NF-κB signaling in fetal lung macrophages disrupts airway morphogenesis.
NF-κB signaling in fetal lung macrophages disrupts airway morphogenesis.
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DOI：
10.4049/jimmunol.1101495
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发表时间：
2011-09-01
期刊：
影响因子：
--
通讯作者：
Prince LS
中科院分区：
文献类型：
--
作者：
Blackwell TS;Hipps AN;Yamamoto Y;Han W;Barham WJ;Ostrowski MC;Yull FE;Prince LS
支气管肺发育不良是极早产儿常见的肺部并发症。肺部发育停滞会导致支气管肺发育不良，但导致这种停滞的分子途径尚不清楚。肺损伤和炎症会增加疾病风险，但炎症反应的细胞部位以及局部炎症信号传导在抑制肺形态发生中的潜在作用尚不清楚。在这里，我们发现胎鼠肺中存在的组织巨噬细胞介导对脂多糖的炎症反应，并且巨噬细胞的激活抑制气道形态发生。巨噬细胞耗竭或 NF-κB 信号通路的靶向失活可保护培养的肺外植体中的气道分支免受脂多糖的影响。巨噬细胞似乎也是脂多糖暴露后产生 IL-1β 的主要细胞位点。相反，转基因巨噬细胞中的靶向 NF-κB 激活足以抑制气道形态发生。体内巨噬细胞的激活抑制了对正常肺部发育至关重要的多个基因的表达，导致肺间质增厚、气道分支减少和围产期死亡。我们认为，胎儿肺巨噬细胞的激活通过产生局部炎症反应来破坏对肺形成至关重要的发育信号，从而导致支气管肺发育不良。
Bronchopulmonary dysplasia is a common pulmonary complication of extreme prematurity. Arrested lung development leads to bronchopulmonary dysplasia, but the molecular pathways that cause this arrest are unclear. Lung injury and inflammation increase disease risk, but the cellular site of the inflammatory response and the potential role of localized inflammatory signaling in inhibiting lung morphogenesis are not known. Here we show that tissue macrophages present in the fetal mouse lung mediate the inflammatory response to lipopolysaccharide and that macrophage activation inhibits airway morphogenesis. Macrophage depletion or targeted inactivation of the NF-κB signaling pathway protected airway branching in cultured lung explants from the effects of lipopolysaccharide. Macrophages also appear to be the primary cellular site of IL-1β production following lipopolysaccharide exposure. Conversely, targeted NF-κB activation in transgenic macrophages was sufficient to inhibit airway morphogenesis. Macrophage activation in vivo inhibited expression of multiple genes critical for normal lung development, leading to thickened lung interstitium, reduced airway branching, and perinatal death. We propose that fetal lung macrophage activation contributes to bronchopulmonary dysplasia by generating a localized inflammatory response that disrupts developmental signals critical for lung formation.
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