Peixoto Francisca O, Pereira-Terra Patrícia, Moura Rute S, Carvalho-Dias Emanuel, Correia-Pinto Jorge, Nogueira-Silva Cristina
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
Cell Physiol Biochem. 2015;35(1):104-15. doi: 10.1159/000369679. Epub 2015 Jan 2.
BACKGROUND/ AIMS: The knowledge of the molecular network that governs fetal lung branching is an essential step towards the discovery of novel therapeutic targets against pulmonary pathologies. Lung consists of two highly branched systems: airways and vasculature. Ephrins and its receptors, Eph, have been implicated in cardiovascular development, angiogenesis and vascular remodeling. This study aims to clarify the role of these factors during lung morphogenesis.
Ephrins-B1, -B2 and receptor EphB4 expression pattern was assessed in fetal rat lungs between 15.5 and 21.5 days post-conception, by immunohistochemistry. Fetal rat lungs were harvested at 13.5 dpc, cultured during 4 days and treated with increasing doses of ephrins-B1 and -B2 and the activity of key signaling pathways was assessed.
Ephrin-B1 presents mesenchymal expression, whereas ephrin-B2 and its receptor EphB4 were expressed by the epithelium. Both ephrins stimulated pulmonary branching. Moreover, while ephrin-B1 did not affect the pathways studied, ephrin-B2 supplementation decreased activity of JNK, ERK and STAT. This study characterizes the expression pattern of ephrins-B1, -B2 and EphB4 receptor throughout rat lung development.
Our data highlight a possible role of ephrins as molecular stimulators of lung morphogenesis. Moreover, it supports the idea that classical vascular factors might play a role as airway growth promoters.
背景/目的：了解控制胎儿肺分支的分子网络是发现针对肺部疾病新治疗靶点的关键一步。肺由两个高度分支的系统组成：气道和脉管系统。 Ephrins及其受体Eph已被证明与心血管发育、血管生成和血管重塑有关。本研究旨在阐明这些因子在肺形态发生过程中的作用。
通过免疫组织化学评估受孕后15.5至21.5天胎鼠肺中Ephrins-B1、-B2和受体EphB4的表达模式。在受孕13.5天收获胎鼠肺，培养4天，并用递增剂量的Ephrins-B1和-B2处理，评估关键信号通路的活性。
Ephrin-B1呈间充质表达，而Ephrin-B2及其受体EphB4由上皮表达。两种Ephrins均刺激肺分支。此外，虽然Ephrin-B1不影响所研究的信号通路，但补充Ephrin-B2可降低JNK、ERK和STAT的活性。本研究描述了Ephrins-B1、-B2和EphB4受体在大鼠肺发育过程中的表达模式。
我们的数据突出了Ephrins作为肺形态发生分子刺激因子的可能作用。此外，它支持经典血管因子可能作为气道生长促进因子发挥作用的观点。
