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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）小鼠模型中防御新生隐球菌的作用。感染新型隐球菌的MPO-KO小鼠的存活率低于野生型。MPO-KO小鼠的肺真菌负荷显著大于野生型小鼠。在第7天，MPO-KO小鼠表现出弱的Th1反应，新生隐球菌。MPO-KO小鼠表现出比野生型更严重的肺炎，这与肺中IL-1 α/β水平的增加有关。在MPO-KO小鼠中，肺部感染扩散到大脑，偶尔出现脑膜炎。感染MPO-KO小鼠脑内KC水平明显高于对照组。这些数据表明MPO在对隐球菌感染的反应中起主要作用。第二项研究检查了嗜中性粒细胞衍生的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。UVB照射MPO、NADPH氧化酶或两者缺陷的小鼠， ...更多信息滤过率分别在60、48和48小时达到峰值，这比野生型小鼠的72小时峰值早。突变型MIP-2表达高于野生型。突变体中的KC向局部来源的神经元迁移高于野生型。这些结果表明，由中性粒细胞产生的ROS调节MIP-2的表达和中性粒细胞向KC的迁移。这可能解释了早期的突变体中性粒细胞的浸润，在UVB。刺激正常小鼠中性粒细胞与佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）导致加速染色质凝聚和磷脂酰丝氨酸外化，这是不相关的caspase-3激活。Caspase非依赖性死亡被蛋白激酶C和p38丝裂原活化蛋白激酶（p38MAPK）的特异性抑制剂完全抑制。p38 MAPK的激活受蛋白激酶C的调节。另一方面，NADPH氧化酶缺陷型中性粒细胞的细胞死亡被消除。PMA可激活正常和MPO-KO中性粒细胞中的p38 MAPK，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。少