Curcumin protects the developing lung against long-term hyperoxic injury.

Curcumin, a potent anti-inflammatory and antioxidant agent, modulates peroxisome proliferator-activated receptor-γ signaling, a key molecule in the etiology of bronchopulmonary dysplasia (BPD). We have previously shown curcumin's acute protection against neonatal hyperoxia-induced lung injury. However, its longer-term protection against BPD is not known. Hypothesizing that concurrent treatment with curcumin protects the developing lung against hyperoxia-induced lung injury long-term, we determined if curcumin protects against hyperoxic neonatal rat lung injury for the first 5 days of life, as determined at postnatal day (PND) 21. One-day-old rat pups were exposed to either 21 or 95% O2 for 5 days with or without curcumin treatment (5 mg/kg) administered intraperitoneally one time daily, following which the pups grew up to PND21 in room air. At PND21 lung development was determined, including gross and cellular structural and functional effects, and molecular mediators of inflammatory injury. To gain mechanistic insights, embryonic day 19 fetal rat lung fibroblasts were examined for markers of apoptosis and MAP kinase activation following in vitro exposure to hyperoxia for 24 h in the presence or absence of curcumin (5 µM). Curcumin effectively blocked hyperoxia-induced lung injury based on systematic analysis of markers for lung injury (apoptosis, Bcl-2/Bax, collagen III, fibronectin, vimentin, calponin, and elastin-related genes) and lung morphology (radial alveolar count and alveolar septal thickness). Mechanistically, curcumin prevented the hyperoxia-induced increases in cleaved caspase-3 and the phosphorylation of Erk1/2. Molecular effects of curcumin, both structural and cytoprotective, suggest that its actions against hyperoxia-induced lung injury are mediated via Erk1/2 activation and that it is a potential intervention against BPD.

Ontogeny, phylogeny and cellular energy flows for evolution.

The case has previously been made for the 'Singularity of Nature" based on homologies between the inorganic and the organic. But a causal explanation for those homologies was not provided. The following is a hypothetical way to understand how and why physiology emerged from physics, providing a predictive model for cell-molecular evolution.

Consciousness, Redux.

There have been many attempts to explain consciousness, ranging from Plato's archetypes, to Descartes' 'Mind-Body Dualism', and more recently to Chalmers' Qualia, and Andy Clarke's extended mind. Yet none of these conceptualizations of consciousness provide empiric evidence for what consciousness actually constitutes. The present hypothesis is that Consciousness is a product of the Singularity/Big Bang resulting from the endogenization of factors in the environment that have formed our physiology. Understanding the origin of consciousness as the Consciousness of the Singularity/Big Bang requires that it diachronically cuts across space-time. Consciousness functions based on the same data operating system as Cosmology. We can transcend consciousness and approach Consciousness by authoring our own software once we recognize this fundamental, mechanistic interrelationship.

Lung evolution as a cipher for physiology.

In the postgenomic era, we need an algorithm to readily translate genes into physiologic principles. The failure to advance biomedicine is due to the false hope raised in the wake of the Human Genome Project (HGP) by the promise of systems biology as a ready means of reconstructing physiology from genes. like the atom in physics, the cell, not the gene, is the smallest completely functional unit of biology. Trying to reassemble gene regulatory networks without accounting for this fundamental feature of evolution will result in a genomic atlas, but not an algorithm for functional genomics. For example, the evolution of the lung can be "deconvoluted" by applying cell-cell communication mechanisms to all aspects of lung biology development, homeostasis, and regeneration/repair. Gene regulatory networks common to these processes predict ontogeny, phylogeny, and the disease-related consequences of failed signaling. This algorithm elucidates characteristics of vertebrate physiology as a cascade of emergent and contingent cellular adaptational responses. By reducing complex physiological traits to gene regulatory networks and arranging them hierarchically in a self-organizing map, like the periodic table of elements in physics, the first principles of physiology will emerge.

1alpha,25(OH)2D3 and its 3-epimer promote rat lung alveolar epithelial-mesenchymal interactions and inhibit lipofibroblast apoptosis.

