Glucocorticoid-thyroid synergism in lung maturation: a mechanism involving epithelial-mesenchymal interaction.

Abstract

We studied the effects of cortisol and triiodothyronine (T3) on 20-day fetal rat lung cell cultures. Cortisol -enhanced the production of surfactant-associated saturated phosphatidylcholine while T3 did not. However, T3 potentiated the cortisoleffect. We observed that T3 enhanced the response of cultures enriched-with alveolar type 11 cells to fibroblast-pneumonocyte factor (FPF). Intracellular cAMP was increased by exposure of these cultures to FPF, and T3 potentiated this increase. Unlike cortisol, T3 had no effect on production of FPF by fetal lung fibroblasts, as determined by bioassay of fractions of fibroblastconditioned medium partially purified by column chromatography. The time. course of cortisol action on mixed (fibroblast/epithelial) cultures was in keeping with the proposed mechanism: glucocorticoid induction of FPF in fibroblasts, followed by FPF induction of cAMP 'in epithelia and, 'finally, by enhanced production of saturated phosphatidylcholine. Thus, glucocorticoid acting on mesenchyme and thyroid hormone acting on epithelium have a synergistic effect on expression of differentiated epithelial function.In late fetal life, maturation of the mammalian lung is heralded by the ability of alveolar epithelial type II cells to synthesize and secrete the pulmonary surfactant, which is necessary for successful postnatal gas exchange (1). Extensive evidence suggests that both glucocorticoids and thyroid hormones regulate surfactant synthesis in late fetal life. Glucocorticoids enhance surfactant-associated phospholipid synthesis by fetal lung in organ culture (2-4) or in mixed monolayer culture (5, 6), but their effect on clonally derived alveolar type II cells is very much attenuated (7). It is now evident that a major glucocorticoid effect on the alveolar epithelium is indirect: glucocorticoid (cortisol) induces production by fetal lung fibroblasts of fibroblastpneumonocyte factor (FPF), which, in turn, increases phospholipid synthesis by alveolar epithelial type II cells in vitro (7) and in vivo (8). We here report that triiodothyronine (T3) acts directly on alveolar type II cells to enhance responsiveness to FPF.MATERIALS AND METHODS Cell Cultures. All cultures were prepared from 20-day fetal rat lungs. Mixed monolayer cultures were prepared as described (5), modified as follows: mixed cell suspensions were prepared by incubating finely minced lung in Ca2"-, Mg2+-free Hanks' balanced salt solution containing 0.05% trypsin (Worthington), DNase (10 pg/ml; Sigma), and 1% chicken serum (GIBCO) (9). They were plated in 24-well plates (10) at high cell density (4 x 106 cells.per cm2) and maintained in 2 ml of minimal essential medium/10% newborn calf serum for 3 days with daily medium changes.Cultures enriched with respect to alveolar type II cells were prepared as described above, except that 2 hr after initial plating, -at which time a majority of the fibroblasts had attached to the flask (11), the supernatant media were aspirated with unattached cells. The cells were pelleted at 50 x g and the ...

Prenatal Hormone Treatment with Thyrotropin Releasing Hormone and with Thyrotropin Releasing Hormone Plus Dexamethasone Delays Antioxidant Enzyme Maturation but Does Not Inhibit a Protective Antioxidant Enzyme Response to Hyperoxia in Newborn Rat Lung

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Negative Regulation of Antioxidant Enzyme Gene Expression in the Developing Fetal Rat Lung by Prenatal Hormonal Treatments

“…More recently, based on a variety of experimental (animal) evidence that thyroid hormone treatment combined with glucocorticoid treatment has an additive or synergistic effect on stimulating surfactant system development (21,22), combined hormonal therapy has been tested clinically. However, because the human placenta is rather impermeable to thyroid hormone.…”

The effects of short-term manipulation of thyroid hormone status coinciding with primary wool follicle development on fleece characteristics in Merino sheep

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