inoculation also significantly improved the survival of the mice. Conclusions: Exogenous administration of recombinant human thioredoxin-1 significantly improved the survival rate and attenuated lung histological changes in the murine model of influenza pneumonia. The protective mechanism of thioredoxin-1 might be explained by its potent antioxidative and anti-inflammatory actions. Consequently, recombinant human thioredoxin-1 might be a possible pharmacological strategy for severe influenza virus infection in humans. (Crit Care Med 2013; 41:171-181) en-copyright= kn-copyright= en-aut-name=YashiroMasato en-aut-sei=Yashiro en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TsukaharaHirokazu en-aut-sei=Tsukahara en-aut-mei=Hirokazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MatsukawaAkihiro en-aut-sei=Matsukawa en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamadaMutsuko en-aut-sei=Yamada en-aut-mei=Mutsuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=FujiiYosuke en-aut-sei=Fujii en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NagaokaYoshiharu en-aut-sei=Nagaoka en-aut-mei=Yoshiharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TsugeMitsuru en-aut-sei=Tsuge en-aut-mei=Mitsuru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamashitaNobuko en-aut-sei=Yamashita en-aut-mei=Nobuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ItoToshihiro en-aut-sei=Ito en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YamadaMasao en-aut-sei=Yamada en-aut-mei=Masao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MasutaniHiroshi en-aut-sei=Masutani en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pediat affil-num=2 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pediat affil-num=3 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pathol & Expt Med affil-num=4 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pediat affil-num=5 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pediat affil-num=6 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pediat affil-num=7 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pediat affil-num=8 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pediat affil-num=9 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pathol & Expt Med affil-num=10 en-affil= kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Virol affil-num=11 en-affil= kn-affil=Kyoto Univ, Inst Virus Res, Dept Biol Responses en-keyword=acute lung injury kn-keyword=acute lung injury en-keyword=cytokine kn-keyword=cytokine en-keyword=influenza virus kn-keyword=influenza virus en-keyword=mouse kn-keyword=mouse en-keyword=oxidative stress kn-keyword=oxidative stress en-keyword=thioredoxin-1 kn-keyword=thioredoxin-1 END start-ver=1.4 cd-journal=joma no-vol=125 cd-vols= no-issue=2 article-no= start-page=109 end-page=112 dt-received= dt-revised= dt-accepted= dt-pub-year=2013 dt-pub=20130801 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=Therapeutic effects of redox-active protein thioredoxin(TRX)-1 in influenza-virus-induced pneumonia in mice kn-title=マウスインフルエンザ肺炎におけるレドックス制御蛋白チオレドキシン（TRX-1）の治療的効果 en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=YashiroMasato en-aut-sei=Yashiro en-aut-mei=Masato kn-aut-name=八代将登 kn-aut-sei=八代 kn-aut-mei=将登 aut-affil-num=1 ORCID= en-aut-name=TsukaharaHirokazu en-aut-sei=Tsukahara en-aut-mei=Hirokazu kn-aut-name=塚原宏一 kn-aut-sei=塚原 kn-aut-mei=宏一 aut-affil-num=2 ORCID= en-aut-name=MatsukawaAkihiro en-aut-sei=Matsukawa en-aut-mei=Akihiro kn-aut-name=松川昭博 kn-aut-sei=松川 kn-aut-mei=昭博 aut-affil-num=3 ORCID= en-aut-name=YamadaMutsuko en-aut-sei=Yamada en-aut-mei=Mutsuko kn-aut-name=山田睦子 kn-aut-sei=山田 kn-aut-mei=睦子 aut-affil-num=4 ORCID= en-aut-name=FujiiYosuke en-aut-sei=Fujii en-aut-mei=Yosuke kn-aut-name=藤井洋輔 kn-aut-sei=藤井 kn-aut-mei=洋輔 aut-affil-num=5 ORCID= en-aut-name=NagaokaYoshiharu en-aut-sei=Nagaoka en-aut-mei=Yoshiharu kn-aut-name=長岡義晴 kn-aut-sei=長岡 kn-aut-mei=義晴 aut-affil-num=6 ORCID= en-aut-name=TsugeMitsuru en-aut-sei=Tsuge en-aut-mei=Mitsuru kn-aut-name=津下充 kn-aut-sei=津下 kn-aut-mei=充 aut-affil-num=7 ORCID= en-aut-name=YamashitaNobuko en-aut-sei=Yamashita en-aut-mei=Nobuko kn-aut-name=山下信子 kn-aut-sei=山下 kn-aut-mei=信子 aut-affil-num=8 ORCID= en-aut-name=ItoToshihiro en-aut-sei=Ito en-aut-mei=Toshihiro kn-aut-name=伊藤利洋 kn-aut-sei=伊藤 kn-aut-mei=利洋 aut-affil-num=9 ORCID= en-aut-name=YamadaMasao en-aut-sei=Yamada en-aut-mei=Masao kn-aut-name=山田雅夫 kn-aut-sei=山田 kn-aut-mei=雅夫 aut-affil-num=10 ORCID= en-aut-name=MasutaniHiroshi en-aut-sei=Masutani en-aut-mei=Hiroshi kn-aut-name=増谷弘 kn-aut-sei=増谷 kn-aut-mei=弘 aut-affil-num=11 ORCID= en-aut-name=YodoiJunji en-aut-sei=Yodoi en-aut-mei=Junji kn-aut-name=淀井淳司 kn-aut-sei=淀井 kn-aut-mei=淳司 aut-affil-num=12 ORCID= en-aut-name=MorishimaTsuneo en-aut-sei=Morishima en-aut-mei=Tsuneo kn-aut-name=森島恒雄 kn-aut-sei=森島 kn-aut-mei=恒雄 aut-affil-num=13 ORCID= affil-num=1 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 小児医科学 affil-num=2 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 