Prostaglandins regulate surfactant protein A (SP-A) gene expression in human fetal lung in vitro

Michael J. Acarregui, Jeanne M. Snyder, Murray D. Mitchell, Carole R. Mendelson

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Abstract

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 >10-8 M, 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 PGF, the prostacyclin metabolite, 6-keto-PGF, 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 dexamethasone and indomethacin also were observed on two morpholological 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 (≥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.

Original languageEnglish (US)
Pages (from-to)1105-1113
Number of pages9
JournalEndocrinology
Volume127
Issue number3
StatePublished - Sep 1990

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Pulmonary Surfactant-Associated Protein A
Prostaglandins
Dexamethasone
Gene Expression
Lung
Dinoprostone
Indomethacin
Messenger RNA
In Vitro Techniques
Thromboxane B2
Thromboxane A2
Dinoprost
RNA Stability
Epoprostenol
Glucocorticoids
Cell Differentiation
Fetus
Steroids

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Prostaglandins regulate surfactant protein A (SP-A) gene expression in human fetal lung in vitro. / Acarregui, Michael J.; Snyder, Jeanne M.; Mitchell, Murray D.; Mendelson, Carole R.

In: Endocrinology, Vol. 127, No. 3, 09.1990, p. 1105-1113.

Research output: Contribution to journalArticle

Acarregui, Michael J. ; Snyder, Jeanne M. ; Mitchell, Murray D. ; Mendelson, Carole R. / Prostaglandins regulate surfactant protein A (SP-A) gene expression in human fetal lung in vitro. In: Endocrinology. 1990 ; Vol. 127, No. 3. pp. 1105-1113.
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