Although alveolar wall thinning has been attributed to apoptosis of interstitial lung lipofibroblasts (LFs), the underlying molecular mechanism(s) remains unknown. Although the physiological vitamin D steroid hormone 1alpha,25(OH)(2)D(3) (1,25D) has been suggested as a local paracrine/autocrine effector of fetal lung maturation and is known to affect fibroblast apoptosis, its effects on LF apoptosis are unknown. We determined the role of 1,25D and its metabolite, C-3-epimer (3-epi-1,25D), on LF and alveolar type II (ATII) cell differentiation, proliferation, and apoptosis. Embryonic day 19 Sprague-Dawley fetal rat lung LFs and ATII cells were treated with 1,25D or 3-epi-1,25D (1 x 10(-10) to 1 x 10(-8) M) for 24 h, and cell proliferation, apoptosis, and differentiation were assessed. Both 1,25D and 3-epi-1,25D exhibited dose-dependent increases in expression of the key homeostatic epithelial-mesenchymal differentiation markers, increased LF and ATII cell proliferation, and decreased apoptosis. Furthermore, rat pups administered 1,25D from postnatal days 0 to 14 showed increased expressions of key LF and ATII cell differentiation markers, increased Bcl-2-to-Bax ratio as an index of decreased spontaneous alveolar LF and ATII cell apoptosis, increased alveolar count, and a paradoxical increase in septal thickness. We conclude that spatial- and temporal-specific actions of vitamin D play a critical role in perinatal lung maturation by stimulating key alveolar epithelial-mesenchymal interactions and by modulating LF proliferation/apoptosis. These data not only provide the biological rationale for the presence of an alveolar vitamin D paracrine system, but also provide the first integrated molecular mechanism for increased surfactant synthesis and alveolar septal thinning during perinatal lung maturation.

Leptin stimulates Xenopus lung development: evolution in a dish.

The transition from uni- to multicellular organisms required metabolic cooperativity through cell-cell interactions mediated by soluble growth factors. We have empirically demonstrated such an integrating mechanism by which the metabolic hormone leptin stimulates lung development, causing the thinning of the gas exchange surface and the obligate increase in lung surfactant synthesis. All of these processes have occurred both phylogenetically and developmentally during the course of vertebrate lung evolution from fish to man. Here we show the integrating effects of the environmentally sensitive, pleiotropic hormone leptin on the development of the Xenopus laevis tadpole lung. The process described in this study provides a mechanistically integrated link between the metabolic regulatory hormone leptin and its manifold downstream effects on a wide variety of physiologic structures and functions, including locomotion and respiration, the cornerstones of land vertebrate evolution. It provides physiologic selection pressure at multiple levels to progressively generate Gene Regulatory Networks both within and between organs, from cells to systems. This model provides a cipher for understanding the evolution of complex physiology.

Quantum Mechanics predicts evolutionary biology.

Nowhere are the shortcomings of conventional descriptive biology more evident than in the literature on Quantum Biology. In the on-going effort to apply Quantum Mechanics to evolutionary biology, merging Quantum Mechanics with the fundamentals of evolution as the First Principles of Physiology-namely negentropy, chemiosmosis and homeostasis-offers an authentic opportunity to understand how and why physics constitutes the basic principles of biology. Negentropy and chemiosmosis confer determinism on the unicell, whereas homeostasis constitutes Free Will because it offers a probabilistic range of physiologic set points. Similarly, on this basis several principles of Quantum Mechanics also apply directly to biology. The Pauli Exclusion Principle is both deterministic and probabilistic, whereas non-localization and the Heisenberg Uncertainty Principle are both probabilistic, providing the long-sought after ontologic and causal continuum from physics to biology and evolution as the holistic integration recognized as consciousness for the first time.

Terminal addition in a cellular world.

Recent advances in our understanding of evolutionary development permit a reframed appraisal of Terminal Addition as a continuous historical process of cellular-environmental complementarity. Within this frame of reference, evolutionary terminal additions can be identified as environmental induction of episodic adjustments to cell-cell signaling patterns that yield the cellular-molecular pathways that lead to differing developmental forms. Phenotypes derive, thereby, through cellular mutualistic/competitive niche constructions in reciprocating responsiveness to environmental stresses and epigenetic impacts. In such terms, Terminal Addition flows according to a logic of cellular needs confronting environmental challenges over space-time. A reconciliation of evolutionary development and Terminal Addition can be achieved through a combined focus on cell-cell signaling, molecular phylogenies and a broader understanding of epigenetic phenomena among eukaryotic organisms. When understood in this manner, Terminal Addition has an important role in evolutionary development, and chronic disease might be considered as a form of 'reverse evolution' of the self-same processes.

Evidence for different gestation-dependent effects of cortisol on cultured fetal lung cells.

