Inhibition of Inducible Nitric Oxide Controls Pathogen Load and Brain Damage by Enhancing Phagocytosis of Escherichia coli K1 in Neonatal Meningitis
Inhibition of Inducible Nitric Oxide Controls Pathogen Load and Brain Damage by Enhancing Phagocytosis of Escherichia coli K1 in Neonatal Meningitis
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DOI：
10.2353/ajpath.2010.090851
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发表时间：
2010-03-01
影响因子：
6
通讯作者：
Prasadarao, Nemani V.
中科院分区：
文献类型：
--
作者：
Mittal, Rahul;Gonzalez-Gomez, Ignacio;Prasadarao, Nemani V.
大肠杆菌K1是人类新生儿脑膜炎的主要原因。在这项研究中，我们试图确定诱导型一氧化氮（MOS）在实验性大肠杆菌中的病理生理相关性。大肠杆菌K1脑膜炎。通过使用新生小鼠脑膜炎模型，我们证明了大肠杆菌感染引发小鼠脑中iNOS的表达。此外，iNOS（-/-）小鼠对大肠杆菌K1感染有抵抗力，显示正常的脑组织学，无菌血症，血脑屏障无破坏，炎症反应减少。在感染前用iNOS特异性抑制剂氨基胍（AG）治疗野生型动物，可预防菌血症的发生和脑膜炎的发生。感染动物在出现菌血症后接受AG治疗，也完全清除了循环中的病原体并防止了脑损伤。脑组织病理学和显微CT分析显示E. coli K1感染的小鼠，其被AG施用完全消除。与大肠杆菌K1存活和繁殖的野生型小鼠的巨噬细胞和多形核白细胞相比，从iNOS（-/-）小鼠分离或用AG预处理的腹腔巨噬细胞和多形核白细胞表现出对细菌的摄取和杀伤增强。因此，iNOS产生的NO可能对E.结论：新生儿大肠杆菌感染后，诱导型一氧化氮合酶（iNOS）的表达增加，诱导型一氧化氮合酶（iNOS）的表达降低，可能是治疗新生儿大肠杆菌感染的一种治疗策略。大肠杆菌脑膜炎。(Am J Pathol 2010，176：1292-1305; DOI：10.2353/ajpath.2010.090851）
Escherichia coli K1 is a leading cause of neonatal meningitis in humans. in this study, we sought to determine the pathophysiologic relevance of inducible nitric oxide (MOS) in experimental E. coli K1 meningitis. By using a newborn mouse model of meningitis, we demonstrate that E coli infection triggered the expression of iNOS in the brains of mice. Additionally, iNOS(-/-) mice were resistant to E coli K1 infection, displaying normal brain histology, no bacteremia, no disruption of the blood-brain barrier, and reduced inflammatory response. Treatment with an iNOS specific inhibitor, aminoguanidine (AG), of wild-type animals before infection prevented the development of bacteremia and the occurrence of meningitis. The infected animals treated with AG after the development of bacteremia also completely cleared the pathogen from circulation and prevented brain damage. Histopathological and micro-CT analysis of brains revealed significant damage in E. coli K1-infected mice, which was completely abrogated by AG administration. Peritoneal macrophages and polymorphonuclear leukocytes isolated from iNOS(-/-) mice or pretreated with AG demonstrated enhanced uptake and killing of the bacteria compared with macrophages and polymorphonuclear leukocytes; from wild-type mice in which E coli K1 survive and multiply. Thus, NO produced by iNOS may be beneficial for E. coli to survive inside the macrophages, and prevention of iNOS could be a therapeutic strategy to treat neonatal E. coli meningitis. (Am J Pathol 2010,176:1292-1305; DOI: 10.2353/ajpath.2010.090851)