The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity.
The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity.
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DOI：
10.1152/ajplung.00554.2016
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发表时间：
2017-06
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影响因子：
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通讯作者：
Rachel M. Medal;Amanda M. Im;Yasutoshi Yamamoto;O. Lakhdari;T. Blackwell;H. Hoffman;D. Sahoo;L. Prince
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文献类型：
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作者：
Rachel M. Medal;Amanda M. Im;Yasutoshi Yamamoto;O. Lakhdari;T. Blackwell;H. Hoffman;D. Sahoo;L. Prince
在早产儿中，可溶性炎症介质靶向肺间充质细胞，破坏气道和肺泡形态发生。然而，间充质细胞如何直接响应微生物刺激仍然知之甚少。我们的目的是测量暴露于细菌内毒素脂多糖（LPS）的胎儿肺间充质细胞的全基因组先天免疫反应。通过使用 Affymetrix MoGene 1.0st 阵列，我们发现 LPS 诱导了对 CC 和 CXC 家族趋化因子具有重要影响的独特先天免疫转录本的表达。 E11、E15 和 E18 小鼠肺细胞的转录反应不同。在所有测试的细胞中，LPS 抑制一小部分核心基因的表达，包括 VEGF 受体 Vegfr2。虽然在血管内皮细胞群中得到了最好的表征，但我们在这里证明了胎儿小鼠肺间充质细胞表达 Vegfr2 并对 VEGF-A 刺激做出反应。在间充质细胞中，VEGF-A 增加细胞迁移，激活 ERK/AKT 通路，并促进 FOXO3A 核排斥。通过使用上皮-间质相互作用的实验共培养模型，我们还表明 VEGFR2 抑制可阻止三维结构的形成。 LPS 和酪氨酸激酶抑制均减少了三维结构的形成。我们的数据表明，炎症介导的肺部发育缺陷存在一种新机制，涉及肺间质中 VEGF 信号传导的减少。
In preterm infants, soluble inflammatory mediators target lung mesenchymal cells, disrupting airway and alveolar morphogenesis. However, how mesenchymal cells respond directly to microbial stimuli remains poorly characterized. Our objective was to measure the genome-wide innate immune response in fetal lung mesenchymal cells exposed to the bacterial endotoxin lipopolysaccharide (LPS). With the use of Affymetrix MoGene 1.0st arrays, we showed that LPS induced expression of unique innate immune transcripts heavily weighted toward CC and CXC family chemokines. The transcriptional response was different between cells from E11, E15, and E18 mouse lungs. In all cells tested, LPS inhibited expression of a small core group of genes including the VEGF receptor Vegfr2 Although best characterized in vascular endothelial populations, we demonstrated here that fetal mouse lung mesenchymal cells express Vegfr2 and respond to VEGF-A stimulation. In mesenchymal cells, VEGF-A increased cell migration, activated the ERK/AKT pathway, and promoted FOXO3A nuclear exclusion. With the use of an experimental coculture model of epithelial-mesenchymal interactions, we also showed that VEGFR2 inhibition prevented formation of three-dimensional structures. Both LPS and tyrosine kinase inhibition reduced three-dimensional structure formation. Our data suggest a novel mechanism for inflammation-mediated defects in lung development involving reduced VEGF signaling in lung mesenchyme.