Schwartz D A, Christ W J, Kleeberger S R, Wohlford-Lenane C L
Pulmonary, Critical Care, and Occupational Medicine Division, Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242, USA.
Am J Physiol Lung Cell Mol Physiol. 2001 Apr;280(4):L771-8. doi: 10.1152/ajplung.2001.280.4.L771.
To determine whether the inflammatory effects of inhaled endotoxin could be prevented, we pretreated mice with synthetic competitive antagonists (975, 1044, and 1287) for lipopolysaccharide (LPS) before a LPS inhalation challenge. In preliminary studies, we found that these LPS antagonists did not act as agonists in vitro (THP-1 cells) or in vivo (after intratracheal instillation of 10 microg) and that these compounds (at least 1 microg/ml) effectively antagonized the release of tumor necrosis factor-alpha by LPS-stimulated THP-1 cells. Pretreatment of mice with 10 microg of either 1044 or 1287 resulted in a decrease in the LPS-induced airway hyperreactivity. Moreover, pretreatment of mice with 10 microg of 975, 1044, or 1287 resulted in significant reductions in LPS-induced lung lavage fluid concentrations of total cells, neutrophils, and specific proinflammatory cytokines compared with mice pretreated with sterile saline. Using residual oil fly ash to induce airway inflammation, we found that the action of the LPS antagonists was specific to LPS-induced airway disease. These results suggest that LPS antagonists may be an effective and potentially safe treatment for endotoxin-induced airway disease.
为了确定吸入内毒素的炎症效应是否能够被预防，我们在吸入脂多糖（LPS）激发之前，用脂多糖的合成竞争性拮抗剂（975、1044和1287）对小鼠进行预处理。在初步研究中，我们发现这些LPS拮抗剂在体外（THP-1细胞）或体内（气管内滴注10微克后）均不表现为激动剂，并且这些化合物（至少1微克/毫升）能有效拮抗LPS刺激的THP-1细胞释放肿瘤坏死因子-α。用10微克的1044或1287对小鼠进行预处理，可使LPS诱导的气道高反应性降低。此外，与用无菌盐水预处理的小鼠相比，用10微克的975、1044或1287对小鼠进行预处理，可使LPS诱导的肺灌洗液中总细胞、中性粒细胞和特定促炎细胞因子的浓度显著降低。利用残留油飞灰诱导气道炎症，我们发现LPS拮抗剂的作用对LPS诱导的气道疾病具有特异性。这些结果表明，LPS拮抗剂可能是治疗内毒素诱导的气道疾病的一种有效且潜在安全的方法。
