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Impaired host defense and increased inflammation in mice deficient in myeloperoxidase and NADPH-oxidase

髓过氧化物酶和 NADPH 氧化酶缺陷小鼠的宿主防御受损并增加炎症

基本信息

批准号：
16580243
负责人：
ARATANI Yasuaki
金额：
$ 2.37万
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：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16580243/
关键词：
neutrophil reactive oxygen species infection inflammation apoptosis

项目摘要

The first study investigated the role of myeloperoxidase (MPO) in defense against Cryptococcus neoformans in a MPO-deficient (MPO-KO) mouse model. The survival of MPO-KO mice infected with C.neoformans was lower than that wild-type. The MPO-KO mice had significantly larger lung fungal burdens than wild-type mice. On day 7,MPO-KO mice showed a weak Th1 response to C.neoformans. The MPO-KO mice showed more severe pneumonia than wild-type, which was associated with the increase in the levels of IL-1α/β in the lungs. In MPO-KO mice, the pulmonary infection disseminated to the brain with occasional meningitis. KC level in the brain of infected MPO-KO mice was higher than that of control mice. These data suggest a major role of MPO in the response to cryptococcal infection.The second study examined the role of neutrophil-derived ROS in neutrophil recruitment into ultraviolet B (UVB)-exposed skin of mice. UVB exposure of mice deficient in MPO, NADPH oxidase, or both, caused skin neutrophil in … More filtration peaking at 60, 48, and 48 h, respectively, which was earlier than the 72-h peak in wild-type mice. MIP-2 level was higher in mutant than wild-type. Neutrophil migration toward a localized source of KC was higher in mutant than wild-type. These results suggest that ROS produced by neutrophils regulate expression of MIP-2 and migration of neutrophils toward KC. This may explain the earlier infiltration of mutant neutrophils in response to UVB.Stimulation of normal mouse neutrophils with phorbol 12-myristate 13-acetate (PMA) resulted in an acceleration of chromatin condensation and phosphatidylserine externalization that was not associated with caspase-3 activation. Caspase-independent death was completely inhibited by specific inhibitors for protein kinase C and p38 mitogen-activated protein kinase (p38MAPK), respectively. Activation of p38 MAPK is regulated by protein kinase C. On the other hand, cell death was abolished in NADPH oxidase-deficient neutrophils. p38 MAPK was activated by PMA in normal and MPO-KO neutrophils, whereas no activation was observed in NADPH oxidase-deficient neutrophils. These results strongly suggest that activation of p38 MAPK is regulated by endogenously generated superoxide or its metabolites other than HOCl. Less

第一项研究调查了髓过氧化物酶 (MPO) 在 MPO 缺陷 (MPO-KO) 小鼠模型中防御新型隐球菌的作用。感染新型隐球菌的MPO-KO小鼠的存活率低于野生型。 MPO-KO 小鼠的肺部真菌负荷明显大于野生型小鼠。第7天，MPO-KO小鼠对新型隐球菌表现出较弱的Th1反应。 MPO-KO小鼠表现出比野生型更严重的肺炎，这与肺部IL-1α/β水平的增加有关。在 MPO-KO 小鼠中，肺部感染扩散到大脑，偶尔伴有脑膜炎。感染 MPO-KO 小鼠大脑中的 KC 水平高于对照小鼠。这些数据表明 MPO 在对隐球菌感染的反应中发挥着重要作用。第二项研究检查了中性粒细胞衍生的 ROS 在中性粒细胞募集到紫外线 B (UVB) 暴露的小鼠皮肤中的作用。缺乏 MPO、NADPH 氧化酶或两者的小鼠受到 UVB 照射，会导致皮肤中性粒细胞滤过率分别在 60、48 和 48 小时达到峰值，这早于野生型小鼠的 72 小时峰值。突变体中的MIP-2水平高于野生型。突变型中性粒细胞向 KC 局部来源的迁移高于野生型。这些结果表明，中性粒细胞产生的 ROS 调节 MIP-2 的表达和中性粒细胞向 KC 的迁移。这可能解释了突变中性粒细胞响应 UVB 的早期浸润。用佛波醇 12-肉豆蔻酸酯 13-乙酸酯 (PMA) 刺激正常小鼠中性粒细胞会导致染色质浓缩和磷脂酰丝氨酸外化加速，而这与 caspase-3 激活无关。蛋白激酶 C 和 p38 丝裂原激活蛋白激酶 (p38MAPK) 的特异性抑制剂分别完全抑制 Caspase 依赖性死亡。 p38 MAPK 的激活受蛋白激酶 C 调节。另一方面，NADPH 氧化酶缺陷的中性粒细胞中的细胞死亡被消除。 p38 MAPK 在正常和 MPO-KO 中性粒细胞中被 PMA 激活，而在 NADPH 氧化酶缺陷的中性粒细胞中未观察到激活。这些结果强烈表明 p38 MAPK 的激活受到内源性产生的超氧化物或其代谢物（HOCl 除外）的调节。较少的