George T N, Snyder J M
Department of Pediatrics, University of Iowa College of Medicine, Iowa City 52242, USA.
Pediatr Res. 1997 May;41(5):692-701. doi: 10.1203/00006450-199705000-00015.
Surfactant-associated proteins (SP) play an important role in the function of pulmonary surfactant. We have previously shown that SP-B mRNA is increased whereas SP-A and SP-C mRNA are decreased by all-trans-retinoic acid (RA) in a dose-dependent manner in human fetal lung explants. All-trans-RA binds primarily to the retinoic acid receptors (RARs) and 9-cis-RA binds primarily to the retinoid X receptors (RXRs). Because the fetal lung contains RXRs, we hypothesized that 9-cis-RA regulates surfactant protein gene expression in lung epithelial cells. H441 human lung adenocarcinoma cells, which synthesize SP-A and SP-B mRNA and protein, were treated with either all-trans-RA or 9-cis-RA (10(-10) to 10(-6) M) for 24 h. Neither all-trans-RA nor 9-cis-RA had an effect on SP-A mRNA levels in the H441 cells. All-trans-RA (10(-6) M) significantly increased SP-B mRNA levels in the H441 cells and 9-cis-RA had a smaller, not statistically significant effect. Human fetal lung explants were treated with 9-cis-RA for 6 d. 9-cis-RA did not significantly increase SP-B mRNA levels, significantly inhibited SP-A mRNA levels at all concentrations tested, and significantly inhibited SP-C mRNA levels at 10(-6) M in the human fetal lung explants. Both all-trans-RA (10(-6) M) and 9-cis-RA (10(-6) M) significantly increased SP-B protein levels in the human fetal lung explants. Together, these results are suggestive that all-trans-RA directly regulates SP-B gene expression in human pulmonary epithelial cells. In addition, the inhibitory effect of all-trans-RA and 9-cis-RA on SP-A mRNA levels in pulmonary epithelial cells is probably an indirect effect mediated by other cell types present in fetal lung tissue.
表面活性剂相关蛋白（SP）在肺表面活性剂的功能中起重要作用。我们先前已表明，在人胎儿肺外植体中，全反式维甲酸（RA）以剂量依赖方式使SP-B mRNA增加，而使SP-A和SP-C mRNA减少。全反式RA主要与维甲酸受体（RARs）结合，9-顺式RA主要与类视黄醇X受体（RXRs）结合。由于胎儿肺含有RXRs，我们推测9-顺式RA调节肺上皮细胞中表面活性剂蛋白基因的表达。用全反式RA或9-顺式RA（10^(-10)至10^(-6) M）处理合成SP-A和SP-B mRNA及蛋白的H441人肺腺癌细胞24小时。全反式RA和9-顺式RA对H441细胞中SP-A mRNA水平均无影响。全反式RA（10^(-6) M）显著增加H441细胞中SP-B mRNA水平，而9-顺式RA的作用较小，无统计学意义。用人胎儿肺外植体用9-顺式RA处理6天。9-顺式RA未显著增加SP-B mRNA水平，在所有测试浓度下均显著抑制SP-A mRNA水平，在10^(-6) M时显著抑制人胎儿肺外植体中SP-C mRNA水平。全反式RA（10^(-6) M）和9-顺式RA（10^(-6) M）均显著增加人胎儿肺外植体中SP-B蛋白水平。总之，这些结果提示全反式RA直接调节人肺上皮细胞中SP-B基因的表达。此外，全反式RA和9-顺式RA对肺上皮细胞中SP-A mRNA水平的抑制作用可能是由胎儿肺组织中存在的其他细胞类型介导的间接作用。
