Commentary on the identity of fibroblast pneumocyte factor: rat vs. human.
Commentary on the identity of fibroblast pneumocyte factor: rat vs. human.
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对成纤维细胞肺细胞因子身份的评论：大鼠与人类。
DOI：
10.1038/pr.2017.85
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发表时间：
2017
影响因子：
3.6
通讯作者：
Ballard,PhilipL
中科院分区：
文献类型：
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作者：
Ballard,PhilipL
致编者：在妊娠后期内源性糖皮质激素水平的增加和外源性皮质类固醇治疗在许多物种（包括人类）中加速了胎儿肺成熟，在人类中，产前皮质类固醇治疗是早产儿的标准护理。在他们最近的综述中，King等人(1)探讨了糖皮质激素治疗下胎儿肺2型肺细胞和肺表面活性剂加速出现的机制，并指出“这种刺激作用是间接的”。他们回顾了关于肺成纤维细胞作用的大量证据，以及糖皮质激素诱导的肽因子（称为成纤维细胞-肺细胞因子（FPF））的释放，该因子作用于邻近上皮细胞，以增加表面活性剂磷脂和蛋白质的合成。然而，值得注意的是，FPF的大部分证据都是在大鼠身上发现的，并且与不饱和磷脂酰胆碱（dsc）的合成有关，通过掺入标记胆碱来测量。从皮质醇处理过的器官型培养中分离出来的胎鼠肺上皮细胞对部分纯化的FPF的胆碱结合反应迅速，并且与翻译后胆碱-磷酸胞基转移酶的激活一致，从而增加了PC的产生(2)。在我们早期对人胎儿肺的研究中，地塞米松刺激胆碱掺入DSPC与外植体（~ 50%成纤维细胞）和分离的上皮细胞（~ 10%成纤维细胞）相似，表明对成纤维细胞含量几乎没有明显的剂量反应效应(3)。在人上皮细胞中，地塞米松（在cyclicAMP存在的情况下）增加了与脂质摄取、生物合成和重塑相关的13个基因的mRNA，表明表面活性剂DSPC产生和板层体形成的诱导可能涉及比参与胆碱掺入途径的更多蛋白质的转录调节(4)。需要对人类胎儿肺进行进一步的研究，包括成纤维细胞条件培养基的影响和脂肪生成蛋白调控表达的表征，以确定FPF在人肺DSPC合成中的可能参与。其他对人胎儿肺的研究表明，糖皮质激素对一些关键表面活性剂相关基因的刺激很可能是糖皮质激素直接作用于肺上皮细胞的结果。使用分离的妊娠中期人胎儿肺上皮细胞（纯度为90 - 95%），糖皮质激素治疗可分化为2型细胞，cyclicAMP的存在可增强这种分化。观察到的反应包括糖原减少的形态分化和片状体的出现，与表面活性剂和其他2型细胞特异性功能相关的多种基因的诱导，以及刺激细胞合成和分泌DSPC(3)。几种表面活性剂相关基因的诱导是完全介导的。通过增加2型细胞分化的关键转录因子甲状腺核转录因子1 （TITF1, NKX2-1）的含量，增加部分（SFTPA， SFTPB， SFTPC, ABCA3）。与诱导TITF1的要求一致，CEACAM6的转录率直到7-12h才增加。TITF1在人胎肺上皮细胞中表达，在成纤维细胞中不表达；糖皮质激素在4小时内最大限度地增加TITF1 mRNA，并且这种反应不会被蛋白质合成抑制剂（环己亚胺）阻断，而大鼠肺中FPF会发生这种反应(5)。SFTPB是一种2型细胞特异性蛋白，对表面活性剂的功能至关重要。
To the Editor: Fetal lung maturation is accelerated by increasing levels of endogenous glucocorticoids in late gestation and by exogenous corticosteroid treatment in many species, including humans, in whom antenatal corticosteroid therapy is standard of care for premature infants. In their recent review, King et al.(1) addressed the mechanisms involved in accelerated appearance of fetal lung type 2 pneumocytes and pulmonary surfactant with glucocorticoid treatment and stated that “this stimulatory effect is indirect.” They reviewed the extensive evidence on the role of lung fibroblasts and release of glucocorticoid-induced peptide factor (s) termed fibroblast-pneumonocyte factor (FPF) that acts on adjacent epithelial cells to augment the synthesis of surfactant phospholipids and proteins. It is important to note, however, that the majority of evidence for FPF is in rats and relates to the synthesis of disaturated phosphatidycholine (DSPC) as measured by incorporation of labeled choline. The response for choline incorporation by fetal rat lung epithelial cells, which were isolated from cortisol-treated organotypic cultures, to partially purified FPF was rapid and consistent with posttranslational activation of choline-phosphate cytidylyltransferase contributing to increased PC production (2). In our earlier studies with human fetal lungs, dexamethasone stimulation of choline incorporation into DSPC was similar with explants (~ 50% fibroblasts) and isolated epithelial cells (~ 10% fibroblasts), suggesting little apparent dose–response effect for fibroblast content (3). In human epithelial cells, dexamethasone (in the presence of cyclicAMP) increased mRNA for a total of 13 genes related to lipid uptake, biosynthesis, and remodeling, indicating that induction of surfactant DSPC production and lamellar body formation likely involves transcriptional regulation of more proteins than those that participate in the choline incorporation pathway (4). Additional studies in human fetal lungs, including effects of fibroblast-conditioned medium and characterization of regulated expression of lipogenic proteins, are needed to determine the possible involvement of FPF in human lung DSPC synthesis. Other studies with human fetal lungs indicate that glucocorticoid stimulation of some key surfactant-related genes most likely occurs as a result of glucocorticoid effects directly in lung epithelial cells. On using isolated epithelial cells of second-trimester human fetal lungs, which are90–95% pure, differentiation into type 2 cells occurs with glucocorticoid treatment, which is augmented by the presence of cyclicAMP. The observed responses include morphological differentiation with reduced glycogen and appearance of lamellar bodies, induction of a variety of genes related to surfactant and other type 2 cell-specific functions, and stimulated synthesis and secretion of DSPC from cells (3). Induction of several surfactant-related genes is mediated in full (eg., LAMP3, a lamellar body protein, and CEACAM6, a surfactant-binding protein) or in part (SFTPA, SFTPB, SFTPC, ABCA3) by increased content of nuclear thyroid transcription factor 1 (TITF1, NKX2-1), a key transcription factor in type 2 cell differentiation. Consistent with a requirement for induction of TITF1, the transcription rate for CEACAM6 does not increase until 7–12h. TITF1 is expressed in epithelial cells but not in fetal fibroblasts of human fetal lung; glucocorticoids maximally increase TITF1 mRNA within 4h and this response is not blocked by an inhibitor of protein synthesis (cycloheximide) as occurs for FPF in rat lung (5). Increased transcription of SFTPB, a type 2 cell-specific protein that is critical for surfactant function, occurs within 2 h and is not …