小児医科学 affil-num=3 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 病理学（免疫病理） affil-num=4 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 小児医科学 affil-num=5 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 小児医科学 affil-num=6 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 小児医科学 affil-num=7 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 小児医科学 affil-num=8 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 小児医科学 affil-num=9 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 病理学（免疫病理） affil-num=10 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 病原ウイルス学 affil-num=11 en-affil= kn-affil=京都大学ウイルス研究所 生体応答学研究部門 affil-num=12 en-affil= kn-affil=京都大学ウイルス研究所 生体応答学研究部門 affil-num=13 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科 小児医科学 en-keyword=acute lung injury kn-keyword=acute lung injury en-keyword=cytokine kn-keyword=cytokine en-keyword=influenza virus kn-keyword=influenza virus en-keyword=oxidative stress kn-keyword=oxidative stress en-keyword=thioredoxin-1 kn-keyword=thioredoxin-1 END start-ver=1.4 cd-journal=joma no-vol=144 cd-vols= no-issue=3 article-no= start-page=272 end-page=282 dt-received= dt-revised= dt-accepted= dt-pub-year=2012 dt-pub=201209 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=MAPKs are involved in acetaminophen (APAP)-hepatotoxicity, but the regulatory mechanism remains unknown. Here, we explored the role of Spred-2 that negatively regulates Ras/ERK pathway in APAP-hepatotoxicity. Spred-2 knockout (KO) mice demonstrated exacerbated liver injury, an event that was associated with increased numbers of CD4(+) T, CD8(+) T and NK cells in the liver compared to the control. Levels of CXCL9/CXCL10 that attract and activate these cells were increased in Spred-2 KO-liver. Kupffer cells isolated from Spred-2 KO mice after APAP challenge expressed higher levels of CXCL9/CXCL10 than those from the control. Upon stimulation with APAP or IFN gamma, naive Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFN gamma and decreased numbers of not only NK cells but also CD4(+) T and CD8(+) T cells in the liver. These results suggest that Spred-2 negatively regulates APAP-hepatotoxicity under the control of Kupffer cells and NK cells. en-copyright= kn-copyright= en-aut-name=WakabayashiHiroshi en-aut-sei=Wakabayashi en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ItoToshihiro en-aut-sei=Ito en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FushimiSoichiro en-aut-sei=Fushimi en-aut-mei=Soichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakashimaYuki en-aut-sei=Nakashima en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ItakuraJyunya en-aut-sei=Itakura en-aut-mei=Jyunya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=LiuQiuying en-aut-sei=Liu en-aut-mei=Qiuying kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=WinMin Min en-aut-sei=Win en-aut-mei=Min Min kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SunCuiming en-aut-sei=Sun en-aut-mei=Cuiming kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ChenCao en-aut-sei=Chen en-aut-mei=Cao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SatoMiwa en-aut-sei=Sato en-aut-mei=Miwa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MinoMegumi en-aut-sei=Mino en-aut-mei=Megumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=OginoTetsuya en-aut-sei=Ogino en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MakinoHirofumi en-aut-sei=Makino en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=YoshimuraAkihiko en-aut-sei=Yoshimura en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=MatsukawaAkihiro en-aut-sei=Matsukawa en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci affil-num=2 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci affil-num=3 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci affil-num=4 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci affil-num=5 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci affil-num=6 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci affil-num=7 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci affil-num=8 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci affil-num=9 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci affil-num=10 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci affil-num=11 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci affil-num=12 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci affil-num=13 en-affil= kn-affil=Okayama Univ, Dept Med & Clin Sci, Grad Sch Med Dent & Pharmaceut Sci affil-num=14 en-affil= kn-affil=Keio Univ, Sch Med, Dept Microbiol & Immunol affil-num=15 en-affil= kn-affil=Okayama Univ, Dept Pathol & Expt Med, Grad Sch Med Dent & Pharmaceut Sci en-keyword=Acetaminophen kn-keyword=Acetaminophen en-keyword=Hepatotoxicity kn-keyword=Hepatotoxicity en-keyword=Liver immunology kn-keyword=Liver immunology en-keyword=Signaling pathway kn-keyword=Signaling pathway en-keyword=Toxicology kn-keyword=Toxicology END