TLR4 Is Necessary for Hyaluronan-mediated Airway Hyperresponsiveness after Ozone Inhalation (Publication with Expression of Concern)
TLR4 Is Necessary for Hyaluronan-mediated Airway Hyperresponsiveness after Ozone Inhalation (Publication with Expression of Concern)
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DOI：
10.1164/rccm.200903-0381oc
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发表时间：
2010-04-01
影响因子：
24.7
通讯作者：
Hollingsworth, John W.
中科院分区：
文献类型：
--
作者：
Garantziotis, Stavros;Li, Zhuowei;Hollingsworth, John W.
理由：臭氧是一种常见的环境空气污染物，会导致呼吸道疾病住院。调节臭氧引起的气道高反应性的机制仍然知之甚少。我们之前曾报道过，Toll 样受体 4 (TLR4) 缺陷的动物可以免受臭氧诱导的气道高反应性 (AHR)，并且透明质酸 (HA) 介导臭氧诱导的 AHR。然而，TLR4 和透明质酸在臭氧气道反应中的关系仍未被探索。目的：我们假设 HA 作为内源性 TLR4 配体，在臭氧诱导的环境气道损伤后发生 AHR。方法：将 TLR4 缺陷型和野生型 C57BL/6 小鼠暴露于吸入臭氧或气管内 HA，并测量炎症和 AHR 反应。测量和主要结果：吸入臭氧后，TLR4 缺陷小鼠的细胞炎症、肺损伤和可溶性 HA 水平与 C57BL/6 小鼠相似。然而，TLR4缺陷型小鼠在臭氧暴露后以及直接气管内滴注不含内毒素的低分子量HA后可部分免受AHR的影响。在接触臭氧或 HA 后，在支气管肺泡灌洗液中观察到类似的 TLR4 依赖性细胞因子模式。暴露于臭氧会增加肺巨噬细胞上 TLR4 的免疫组织学染色。此外，骨髓源性巨噬细胞的体外 HA 暴露诱导 NF-κ B 并以依赖于 TLR4 的方式产生类似模式的促炎细胞因子。 结论：我们的观察结果支持细胞外基质 HA 导致臭氧诱导的气道疾病的观察结果。此外，我们的结果支持 TLR4 通过介导促炎细胞因子的产生和臭氧诱导的 AHR 的发展来促进对 HA 的生物反应。
Rationale: Ozone is a common environmental air pollutant that contributes to hospitalizations for respiratory illness. The mechanisms, which regulate ozone-induced airway hyperresponsiveness, remain poorly understood. We have previously reported that toll-like receptor 4 (TLR4) deficient animals are protected against ozone-induced airway hyperresponsiveness (AHR) and that hyaluronan (HA) mediates ozone-induced AHR. However, the relation between TLR4 and hyaluronan in the airway response to ozone remains unexplored.Objectives: We hypothesized that HA acts as an endogenous TLR4 ligand for the development of AHR after ozone-induced environmental airway injury.Methods: TLR4-deficient and wild-type C57BL/6 mice were exposed to either inhaled ozone or intratracheal HA and the inflammatory and AHR response was measured.Measurements and Main Results: TLR4-deficient mice have similar levels of cellular inflammation, lung injury, and soluble HA levels as those of C57BL/6 mice after inhaled ozone exposure. However, TLR4-deficient mice are partially protected from AHR after ozone exposure as well as after direct intratracheal instillation of endotoxin-free low molecular weight HA. Similar patterns of TLR4-dependent cytokines were observed in the bronchial alveolar lavage fluid after exposure to either ozone or HA. Exposure to ozone increased immunohistological staining of TLR4 on lung macrophages. Furthermore, in vitro HA exposure of bone marrow derived macrophages induced NF-kappa B and production of a similar pattern of proinflammatory cytokines in a manner dependent on TLR4.Conclusions: Our observations support the observation that extracellular matrix HA contributes to ozone-induced airways disease. Furthermore, our results support that TLR4 contributes to the biological response to HA by mediating both the production of proinflammatory cytokines and the development of ozone-induced AHR.