Gao Xiao-pei, Standiford Thedodore J, Rahman Arshad, Newstead Michael, Holland Steven M, Dinauer Mary C, Liu Qing-hui, Malik Asrar B
Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
J Immunol. 2002 Apr 15;168(8):3974-82. doi: 10.4049/jimmunol.168.8.3974.
We addressed the role of O(2) generated by the NADPH oxidase complex in the mechanism of polymorphonuclear leukocyte (PMN) accumulation and transalveolar migration and lung microvascular injury. Studies were made in mice lacking the p47(phox) and gp91(phox) subunits of NADPH oxidase (p47(phox-/-) and gp91(phox-/-)) in which PMN are incapable of the respiratory burst. The mice were challenged i.p. with live Escherichia coli to induce sepsis. We observed time-dependent increases in PMN sequestration and migration from 1 to 6 h after challenge with 2 x 10(8) E. coli. The responses in knockout mice were greater post-E. coli challenge compared with control mice; i.e., transalveolar PMN migration post-E. coli challenge increased by approximately 50% in the null mice above values in wild type. The increased PMN infiltration was associated with decreased lung bacterial clearance. The generation of the chemoattractant macrophage-inflammatory protein-2 in lung tissue was greater in NADPH oxidase-defective mice after E. coli challenge than control mice; moreover, macrophage-inflammatory protein-2 Ab pretreatment prevented the PMN infiltration. We also observed that E. coli failed to increase lung microvascular permeability in p47(phox-/-) and gp91(phox-/-) mice despite the greater lung PMN sequestration. Thus, O(2) production is required for the induction of sepsis-induced lung microvascular injury. We conclude that NADPH oxidase-derived O(2) generation has an important bactericidal role, such that an impairment in bacterial clearance in NADPH oxidase-defective mice results in increased chemokine generation and lung tissue PMN infiltration.
我们探讨了烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶复合物产生的氧（O₂）在多形核白细胞（PMN）聚集、跨肺泡迁移及肺微血管损伤机制中的作用。我们对缺乏NADPH氧化酶的p47（phox）和gp91（phox）亚基的小鼠（p47（phox-/-）和gp91（phox-/-））进行了研究，这些小鼠的PMN无法产生呼吸爆发。通过腹腔注射活的大肠杆菌对小鼠进行攻击以诱导脓毒症。在用2×10⁸大肠杆菌攻击后1至6小时，我们观察到PMN隔离和迁移呈时间依赖性增加。与对照小鼠相比，基因敲除小鼠在大肠杆菌攻击后的反应更大；即，在大肠杆菌攻击后，基因敲除小鼠的跨肺泡PMN迁移比野生型小鼠的值增加了约50%。PMN浸润增加与肺细菌清除率降低有关。大肠杆菌攻击后，NADPH氧化酶缺陷小鼠肺组织中趋化因子巨噬细胞炎性蛋白-2的产生比对照小鼠更多；此外，巨噬细胞炎性蛋白-2抗体预处理可防止PMN浸润。我们还观察到，尽管肺中PMN隔离更多，但大肠杆菌未能增加p47（phox-/-）和gp91（phox-/-）小鼠的肺微血管通透性。因此，脓毒症诱导的肺微血管损伤的诱导需要O₂的产生。我们得出结论，NADPH氧化酶衍生的O₂产生具有重要的杀菌作用，因此NADPH氧化酶缺陷小鼠中细菌清除受损导致趋化因子产生增加和肺组织PMN浸润增加。
