Impaired host defense in mice deficient in myeloperoxidase

髓过氧化物酶缺陷小鼠的宿主防御受损

• 批准号: 14560251
• 负责人: ARATANI Yasuaki
• 金额: $ 2.18万
• 依托单位: Yokohama City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14560251/
• 关键词: neutrophil; myeloperoxidase; immunology; infectious disease; reactive oxygen species

Myeloperoxidase (MPO) is located within neutrophils capable of producing hypochlorous acid. Generation of oxidative products by phagocytic cells is known to be an important host defense mechanism directed toward killing of invading microorganisms. The importance of two major oxidant-producing enzymes, myeloperoxidase (MPO) and NADPH-oxidase, in in vivo fungicidal action was directly compared with genetically engineered mice. Although both MPO-deficient (MPO-KO) and NADPH-oxidase-deficient (CGD) mice showed increased susceptibility to pulmonary infections with Candida albicans and Aspergillus fumigatus compared with normal mice, superoxide (O_<2->) produced by NADPH-oxidase is more important than hypochlorous acid (HOCl) produced by MPO. We also observed that MPO-KO/CGD double knockout mice showed comparable levels of susceptibility to the CGD mice against C.albicans and A.fumigatus, indicating that MPO is unable to play a role in host defense in the absence of NADPH-oxidase. This strongly suggests that hydrogen peroxide, the precursor of HOCl, is solely derived from O_<2-> produced by NADPH-oxidase.To define the in vivo contribution of MPO to host defense against Cryptococcus infection, MPO-KO and control mice were infected with C.neoformans, and their survivals and fungal organ burdens were persued and the resulting data emphasize the essential role of MPO-dependent oxidative system for host defense against C.neoformans in vivo.

髓过氧化物酶(MPO)位于中性粒细胞内，能够产生次氯酸。吞噬细胞产生氧化产物被认为是一种重要的宿主防御机制，直接杀死入侵的微生物。两种主要的氧化剂产生酶，髓过氧化物酶(MPO)和NADPH-氧化酶，在体内杀菌作用中的重要性直接与基因工程小鼠进行比较。尽管MPO缺陷(MPO-KO)和NADPH-氧化酶缺陷(CGD)小鼠与正常小鼠相比，对白念珠菌和烟曲霉肺部感染的易感性增加，但NADPH-氧化酶产生的超氧化物(O_&lt；2-&gt；)比MPO产生的次氯酸(HOCl)更重要。我们还观察到MPO-KO/CGD双基因敲除小鼠对CGD小鼠对白色念珠菌和烟曲霉菌的敏感性水平相当，这表明在没有NADPH-氧化酶的情况下，MPO无法发挥宿主防御作用。为了确定MPO在体内对宿主防御新生隐球菌感染的贡献，研究了MPO-KO和对照小鼠感染新生弧菌后的存活和真菌器官负担，结果强调了MPO依赖的氧化系统在宿主体内防御新生隐球菌中的重要作用。

项目成果

Kawai, Y., Furuhata, A., Toyokuni, S., Aratani, Y., Uchida, K.: "Formation of acrolein-derived 2'-deoxyadenosine adduct in an iron-induced carcinogenesis model."J.Biol.Chem.. 278. 50346-50354 (2003)

Kawai, Y.、Furuhata, A.、Toyokuni, S.、Aratani, Y.、Uchida, K.：“在铁诱导的致癌模型中形成丙烯醛衍生的 2-脱氧腺苷加合物。”J.Biol.Chem

Akimitsu, N., Adachi, N., Hirai, H., Hossain, m., Hamamoto, H., Kobayashi, M., Aratani, Y., Koyama, H., Sekimizu, K: "Enforced cytokinesis without complete nuclear division in embryonic cells depleting the activity of DNA topoisomerase IIα."Genes Cells..

Akimitsu, N.、Adachi, N.、Hirai, H.、Hossain, m.、Hamamoto, H.、Kobayashi, M.、Aratani, Y.、Koyama, H.、Sekimizu, K：“没有完全核的强制胞质分裂胚胎细胞分裂会耗尽 DNA 拓扑异构酶 IIα 的活性。“Genes Cells..

Kawai, Y.: "Formation of acrolein-derived 2'-deoxyadenosine adduct in an iron-induced carcinogenesis model"J.Biol.Chem.. 278. 50346-50354 (2003)

Kawai，Y.：“铁诱导的致癌模型中丙烯醛衍生的 2-脱氧腺苷加合物的形成”J.Biol.Chem.. 278. 50346-50354 (2003)

Xiao, H.: "Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase (MPO-ANCA) cause glomerulonephritis and vasculitis in mice"J. Clin. Invest.. 110. 955-963 (2002)

肖，H.：“髓过氧化物酶特异性抗中性粒细胞胞质自身抗体（MPO-ANCA）导致小鼠肾小球肾炎和血管炎”J.

Akimitsu, N.: "Enforced cytokinesis without complete nuclear division in embryonic cells depleting the activity of DNA topoisomerase IIα"Genes Cells.. 8. 393-402 (2003)

Akimitsu, N.：“在胚胎细胞中强制胞质分裂，但没有完成核分裂，从而耗尽了 DNA 拓扑异构酶 IIα 的活性”Genes Cells.. 8. 393-402 (2003)