Host Defense and Inflammatory Diseases in Mice Deficient in Myeloperoxidase

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在体内对早期宿主防御肺部感染的贡献，我们用多种真菌和细菌感染MPO缺陷小鼠[MPO(-/-)]和对照小鼠[MPO(+/+)]。MPO（-/-）小鼠对白色念珠菌、热带念珠菌、asahitrichosporon和铜绿假单胞菌的细胞毒性严重降低。相反，突变小鼠对烟曲霉和肺炎克雷伯菌的清除时间略有但明显延迟，对光秃假丝酵母菌、新型隐球菌、金黄色葡萄球菌和肺炎链球菌的耐药性也与野生型相当。这些结果表明，mpo依赖的氧化系统对宿主防御真菌和细菌很重要。由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。以MPO（-/-）和nadph氧化酶缺陷小鼠（CGD小鼠）感染不同剂量的白色念菌，比较两种酶对宿主防御的重要性。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氧化酶在早期宿主防御大量念珠菌的过程中同样重要。中性粒细胞凋亡是一种参与炎症消退的机制。为了探讨中性粒细胞产生HOCl在细胞凋亡中的作用，我们比较了MPO（+/+）小鼠和MPO（-/-）小鼠分离的中性粒细胞的凋亡率。PMA刺激MPO（-/-）中性粒细胞的凋亡明显慢于MPO（+/+）中性粒细胞。MPO（+/+）中性粒细胞暴露于H_2O_2和PMA可显著加速细胞凋亡。这种加速被一种超氧化物清除剂所抑制。这些结果表明HOCl和超氧化物的共存加速了中性粒细胞的凋亡。少

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