It is clear that steroid hormones of placental and fetal adrenal origin have critically important roles in regulating key physiological events essential to the maintenance of pregnancy and development of the fetus for extrauterine life Thus, progesterone has suppressive actions on lymphocyte proliferation and activity and on the immune system to prevent rejection of the developing fetus and placenta (see Fig 9) Progesterone also suppresses the calcium-calmodulin-MLCK system and thus activity of uterine smooth muscle, thereby promoting myometrial quiescence to ensure the maintenance of pregnancy Estrogen enhances uteroplacental blood flow and possibly placental neovascularization to provide optimal gas exchange and the nutrients required for the rapidly developing fetus and placenta In turn, estrogen has specific stimulatory effects on the receptor-mediated uptake of LDL by, and P-450scc activity within, syncytiotrophoblasts, thus promoting the biosynthesis of progesterone Moreover, there is an estrogen-dependent developmental regulation of expression of the LDL receptor and NAD-dependent 11 beta-HSD in the placenta, processes reflecting functional/biochemical differentiation of the trophoblast cells with advancing gestation The increase in 11 beta-HSD causes a change in transplacental corticosteroid metabolism, which results in activation of the HPAA in the fetus As a result of this cascade of events, there is an increase in expression of pituitary POMC/ACTH and key enzymes, eg 3 beta-HSD and P-450 17 alpha-hydroxylase, important for de novo cortisol formation by, and consequently maturation of, the fetal adrenal gland In turn, cortisol has well defined actions on surfactant biosynthesis and consequently fetal lung maturation, as well as effects on placental CRH/POMC release, which may be important to the initiation of labor At midgestation, estrogen also selectively feeds back on the fetal adrenal to suppress DHA and maintain physiologically normal levels of estrogen Preparation of the breast for lactation and nourishment of the newborn appears to involve a multifactorial system of regulation that includes estrogen It is apparent, therefore, that autocrine/paracrine, as well as endocrine, systems of regulation are operative within the fetoplacental unit during primate pregnancy A major goal of this review has been to illustrate the critically close functional communication existing between the developing placenta and fetus in the biosynthesis and the actions of steroid hormones during primate pregnancy The functional interaction of the human fetal adrenal and placenta with respect to the biosynthesis of estrogen was demonstrated many years ago However, the recent studies presented in this review show that the endocrine interaction between the fetus and placenta is more extensive, involving complex physiological regulatory mechanisms Thus, as illustrated in Fig 9, estrogen, acting via its receptor within the placenta and other reproductive tissues, orchestrates the dynamic interchange between the placenta and fetus responsible for the developmental regulation of the biosynthesis of the various steroid and peptide hormones and their receptors necessary for the maintenance of pregnancy and development of a live newborn It would appear, therefore, that the immediate and long range challenges in this area of reproductive endocrinology are to employ in vitro molecular and in vivo experimental approaches simultaneously to elucidate the nature of these complex interactions and define the cellular and molecular mechanisms underlying these important regulatory events

Actions of Placental and Fetal Adrenal Steroid Hormones in Primate Pregnancy

RESEARCH PAPERS Proteins Ostrich crystallins. Structural characterization of 8-crystallin with enzymic activity Characterization of antibodies to the glycosyl-phosphatidylinositol membrane anchors of mammalian proteins Identification of valine/leucine/isoleucine and threonine/alanine/ glycine proton-spin systems of Escherichia coli adenylate kinase by selective deuteration and selective protonation

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Function and regulation of expression of pulmonary surfactant-associated proteins.

The surfactant-associated proteins SP-A and SP-D are members of a family of collagenous host defense lectins, designated collectins. There is increasing evidence that these pulmonary epithelial-derived proteins are important components of the innate immune response to microbial challenge, and that they participate in other aspects of immune and inflammatory regulation within the lung. The collectins bind to glycoconjugates and/or lipid moieties expressed by a wide variety of microorganisms and certain other organic particles in vitro. Although binding may facilitate microbial clearance through aggregation or other direct effects on the organism, SP-A and SP-D also have the capacity to modulate leukocyte function and, in some circumstances, to enhance their killing of microorganisms. The biologic activity of cell wall components, such as gram-negative bacterial polysaccharides, may be altered by interactions with collectins. Complementary or cooperative interactions between SP-A and SP-D could contribute t...

