Cheah Fook-Choe, Presicce Pietro, Tan Tian-Lee, Carey Brenna C, Kallapur Suhas G
Neonatal Intensive Care Unit, Department of Paediatrics, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Hospital Canselor Tuanku Muhriz, Kuala Lumpur, Malaysia.
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
Front Pediatr. 2021 Mar 11;9:614209. doi: 10.3389/fped.2021.614209. eCollection 2021.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory cytokine that is increased in the amniotic fluid in chorioamnionitis and elevated in the fetal lung with endotoxin exposure. Although GM-CSF has a pivotal role in fetal lung development, it stimulates pulmonary macrophages and is associated with the development of bronchopulmonary dysplasia (BPD). How antenatal GM-CSF results in recruitment of lung macrophage leading to BPD needs further elucidation. Hence, we used a transgenic and knock-out mouse model to study the effects of GM-CSF focusing on the fetal lung macrophage. Using bitransgenic (BTg) mice that conditionally over-expressed pulmonary GM-CSF after doxycycline treatment, and GM-CSF knock-out (KO) mice with no GM-CSF expression, we compared the ontogeny and immunophenotype of lung macrophages in BTg, KO and control mice at various prenatal and postnatal time points using flow cytometry and immunohistology. During fetal life, compared to controls, BTg mice over-expressing pulmonary GM-CSF had increased numbers of lung macrophages that were CD68 and these were primarily located in the interstitium rather than alveolar spaces. The lung macrophages that accumulated were predominantly CD11bF4/80 indicating immature macrophages. Conversely, lung macrophages although markedly reduced, were still present in GM-CSF KO mice. Increased exposure to GM-CSF antenatally, resulted in accumulation of immature macrophages in the fetal lung interstitium. Absence of GM-CSF did not abrogate but delayed the transitioning of interstitial macrophages. Together, these results suggest that other perinatal factors may be involved in modulating the maturation of alveolar macrophages in the developing fetal lung.
粒细胞-巨噬细胞集落刺激因子（GM-CSF）是一种促炎细胞因子，在绒毛膜羊膜炎的羊水和内毒素暴露后的胎儿肺中均会升高。尽管GM-CSF在胎儿肺发育中起关键作用，但它会刺激肺巨噬细胞并与支气管肺发育不良（BPD）的发生有关。产前GM-CSF如何导致肺巨噬细胞募集从而引发BPD尚需进一步阐明。因此，我们使用转基因和基因敲除小鼠模型来研究GM-CSF对胎儿肺巨噬细胞的影响。我们使用了双转基因（BTg）小鼠，其在强力霉素处理后有条件地过度表达肺GM-CSF，以及无GM-CSF表达的GM-CSF基因敲除（KO）小鼠，通过流式细胞术和免疫组织学比较了BTg、KO和对照小鼠在不同产前和产后时间点肺巨噬细胞的个体发生和免疫表型。在胎儿期，与对照组相比，过度表达肺GM-CSF的BTg小鼠肺巨噬细胞数量增加，这些细胞为CD68阳性，主要位于间质而非肺泡腔。积累的肺巨噬细胞主要为CD11bF4/80阳性，表明是未成熟巨噬细胞。相反，GM-CSF基因敲除小鼠的肺巨噬细胞数量虽然明显减少，但仍然存在。产前GM-CSF暴露增加导致未成熟巨噬细胞在胎儿肺间质中积累。GM-CSF的缺失并未消除但延迟了间质巨噬细胞的转变。总之，这些结果表明其他围产期因素可能参与调节发育中胎儿肺内肺泡巨噬细胞的成熟。
