Toll-like receptor 4 deficiency causes pulmonary emphysema
Toll-like receptor 4 deficiency causes pulmonary emphysema
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DOI：
10.1172/jci28139
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发表时间：
2006-11-01
影响因子：
15.9
通讯作者：
Lee, Patty J.
中科院分区：
文献类型：
--
作者：
Zhang, Xuchen;Shan, Peiying;Lee, Patty J.
TLR 已在病原体挑战的背景下进行了广泛研究，但它们在未受到挑战的肺部中的作用尚不清楚。鉴于肺部的 TLR 与外部环境直接接触，因此它们是对空气成分（即颗粒物和氧气）做出反应的主要候选者。肺部在持续的环境暴露下保持结构完整性的机制对于我们了解肺部疾病至关重要。肺气肿的特点是肺弹性逐渐丧失和不可逆的气腔扩大，通常发生在生命的最后几十年和多年的侮辱（最常见的是香烟烟雾）之后。在这里，我们发现 Tlr4(-/-) 小鼠随着年龄的增长表现出肺气肿。过继转移实验表明，肺结构细胞中 TLR4 的表达是维持正常肺结构所必需的。 TLR4 缺陷导致肺和内皮细胞中一种新型 NADPH 氧化酶 (Nox) Nox3 的上调，从而导致氧化剂生成和弹力分解活性增加。用化学NADPH抑制剂或Nox3 siRNA治疗Tlr4(-/-)小鼠或内皮细胞逆转了观察到的表型。我们的数据确定了 TLR4 通过调节氧化剂生成维持肺结构完整性的作用，并为肺气肿的发展提供了见解。
TLRs have been studied extensively in the context of pathogen challenges, yet their role in the unchallenged lung is unknown. Given their direct interface with the external environment, TLRs in the lungs are prime candidates to respond to air constituents, namely particulates and oxygen. The mechanism whereby the lung maintains structural integrity in the face of constant ambient exposures is essential to our understanding of lung disease. Emphysema is characterized by gradual loss of lung elasticity and irreversible airspace enlargement, usually in the later decades of life and after years of insult, most commonly cigarette smoke. Here we show Tlr4(-/-) mice exhibited emphysema as they aged. Adoptive transfer experiments revealed that TLR4 expression in lung structural cells was required for maintaining normal lung architecture. TLR4 deficiency led to the upregulation of what we believe to be a novel NADPH oxidase (Nox), Nox3, in lungs and endothelial cells, resulting in increased oxidant generation and elastolytic activity. Treatment of Tlr4(-/-) mice or endothelial cells with chemical NADPH inhibitors or Nox3 siRNA reversed the observed phenotype. Our data identify a role for TLR4 in maintaining constitutive lung integrity by modulating oxidant generation and provide insights into the development of emphysema.