Lefort J, Motreff L, Vargaftig B B
Unité de Pharmacologie Cellulaire, Institut Pasteur, Paris, France.
Am J Respir Cell Mol Biol. 2001 Mar;24(3):345-51. doi: 10.1165/ajrcmb.24.3.4289.
The effects of the administration of Escherichia coli endotoxin (lipopolysaccharide, LPS) into the airways of C57Bl/6 mice were studied. Neutrophil sequestration in the lungs and their enrichment, together with tumor necrosis factor (TNF)-alpha, in bronchoalveolar lavage fluid (BALF) were associated with bronchoconstriction and bronchopulmonary hyperreactivity (BHR) to methacholine and alveolocapillary dysfunction. Granulocyte depletion by the myelotoxic drug vinblastine failed to modify TNF-alpha production and prevented LPS-induced neutrophil recruitment to lungs and BALF, bronchoconstriction, and BHR. Neutrophils were again sequestered in the lungs when LPS was administered 4 to 5 d after vinblastine, whereas inhibition of their passage to BALF persisted. Under those conditions, bronchoconstriction and BHR by LPS also recovered, showing that these functional effects are independent from BALF neutrophil enrichment but require lung sequestration. Administration of granulocyte colony-stimulating factor after vinblastine counteracted its effects and allowed the recovery of lung neutrophil sequestration by LPS and a partial recovery of bronchoconstriction under conditions where neutrophils still failed to migrate to BALF. Dexamethasone (the phosphate salt and its free base) suppressed LPS-induced TNF-alpha generation in BALF and its neutrophil enrichment, whereas neutrophil lung sequestration, bronchoconstriction, BHR, and alveolocapillary dysfunction were marginally reduced and only so at low doses of dexamethasone, higher doses being inactive or aggravating. In situ neutrophil activation could account for LPS-induced bronchoconstriction and BHR, both of which are refractory to steroids and appear to be mediated by unrelated mechanisms, which may be relevant for acute respiratory distress syndrome, a condition for which LPS administration is used as a model.
研究了将大肠杆菌内毒素（脂多糖，LPS）注入C57Bl/6小鼠气道的影响。肺中的中性粒细胞滞留及其在支气管肺泡灌洗液（BALF）中与肿瘤坏死因子（TNF）-α的富集与支气管收缩以及对乙酰甲胆碱的支气管肺高反应性（BHR）和肺泡毛细血管功能障碍有关。骨髓毒性药物长春碱导致的粒细胞减少未能改变TNF-α的产生，并阻止了LPS诱导的中性粒细胞向肺和BALF的募集、支气管收缩和BHR。在长春碱给药后4至5天给予LPS时，中性粒细胞再次滞留在肺中，而其向BALF的迁移抑制仍然存在。在这些条件下，LPS引起的支气管收缩和BHR也恢复了，表明这些功能效应独立于BALF中性粒细胞富集，但需要肺滞留。长春碱给药后给予粒细胞集落刺激因子可抵消其作用，并在中性粒细胞仍无法迁移至BALF的情况下，使LPS诱导的肺中性粒细胞滞留恢复以及支气管收缩部分恢复。地塞米松（磷酸盐及其游离碱）抑制LPS诱导的BALF中TNF-α的产生及其中性粒细胞富集，而中性粒细胞肺滞留、支气管收缩、BHR和肺泡毛细血管功能障碍仅在低剂量地塞米松时略有降低，高剂量则无活性或会加重病情。原位中性粒细胞活化可能是LPS诱导的支气管收缩和BHR的原因，这两者对类固醇均具有抗性，并且似乎由不相关的机制介导，这可能与急性呼吸窘迫综合征有关，在该综合征中LPS给药被用作模型。
