Savov Jordan D, Brass David M, Lawson Barbara L, McElvania-Tekippe Erin, Walker Julia K L, Schwartz David A
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Am J Physiol Lung Cell Mol Physiol. 2005 Aug;289(2):L329-37. doi: 10.1152/ajplung.00014.2005. Epub 2005 Apr 15.
Although chronic inhalation of endotoxin or lipopolysaccharide (LPS) causes all of the classic features of asthma, including airway hyperreactivity, airway inflammation, and airway remodeling, the mechanisms involved in this process are not clearly understood. The objective of this study was to determine whether intratracheal treatment with LPS antagonist (E5564, a lipid A analog) prevented the development of chronic endotoxin-induced airway disease in a mouse model of environmental airway disease. Pretreatment with 10 and 100 microg of E5564 was found to inhibit the airway response (hyperreactivity and inflammation) for up to 48 h after the administration of the compound. Repeated dosing with 50 microg of E5564 intratracheally did not cause any measurable toxicity. Therefore, in a chronic experiment, mice were treated with either E5564 (50 microg) or vehicle three times weekly for 5 wk and simultaneously daily exposed to either LPS (4.65 +/- 0.30 microg/m3) or saline aerosol. E5564 was effective in decreasing the airway hyperreactivity to methacholine, the air space neutrophilia, the interleukin-6 in the lung lavage fluid, and the neutrophil infiltration of the airways 36 h after 5 wk of LPS inhalation. Less collagen deposition was observed in the airways of E5564-treated mice compared with vehicle-treated mice after a 4-wk recovery period. Our results indicate that E5564, a Toll-like receptor 4 antagonist, minimizes the physiological and biological effects of chronic LPS inhalation, suggesting a therapeutic role for competitive LPS antagonists in preventing or reducing endotoxin-induced environmental airway disease.
尽管长期吸入内毒素或脂多糖（LPS）会引发哮喘的所有典型特征，包括气道高反应性、气道炎症和气道重塑，但这一过程所涉及的机制尚未完全明确。本研究的目的是确定在环境性气道疾病小鼠模型中，气管内给予LPS拮抗剂（E5564，一种脂质A类似物）是否能预防慢性内毒素诱导的气道疾病的发生。研究发现，预先给予10微克和100微克的E5564可在给予该化合物后长达48小时内抑制气道反应（高反应性和炎症）。气管内重复给予50微克的E5564未引起任何可测量的毒性。因此，在一项慢性实验中，小鼠每周接受三次E5564（50微克）或赋形剂治疗，持续5周，同时每天暴露于LPS（4.65±0.30微克/立方米）或盐雾气溶胶中。在吸入LPS 5周后36小时，E5564可有效降低气道对乙酰甲胆碱的高反应性、气腔中性粒细胞增多、肺灌洗液中的白细胞介素-6以及气道中的中性粒细胞浸润。在4周的恢复期后，与接受赋形剂治疗的小鼠相比，接受E5564治疗的小鼠气道中观察到的胶原蛋白沉积较少。我们的结果表明，Toll样受体4拮抗剂E5564可将长期吸入LPS的生理和生物学效应降至最低，这表明竞争性LPS拮抗剂在预防或减少内毒素诱导的环境性气道疾病中具有治疗作用。
