Hollingsworth John W, Cook Donald N, Brass David M, Walker Julia K L, Morgan Daniel L, Foster W Michael, Schwartz David A
Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Am J Respir Crit Care Med. 2004 Jul 15;170(2):126-32. doi: 10.1164/rccm.200311-1499OC. Epub 2004 Mar 12.
Inhalation of toxins commonly found in air pollution contributes to the development and progression of asthma and environmental airway injury. In this study, we investigated the requirement of toll-like receptor 4 (TLR4) in mice for pulmonary responses to three environmental toxins: aerosolized lipopolysaccharide, particulate matter (residual oil fly ash), and ozone. The physiologic and biologic responses to these toxins were evaluated by the extent of airway responsiveness, neutrophil recruitment to the lower respiratory tract, changes in inflammatory cytokines, and the concentration of protein in the lavage fluid. Genetically engineered, TLR4-deficient mice (C57BL/6(TLR4-/-)) were unresponsive to inhaled lipopolysaccharide, except for minimal increases in some inflammatory cytokines. In contrast, C57BL/6(TLR4-/-) mice did not differ from wild-type mice in their airway response to instilled residual oil fly ash or acute ozone exposure; however, we found that, despite a robust inflammatory response, C57BL/6(TLR4-/-) mice are protected against the development of airway hyperresponsiveness after subchronic ozone exposure. These data demonstrate in the mouse that the requirement of TLR4 for pulmonary inflammation depends on the nature of the toxin and appears specific to toxin and exposure conditions.
吸入空气污染中常见的毒素会导致哮喘的发展和恶化以及环境性气道损伤。在本研究中，我们调查了小鼠体内的Toll样受体4（TLR4）对三种环境毒素的肺部反应的必要性：雾化脂多糖、颗粒物（残留油飞灰）和臭氧。通过气道反应性程度、中性粒细胞向呼吸道下部的募集、炎性细胞因子的变化以及灌洗液中的蛋白质浓度来评估对这些毒素的生理和生物学反应。基因工程改造的TLR4缺陷小鼠（C57BL/6(TLR4-/-)）对吸入的脂多糖无反应，除了某些炎性细胞因子有轻微增加。相比之下，C57BL/6(TLR4-/-)小鼠在对注入残留油飞灰或急性臭氧暴露的气道反应方面与野生型小鼠没有差异；然而，我们发现，尽管有强烈的炎症反应，但C57BL/6(TLR4-/-)小鼠在亚慢性臭氧暴露后可免受气道高反应性的发展。这些数据在小鼠中证明，TLR4对肺部炎症的需求取决于毒素的性质，并且似乎对毒素和暴露条件具有特异性。
