PROSTAGLANDINS REGULATE SURFACTANT PROTEIN-A (SP-A) GENE-EXPRESSION IN HUMAN FETAL LUNG INVITRO
PROSTAGLANDINS REGULATE SURFACTANT PROTEIN-A (SP-A) GENE-EXPRESSION IN HUMAN FETAL LUNG INVITRO
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DOI：
10.1210/endo-127-3-1105
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发表时间：
1990-09-01
期刊：
影响因子：
4.8
通讯作者：
MENDELSON, CR
中科院分区：
文献类型：
--
作者：
ACARREGUI, MJ;SNYDER, JM;MENDELSON, CR
我们先前观察到地塞米松对体外培养的人胎肺表面活性蛋白A(SP-A)基因表达有双向影响。在10~(-10)~10~(-9)M浓度下，地塞米松可增加SP-AmRNA的表达，而在10~(-8)M浓度时，激素对SP-A的表达有明显的抑制作用。在确定这些作用的分子机制的研究中，我们观察到地塞米松引起SP-A基因转录的剂量依赖性刺激，但矛盾地导致SP-A mRNA稳定性的剂量依赖性抑制。鉴于糖皮质激素对多种组织中前列腺素(PG)合成的抑制作用，本研究旨在研究糖皮质激素对体外培养的人胎肺SP-A基因表达的影响，并探讨地塞米松(>；10-8M)降低SP-A基因表达的作用是否与其抑制PG合成有关。我们发现地塞米松(10-7M)能显著降低前列腺素E_2和前列腺素F_(2α)、前列环素代谢产物6-酮-前列腺素F_(1α)和血栓素A_2代谢物血栓素B_2的分泌水平。吲哚美辛也能显著降低这些分泌前列腺素的水平，对体外培养的人胎肺SP-AmRNA水平有明显的降低作用。吲哚美辛的抑制作用与培养中胎肺cAMP的形成减少73%有关，并可通过与二丁酰cAMP或PGE2同时孵育而被阻止。在没有或存在消炎痛的情况下，PGE2显著增加人胎肺组织cAMP的形成。观察地塞米松和消炎痛对肺分化的两个形态指标：肺泡腔体积密度和板层体体密度的抑制作用。PGE2可显著增加人胎肺外植体的管腔体积密度。地塞米松(10~(-7)M)与前列腺素E_2或二丁酰cAMP同时孵育不能阻止地塞米松(10~(-7)M)对SP-amRNA水平的抑制作用，且地塞米松对体外胎肺cAMP的形成无明显影响，提示地塞米松(10~(-8)M)降低SP-amRNA水平的作用至少部分是通过抑制PG合成以外的作用来实现的。我们的发现进一步提示，人胎肺体外合成PGE2的增加可能促进cAMP的形成，从而诱导II型细胞分化和SP-A基因表达。
We previously have observed that dexamethasone has a biphasic effect on surfactant protein A (SP-A) mRNA levels in human fetal lung in vitro. At concentrations of 10-10-10-9 M, dexamethasone increases the levels of SP-A mRNA, whereas at concentrations >10-8M, the steroid is markedly inhibitory. In studies to define the molecular mechanisms for these effects, we observed that dexamethasone causes a dose-dependent stimulation of SP-A gene transcription, but paradoxically causes a dose-dependent inhibition of SP-A mRNA stability. In light of the well-characterized inhibitory effect of glucocorticoids on prostaglandin (PG) synthesis in a number of tissues, it was our objective in the present study to investigate the role of PGs on SP-A gene expression in human fetal lung in vitro and to determine whether the action of dexamethasone (>10-8 M) to reduce SP-A mRNA levels could be mediated by its effect to inhibit PG synthesis. We found that dexamethasone (10-7 M) caused a marked decrease in the secreted levels of the PGE2 and PGF2.alpha., the prostacyclin metabolite, 6-keto-PGF1.alpha., and the thromboxane A2 metabolite, thromboxane B2. Indomethacin, which also caused a pronounced reduction in the levels of these secreted prostanoids, had a marked effect to reduce SP-A mRNA levels in human fetal lung in vitro. The inhibitory effects of indomethacin were associated with an 73% reduction in cAMP formation by the fetal lung in culture, and were prevented by simultaneous incubation with dibutyryl cAMP or with PGE2. PGE2 markedly increased cAMP formation by the human fetal lung tissue incubated in the absence or presence of indomethacin. Inhibitory effects of dexamethaxone and indomethacin also were observed on two morphological indices of lung differentiation, alveolar lumenal volume density, and lamellar body volume density. PGE2 significantly increased lumenal volume density of the human fetal lung explants. The finding that the inhibitory action of dexamethasone (10-7 M) on SP-A mRNA levels could not be prevented by simultaneous incubation with either PGE2 or dibutyryl cAMP and that dexamethasone had no apparent effect on cAMP formation by the fetal lung in vitro is suggestive that the action of dexamethasone (.gtoreq.10-8 M) to reduce SP-A mRNA levels is mediated at least in part by actions alternative to its inhibitory effects on PG synthesis. Our findings are further suggestive that increased PGE2 synthesis by human fetal lung in vitro may promote increased cAMP formation with a consequent induction of type II cell differentiation and SP-A gene expression.