Host Defense and Inflammatory Diseases in Mice Deficient in Myeloperoxidase

髓过氧化物酶缺陷小鼠的宿主防御和炎症性疾病

• 批准号: 12660274
• 负责人: ARATANI Yasuaki
• 金额: $ 1.98万
• 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: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12660274/
• 关键词: neutrophil; myeloperoxidase; immunology; infectious disease; reactive oxygen species; 感染

Myeloperoxidase (MPO) is located within neutrophils capable of producing hypochlorous acid. To define the in vivo contribution of MPO to early host defense against pulmonary infections, MPO-deficient [MPO(-/-)] and control [MPO(+/+)] mice were infected with various fungi and bacteria. MPO(-/-) mice showed severely reduced cytotoxicity to Candida albicans, Candida Tropicalis, trichosporon asahii, and Pseudomonas aeruginosa. On the contrary, the mutant mice showed slightly but significantly delayed clearance of Aspergillus fumigatus and Klebsiella pneumoniae, and showed comparable levels of resistance to the wild-type against Candida glabrata, Cryptococcus neoformans, Staphylococcus aureus, and Streptococcus pneumoniae. These results suggest that MPO-dependent oxidative system is important for host defense against fungi and bacteria. Oxygen metabolites generated by MPO and NADPH-oxidase contribute to microbial killing by phagocytes. To compare the importance of the two enzymes for host d … More efense, MPO(-/-) and NADPH-oxidase-deficient mice (CGD mice) were infected with different doses of C. albicans. Interestingly, at the highest dose, the mortality of MPO(-/-) mice was comparable to CGD mice, but was the same as normal mice at the lowest dose, suggesting that MPO and NADPH-oxidase are equally important for early host defense against a large inocula of Candida.Neutrophil apoptosis represents a mechanism involved in the resolution of inflammation. To explore the role of HOCl produced by neutrophils in apoptosis, we compared the rates of apoptosis in neutrophils isolated from MPO(+/+) mice and MPO(-/-) mice lacking HOCl generation. Apoptosis in MPO(-/-) neutrophils stimulated by PMA was significantly slower than that in MPO(+/+) neutrophils. Exposure of MPO(+/+) neutrophils to H_2O_2 together with PMA resulted in a dramatical acceleration of apoptosis. This acceleration was inhibited by an superoxide scavenger. These results suggest that coexistence of HOCl and superoxide accelerate the neutrophil apoptosis. Less

髓过氧化物酶（MPO）位于能够产生次氯酸的中性粒细胞内。为了确定MPO对肺部感染的早期宿主防御的体内贡献，用各种真菌和细菌感染MPO缺陷[MPO（-/-）]和对照[MPO（+/+）]小鼠。MPO（-/-）小鼠对白色念珠菌、热带念珠菌、阿萨希丝孢酵母和铜绿假单胞菌的细胞毒性严重降低。相反，突变小鼠表现出轻微但显著延迟的烟曲霉和肺炎克雷伯菌的清除，并表现出与野生型相当的抗光滑念珠菌、新型隐球菌、金黄色葡萄球菌和肺炎链球菌的耐药性。这些结果表明，MPO依赖的氧化系统是重要的宿主防御真菌和细菌。MPO和NADPH氧化酶产生的氧代谢产物有助于吞噬细胞杀死微生物。比较这两种酶对宿主细胞的重要性， ...更多信息 用不同剂量的C.白色念珠菌有趣的是，在最高剂量下，MPO（-/-）小鼠的死亡率与CGD小鼠相当，但在最低剂量下与正常小鼠相同，这表明MPO和NADPH氧化酶对于早期宿主防御大的念珠菌接种物同样重要。为了探索嗜中性粒细胞产生的HOCl在细胞凋亡中的作用，我们比较了从MPO（+/+）小鼠和缺乏HOCl产生的MPO（-/-）小鼠分离的嗜中性粒细胞的细胞凋亡率。PMA刺激MPO（-/-）中性粒细胞凋亡明显慢于MPO（+/+）中性粒细胞。H_2O_2和PMA共同作用于MPO（+/+）中性粒细胞，可显著加速细胞凋亡。这种加速被超氧化物清除剂抑制。结果表明，HOCl和超氧阴离子共存可加速中性粒细胞凋亡。少

项目成果

Akiko Ishida-Okawara: "Contribution of myeloperoxidase to coronary artery vasculius associated with MPO-ANCA production"Inflammation. 25. 381-387 (2001)

Akiko Ishida-Okawara：“髓过氧化物酶对与 MPO-ANCA 产生相关的冠状动脉血管的贡献”炎症。

Yasuaki Aratani: "Differential host susceptibility to pulmonary infection with bacteria and fungi in mice deficient in myeloperoxidase"J. Infect. Dis.. 182. 1276-1279 (2000)

Yasuaki Aratani：“髓过氧化物酶缺陷小鼠对细菌和真菌肺部感染的不同宿主易感性”J。

Shunya Takizawa: "Deficiency of myeloperoxidase increases infarct volume and nitrotyrosine formation in mouse brain"J. Cereb. Blood Flow Met.. 22. 50-54 (2002)

Shunya Takizawa：“髓过氧化物酶的缺乏会增加小鼠大脑中的梗塞体积和硝基酪氨酸的形成”J。

Shinya Takizawa: "Deficiency of myeloperoxidase increases infarct volume and nitrotyrosine formation in mouse brain"J. Cereb. Blood Flow Met.. 22. 50-54 (2002)

Shinya Takizawa：“髓过氧化物酶的缺乏会增加小鼠大脑中的梗塞体积和硝基酪氨酸的形成”J。

Shunya Takizawa: "Deficiency of myeloperoxidase increases infarct volume and nitrotyrosine formation in mouse brain"J.Cereb.Blood Flow Met.. 22. 50-54 (2002)

Shunya Takizawa：“髓过氧化物酶缺乏会增加小鼠大脑中的梗塞体积和硝基酪氨酸形成”J.Cereb.Blood Flow Met.. 22. 50-54 (2002)