Collectins and pulmonary host defense.

Meat as a component of a healthy diet - are there any risks or benefits if meat is avoided in the diet?

Parturition is timed to begin only after the developing embryo is sufficiently mature to survive outside the womb. It has been postulated that the signal for the initiation of parturition arises from the fetus although the nature and source of this signal remain obscure. Herein, we provide evidence that this signal originates from the maturing fetal lung. In the mouse, secretion of the major lung surfactant protein, surfactant protein A (SP-A), was first detected in amniotic fluid (AF) at 17 days postcoitum, rising progressively to term (19 days postcoitum). Expression of IL-1β in AF macrophages and activation of NF-κB in the maternal uterus increased with the gestational increase in SP-A. SP-A stimulated IL-1β and NF-κB expression in cultured AF macrophages. Studies using Rosa 26 Lac-Z (B6;129S-Gt(rosa)26Sor) (Lac-Z) mice revealed that fetal AF macrophages migrate to the uterus with the gestational increase in AF SP-A. Intraamniotic (i.a.) injection of SP-A caused preterm delivery of fetuses within 6-24 h. By contrast, injection of an SP-A antibody or NF-κB inhibitor into AF delayed labor by >24 h. We propose that augmented production of SP-A by the fetal lung near term causes activation and migration of fetal AF macrophages to the maternal uterus, where increased production of IL-1β activates NF-κB, leading to labor. We have revealed a response pathway that ties augmented surfactant production by the maturing fetal lung to the initiation of labor. We suggest that SP-A secreted by the fetal lung serves as a hormone of parturition.

https://www.pnas.org/content/pnas/101/14/4978.full.pdf

Surfactant protein secreted by the maturing mouse fetal lung acts as a hormone that signals the initiation of parturition

In the present study we investigated the effects of dexamethasone (DEX) on the accumulation of the major pulmonary surfactant-associated protein (SP-A), a glycoprotein of about 35,000 mol wt, and on the levels of mRNA encoding this protein in human fetal lung in organ culture. In addition, the effects of DEX on the structural development of the fetal lung tissue was investigated using morphometric techniques. We observed that DEX had a biphasic effect on the accumulation of SP-A and its mRNA; at concentrations of 10(-10) and 10(-9) M, a stimulatory effect was observed, while at concentrations of 10(-8) M or greater, the glucocorticoid was markedly inhibitory. The inhibitory effect of DEX (10(-7) M) was evident at all time points of incubation and was apparent within 24 h of its addition to the medium at any time during the culture period. In addition, DEX (10(-7) M) antagonized the stimulatory effects of (Bu)2cAMP on the accumulation of SP-A and its mRNA. DEX also had pronounced effects on the morphological development of human fetal lung tissue. At a concentration of 10(-7) M or greater, DEX caused a marked reduction of alveolar lumen size compared to that of fetal lung explants maintained in control medium. A biphasic effect of DEX on the volume density of type II cells in fetal lung explants was observed; at a concentration of 10(-10) M, DEX significantly increased the volume density of type II cells, whereas at a concentration of 10(-7) M or more, the glucocorticoid significantly reduced the volume density of type II cells compared to that of control explants. These findings suggest that synthetic glucocorticoids at concentrations of 10(-10) and 10(-9) M are stimulatory whereas elevated levels are inhibitory of SP-A synthesis and morphological development of the human fetal lung.

