Innate immune responses to LPS in mouse lung are suppressed and reversed by neutralization of GM-CSF via repression of TLR-4
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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DOI：
10.1152/ajplung.00275.2003
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发表时间：
2004-04-01
影响因子：
4.9
通讯作者：
Anderson, GP
中科院分区：
文献类型：
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作者：
Bozinovski, S;Jones, J;Anderson, GP
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是必不可少的，但也涉及一些肺部疾病的发病机制。对基因改变小鼠的研究表明，粒细胞-巨噬细胞集落刺激因子（GM-CSF）参与了肺对LPS的反应;然而，GM-CSF中和的生理作用的特征很差。我们进行了详细的动力学和剂量-反应分析的肺部炎症反应的LPS的存在下，特异性GM-CSF中和抗体22 E9。LPS注入BALB/c小鼠的肺中诱导剂量依赖性炎症，包括强烈的嗜中性粒细胞、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激发之后给予时，抗GM-CSF的中和以剂量依赖性方式抑制这些炎症指数小于或等于85%。本文首次报道抗GM-CSF可降低肺Toll样受体-4的生理表达。我们观察到Toll样受体-4表达降低与内毒素反应中TNF-α峰值水平的类似下降相关。因此，24小时内关键炎症介质的持续表达减少。这些数据扩展了对GM-CSF对肺中先天免疫应答的贡献的理解，并表明阻断GM-CSF可能有益于某些肺疾病，其中LPS与病因学有关。
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 less than or equal to 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-alpha 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.