Macrophages are necessary for maximal nuclear factor-κB activation in response to endotoxin
Macrophages are necessary for maximal nuclear factor-κB activation in response to endotoxin
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DOI：
10.1165/ajrcmb.26.5.4748
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发表时间：
2002-05-01
影响因子：
6.4
通讯作者：
Christman, JW
中科院分区：
文献类型：
--
作者：
Koay, MA;Gao, X;Christman, JW
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 (IT) 和/或静脉内 (IV) 途径施用二氯亚甲基二膦酸盐（氯膦酸盐）来消除巨噬细胞。 IT 或 IV 给药后 48 小时，氯膦酸盐减少了肺灌洗液中巨噬细胞的数量，但 IT + IV 联合氯膦酸盐实现了最严重的消除（90％）。虽然单独使用IT氯膦酸盐对肺部炎症的进展影响不大，但与用空脂质体治疗的小鼠相比，IT+IV氯膦酸盐联合治疗在暴露于雾化LPS 4小时后使中性粒细胞性肺泡炎减少了80%。这种减少与核因子 (NF)-κB 激活受损和肺灌洗液中肿瘤坏死因子 (TNF)-α 浓度降低有关。 IT+IV 联合氯膦酸盐可显着降低腹膜内 (IP) LPS 后肺 NF-κB 的激活和中性粒细胞性肺泡炎的强度；然而，单独静脉注射氯膦酸盐对肝脏或肺组织中的 NF-κB 激活或中性粒细胞性肺泡炎的发展没有影响。我们得出的结论是，巨噬细胞的全面耗竭会减少 NF-κB 的激活、细胞因子的产生以及革兰氏阴性细菌内毒素引起的中性粒细胞性肺部炎症。这些发现定义了巨噬细胞作为启动 NF-κB 依赖性先天免疫反应的关键成分的作用。
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 (IT) and/or intravenous (IV) routes. Clodronate reduced the number of macrophages in lung lavage 48 h after either IT or IV administration, but combined IT+IV clodronate achieved the most profound depletion (90%). Although IT clodronate alone had little effect on the evolution of lung inflammation, combined IT+IV 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)-kappaB and lower concentrations of tumor necrosis factor (TNF)-alpha in lung lavage fluid. Combined IT+IV clodronate markedly reduced lung NF-kappaB activation and the intensity of neutrophilic alveolitis after intraperitoneal (IP) LPS; however, IV clodronate alone had no effect on NF-kappaB activation in either liver or lung tissue or the development of neutrophilic alveolitis. We conclude that generalized macrophage depletion reduces NF-kappaB 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-kappaB-dependent innate immune response.