Glucocorticoid Regulation of the Major Surfactant Associated Protein (SP-A) and Its Messenger Ribonucleic Acid and of Morphological Development of Human Fetal Lung in Vitro*

The use of beta-adrenergic agonists in the treatment of preterm labor has been found to be associated with a decreased incidence of respiratory distress syndrome (RDS) in premature newborns. beta-Sympathomimetic agents, which activate adenylate cyclase and increase tissue cAMP levels, as well as cAMP analogs stimulate surfactant glycerophospholipid synthesis and secretion by fetal lung tissue. In the present study, we used antibodies directed against the major human pulmonary surfactant apoprotein, a 35,000-dalton glycoprotein, to evaluate the effects of the cAMP analog dibutyryl cAMP (Bt2cAMP) and the beta-adrenergic agonist terbutaline on surfactant apoprotein synthesis in human fetal lung explants in organ culture. By use of immunoblot analysis, we found that Bt2cAMP (1 mM) markedly stimulated accumulation of the major surfactant apoprotein in human fetal lung explants, as did terbutaline. Bt2cAMP treatment also increased the relative rate of incorporation of [35S]methionine into the major surfactant apoprotein. The Bt2cAMP-induced increase in surfactant apoprotein synthesis and accumulation was associated with an increase in the levels of translatable surfactant apoprotein mRNA. Morphometric analysis at both the light and electron microscopic levels was used to evaluate the effects of Bt2cAMP on the morphology of the human fetal lung in vitro. After 48-h incubation with Bt2cAMP, the prealveolar ducts of the fetal lung explants were enlarged greatly, and the relative amount of interalveolar connective tissue was reduced compared to those in control tissues. The volume density of type II cells in the Bt2cAMP-treated explants was significantly greater than that in control explants at this time point; however, after 4 and 6 days of incubation, the volume density of type II cells in control and Bt2cAMP-treated tissues was similar, and the lumina of the prealveolar ducts of control tissues had a volume density similar to that of Bt2cAMP-treated explants. Bt2cAMP also had pronounced effects on the ultrastructural morphology of the human fetal lung explants. Large quantities of secreted lamellar bodies and tubular myelin were observed in the lumina of the prealveolar ducts of the Bt2cAMP-treated tissue. Few lamellar bodies and no tubular myelin were observed in the lumina of the prealveolar ducts of control tissues. These findings suggest that cAMP may serve an important regulatory role in the synthesis and secretion of the major surfactant apoprotein by human fetal lung.

Adenosine 3',5'-monophosphate analogs and β-adrenergic agonists induce the synthesis of the major surfactant apoprotein in human fetal lung in vitro

Pulmonary surfactant is a developmentally-regulated lipoprotein synthesized and secreted by the type II cells of the pulmonary alveolus where surfactant glycerophospholipids and proteins act to reduce surface tension at the alveolar air-liquid interface. Surfactant protein A (SP-A), the major surfactant-associated protein, appears to serve an important role in surfactant function and reutilization by type II cells. SP-A synthesis and gene expression are initiated in fetal lung tissue in concert with the developmental induction of surfactant glycerophospholipid synthesis. In studies using midtrimester human fetal lung explants maintained in organ culture, we have observed that cyclic AMP and glucocorticoids have pronounced effects on morphologic development and on the levels of SP-A gene expression. Cyclic AMP analogues act primarily to induce SP-A gene transcription; whereas, glucocorticoids have complex effects at both the transcriptional and posttranscriptional levels. We also have found that human fetal lung in vitro secretes into the culture medium relatively large amounts of prostaglandins (PG) PGE2 and PGF2 alpha and the PGI2 and thromboxane A2 metabolites, 6-keto-PGF1 alpha and TxB2, respectively. The prostaglandin synthesis inhibitor, indomethacin, markedly inhibits SP-A gene expression and cyclic AMP formation by human fetal lung in culture; the inhibitory effect of indomethacin on SP-A gene expression can be prevented by simultaneous incubation with either Bt2cAMP or PGE2. These findings are suggestive that prostaglandins acting through cyclic AMP also may serve an important role in the regulation of SP-A gene expression in human fetal lung tissue.

Mikal Janelle Odom

Papers

Glucocorticoid Regulation of the Major Surfactant Associated Protein (SP-A) and Its Messenger Ribonucleic Acid and of Morphological Development of Human Fetal Lung in Vitro*

Adenosine 3',5'-monophosphate analogs and β-adrenergic agonists induce the synthesis of the major surfactant apoprotein in human fetal lung in vitro

Developmental and hormonal regulation of surfactant protein A (SP-A) gene expression in fetal lung.