A role for macrophage migration inhibitory factor in the neonatal respiratory distress syndrome
A role for macrophage migration inhibitory factor in the neonatal respiratory distress syndrome
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DOI：
10.4049/jimmunol.180.1.601
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发表时间：
2008-01-01
影响因子：
4.4
通讯作者：
Bucala, Richard J.
中科院分区：
文献类型：
--
作者：
Kevill, Katharine A.;Bhandari, Vineet;Bucala, Richard J.
通过新生儿呼吸窘迫综合征（RDS）小鼠模型，我们证明了巨噬细胞迁移抑制因子（MIF）在肺成熟发育阶段的核心作用，而人类新生儿最容易受到RDS的影响。我们在胚胎期第18天，在肺发育的早期囊状阶段早产小鼠幼崽。早产的MIF基因缺陷幼崽中只有8%存活了8小时，而野生型对照组的存活率为75% （p < 0.001）。当用MIF缺乏症的杂合子培育所有基因型的幼崽时，这种表型得到了纠正。肺中MIF的局部生成在胚胎第18天增加，持续到胚胎第19.5天足月，并在成年期减少，因此与这一发育窗口期一致。组织学评估显示，MIF基因缺陷的幼崽肺不太成熟，血管内皮生长因子和皮质酮水平较低，这两种因素促进胎儿肺成熟。体外研究支持MIF在肺上皮细胞产生表面活性剂中的作用。在一组患有RDS的新生儿中，较高的肺内MIF水平与较低的发生支气管肺发育不良（RDS的一种后遗症）的可能性相关（p < 0.03）。这项研究首次证明了MIF在肺成熟中的作用，并支持MIF在新生儿肺部疾病中的保护作用。
Using a mouse model of neonatal respiratory distress syndrome (RDS), we demonstrate a central role for macrophage migration inhibitory factor (MIF) in lung maturation at the developmental stage when human neonates are most susceptible to RDS. We prematurely delivered mouse pups at embryonic day 18, during the early saccular stage of pulmonary development. Only 8% of the prematurely delivered pups genetically deficient in MIF survived 8 h vs 75% of wild-type controls (p < 0.001). This phenotype was corrected when pups of all genotypes were bred from dams heterozygote for MIF deficiency. Local production of MIF in the lung increased at embryonic day 18, continued until full-term at embryonic day 19.5, and decreased in adulthood, thus coinciding with this developmental window. The lungs of pups genetically deficient in MIF were less mature upon histological evaluation, and demonstrated lower levels of vascular endothelial growth factor and corticosterone - two factors that promote fetal lung maturation. In vitro studies support a role for MIF in surfactant production by pulmonary epithelial cells. In a cohort of human neonates with RDS, higher intrapulmonary MIF levels were associated with a lower likelihood of developing bronchopulmonary dysplasia, a sequelae of RDS (p < 0.03). This study demonstrates for the first time a role for MIF in lung maturation, and supports a protective role for MIF in newborn lung disease.