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

第一项研究在MPO缺陷(MPO-KO)小鼠模型中研究了髓过氧化物酶(MPO)在防御新生隐球菌中的作用。感染新生弧菌的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小鼠对新生葡萄球菌的Th1反应较弱。MPO-KO小鼠表现出比野生型更严重的肺炎，这与肺组织中IL-1α/β水平的升高有关。在MPO-KO小鼠中，肺部感染扩散到大脑，偶尔伴有脑膜炎。MPO-KO感染组小鼠脑内KC水平高于对照组。这些数据表明MPO在应对隐球菌感染中发挥了重要作用。第二项研究探讨了中性粒细胞衍生的ROS在中性粒细胞重新聚集到紫外线B(UVB)暴露的小鼠皮肤中的作用。紫外线照射MPO和/或NADPH氧化酶缺陷小鼠可引起…皮肤中性粒细胞更多的滤过分别在60、48和48h达到峰值，早于野生型小鼠的72h峰值。突变体的MIP-2水平高于野生型。中性粒细胞向局部来源的KC的迁移，突变型高于野生型。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。这可能解释了突变的中性粒细胞对UVB反应的早期渗透。佛波酯(PMA)刺激正常小鼠中性粒细胞导致染色质缩合和磷脂酰丝氨酸外化的加速，而这与caspase-3的激活无关。蛋白激酶C和p38丝裂原活化蛋白激酶(P38MAPK)的特异性抑制剂可完全抑制caspase非依赖性死亡。P38MAPK的激活受蛋白激酶C的调节，另一方面，NADPH氧化酶缺陷的中性粒细胞的细胞死亡被消除。在正常和MPO-KO中性粒细胞中，p38MAPK被PMA激活，而在NADPH氧化酶缺陷的中性粒细胞中不被激活。这些结果有力地表明，p38MAPK的激活受内源性产生的超氧化物或其代谢产物的调节，而不是HOCl。较少

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