Koay M Audrey, Gao Xiang, Washington Mary Kay, Parman Kelly S, Sadikot Ruxana T, Blackwell Timothy S, Christman John W
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2650, USA.
Am J Respir Cell Mol Biol. 2002 May;26(5):572-8. doi: 10.1165/ajrcmb.26.5.4748.
To define the role of macrophages in regulating the lung's response to Escherichia coli endotoxin (lipopolysaccharide [LPS]), depletion of macrophages was accomplished by administration of dichloromethylene diphosphonate (clodronate) delivered via intratracheal (i.t.) and/or intravenous (i.v.) routes. Clodronate reduced the number of macrophages in lung lavage 48 h after either i.t. or i.v. administration, but combined i.t. + i.v. clodronate achieved the most profound depletion (90%). Although i.t. clodronate alone had little effect on the evolution of lung inflammation, combined i.t. + i.v. clodronate treatment decreased neutrophilic alveolitis 4 h after exposure to aerosolized LPS by 80% compared with mice treated with empty liposomes. This decrease was associated with impaired activation of nuclear factor (NF)-kappa B and lower concentrations of tumor necrosis factor (TNF)-alpha in lung lavage fluid. Combined i.t. + i.v. clodronate markedly reduced lung NF-kappa B activation and the intensity of neutrophilic alveolitis after intraperitoneal (i.p.) LPS; however, i.v. clodronate alone had no effect on NF-kappa B activation in either liver or lung tissue or the development of neutrophilic alveolitis. We conclude that generalized macrophage depletion reduces NF-kappa B activation, generation of cytokines, and neutrophilic lung inflammation in response to gram negative bacterial endotoxin. These findings define the role of the macrophage as a critical component for initiation of the NF-kappa B-dependent innate immune response.
为了确定巨噬细胞在调节肺部对大肠杆菌内毒素（脂多糖[LPS]）反应中的作用，通过气管内（i.t.）和/或静脉内（i.v.）途径给予二氯亚甲基二膦酸盐（氯膦酸盐）来实现巨噬细胞的清除。氯膦酸盐在i.t.或i.v.给药后48小时减少了肺灌洗中的巨噬细胞数量，但i.t. + i.v.联合使用氯膦酸盐实现了最显著的清除效果（90%）。尽管单独使用i.t.氯膦酸盐对肺部炎症的发展影响不大，但与用空脂质体处理的小鼠相比，i.t. + i.v.联合使用氯膦酸盐治疗在暴露于雾化LPS后4小时使中性粒细胞性肺泡炎减少了80%。这种减少与肺灌洗液中核因子（NF）-κB的激活受损和肿瘤坏死因子（TNF）-α浓度降低有关。i.t. + i.v.联合使用氯膦酸盐显著降低了腹腔内（i.p.）注射LPS后肺NF-κB的激活和中性粒细胞性肺泡炎的强度；然而，单独使用i.v.氯膦酸盐对肝脏或肺组织中的NF-κB激活以及中性粒细胞性肺泡炎的发展没有影响。我们得出结论，全身性巨噬细胞清除可减少对革兰氏阴性细菌内毒素的NF-κB激活、细胞因子生成和中性粒细胞性肺部炎症。这些发现确定了巨噬细胞作为NF-κB依赖性先天免疫反应启动的关键组成部分的作用。
