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首页> 外文期刊>American Journal of Physiology >Innate immune responses to LPS in mouse lung are suppressed and reversed by neutralization of GM-CSF via repression of TLR-4.
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Innate immune responses to LPS in mouse lung are suppressed and reversed by neutralization of GM-CSF via repression of TLR-4.

机译：通过抑制TLR-4，中和GM-CSF可抑制和逆转小鼠肺对LPS的先天免疫应答。

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摘要

The innate immune inflammatory response to lipopolysaccharide (LPS, an endotoxin) is essential for lung host defense against infection by gram-negative bacteria but is also implicated in the pathogenesis of some lung diseases. Studies on genetically altered mice implicate granulocyte-macrophage colony-stimulating factor (GM-CSF) in lung responses to LPS; however, the physiological effects of GM-CSF neutralization are poorly characterized. We performed detailed kinetic and dose-response analyses of the lung inflammation response to LPS in the presence of the specific GM-CSF-neutralizing antibody 22E9. LPS instilled into the lungs of BALB/c mice induced a dose-dependent inflammation comprised of intense neutrophilia, macrophage infiltration and proliferation, TNF-alpha and matrix metalloproteinase release, and macrophage inflammatory protein-2 induction. The neutralization of anti-GM-CSF in a dose-dependent fashion suppressed these inflammatory indexes by 85% when given before or after LPS or after repeat LPS challenges. Here we report for the first time that the physiological expression of Toll-like receptor-4 in lung is reduced by anti-GM-CSF. We observed that lower Toll-like receptor-4 expression correlated with a similar decline in peak TNF- levels in response to endotoxin. Consequently, sustained expression of key inflammatory mediators over 24 h was reduced. These data expand the understanding of the contribution of GM-CSF to innate immune responses in lung and suggest that blocking GM-CSF might benefit some lung diseases where LPS has been implicated in etiology.
机译：对脂多糖（LPS，一种内毒素）的先天免疫炎症反应对于肺宿主防御革兰氏阴性菌感染至关重要，但也与某些肺部疾病的发病机制有关。基因改造小鼠的研究表明，粒细胞巨噬细胞集落刺激因子（GM-CSF）对LPS的肺反应有影响。但是，GM-CSF中和的生理作用还很差。在特定的GM-CSF中和抗体22E9存在下，我们对LPS的肺部炎症反应进行了详细的动力学和剂量反应分析。注入BALB / c小鼠肺中的LPS引起剂量依赖性炎症，包括强烈的中性粒细胞增多，巨噬细胞浸润和增殖，TNF-α和基质金属蛋白酶释放以及巨噬细胞炎性蛋白2诱导。当在LPS之前或之后或在重复LPS攻击后给予抗GM-CSF时，其剂量依赖性中和将这些炎症指数抑制了85％。在这里，我们首次报道抗GM-CSF降低Toll样受体4在肺中的生理表达。我们观察到较低的Toll样受体4表达与响应内毒素的TNF峰值水平的类似下降相关。因此，减少了关键炎症介质在24小时内的持续表达。这些数据扩展了对GM-CSF对肺内固有免疫反应的贡献的理解，并表明阻断GM-CSF可能有益于病因中涉及LPS的某些肺部疾病。

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