The effect of cortisol (5.5 muM) on primary monolayer cultures of trypsin-dispersed lung cells from rabbit fetuses of 20-28 days gestation was monitored with respect to (a) cellular growth as determined by DNA content after 72 h, at which time all cultures were in the exponential phase of growth, and (b) cellular maturation as reflected by the incorporation of [(14)C]-palmitate into saturated lecithin and its release into the culture medium. Cortisol significantly increased growth in cultures prepared from 20 day (control: 59.8+/-8.9 nmol DNA/flask; cortisol: 118.7+/-15.7, P < 0.001) and 22 day (control: 69.2+/-17.2; cortisol: 106.7+/-13.3, P < 0.001) fetuses but had no effect on the growth of cells from 24 or 26 day fetuses. At 28 days, the effect was reversed, cortisol reducing growth by a factor of two (control: 42.0+/-8.5; cortisol: 19.3+/-4.0, P < 0.001). Incorporation of palmitate into lecithin was expressed as picomoles incorporated per micromole DNA per flask, thus correcting for differences in the number of cells. Cortisol had no effect on palmitate incorporation until day 26, at which time it caused a slight increase (control: 51.2+/-5.5: cortisol: 72.8+/-16.2, P < 0.01) which became very striking by day 28 (control: 19.7+/-3.1; cortisol; 286.8+/-47.0, P < 0.001). The proportion of recovered radiolabeled lecithin that was disaturated rose with gestational age from 72% at 20 days to 98% at 28 days. Saturated lecithin made up over 90% at the two gestational ages (26 and 28 days) where cortisol increased palmitate incorporation. In contrast, cortisol had no effect on the incorporation of palmitate into sphingomyelin at any of the gestational ages studied.The results suggest that cortisol may increase fetal pulmonary cellular growth in early gestation while enhancing maturation and slowing growth as term approaches.

Dihydrotestosterone inhibits fetal rabbit pulmonary surfactant production.

Males have a higher morbidity and mortality for neonatal respiratory distress syndrome (RDS) than females, and respond less well to hormone therapy designed to prevent RDS by stimulating fetal pulmonary surfactant production. We have shown that male fetuses exhibit delayed production of pulmonary surfactant. We tested the hypothesis that the sex difference in fetal pulmonary surfactant production is under hormonal control. Pulmonary surfactant was measured as the saturated phosphatidylcholine/sphingomyelin ratio (SPC/S) in the lung lavage of fetal rabbits at 26 d gestation. There was an association between the sex of neighboring fetuses and the SPC/S ratio of the female fetuses, such that with one or two male neighbors, respectively, females had decreasing SPC/S ratios (P < 0.05). We injected dihydrotestosterone (DHT) into pregnant does from day 12 through day 26 of gestation in doses of 0.1, 1.0, 10, and 25 mg/d, and measured the SPC/S ratio in fetal lung lavage on day 26. In groups with the normal sex difference in fetal serum androgen levels (controls, 0.1 mg DHT/d) the normal sex difference in the SPC/S ratio was also present (females > males, P = 0.03). In the 1-mg/d group there was no sex difference in androgen levels and the sex difference in the SPC/S ratio was also eliminated as the female values were lowered to the male level. Higher doses of DHT (10, 25 mg/d) further reduced the SPC/S ratios. We injected the anti-androgen Flutamide (25 mg/d) from day 12 through day 26 of gestation. This treatment eliminated the normal sex difference in the lung lavage SPC/S ratio by increasing the male ratios to that of the females. We conclude that androgens inhibit fetal pulmonary surfactant production. An understanding of the mechanism of the sex difference in surfactant production may allow development of therapy that is as effective in males as in females for preventing RDS.

CD10/neutral endopeptidase 24.11 in developing human fetal lung. Patterns of expression and modulation of peptide-mediated proliferation.

The cell membrane-associated enzyme CD10/neutral endopeptidase 24.11 (CD10/NEP) functions in multiple organ systems to downregulate responses to peptide hormones. Recently, CD10/NEP was found to hydrolyze bombesin-like peptides (BLP), which are mitogens for normal bronchial epithelial cells and small cell lung carcinomas. Growth of BLP-responsive small cell lung carcinomas was potentiated by CD10/NEP inhibition, implicating CD10/NEP in regulation of BLP-mediated tumor growth. BLP are also likely to participate in normal lung development because high BLP levels are found in fetal lung, and bombesin induces proliferation and maturation of human fetal lung in organ cultures and murine fetal lung in utero. To explore potential roles for CD10/NEP in regulating peptide-mediated human fetal lung development, we have characterized temporal and cellular patterns of CD10/NEP expression and effects of CD10/NEP inhibition in organ cultures. Peak CD10/NEP transcript levels are identified at 11-13 wk gestation by Northern blots and localized to epithelial cells and mesenchyme of developing airways by in situ hybridization. CD10/NEP immunostaining is most intense in undifferentiated airway epithelium. In human fetal lung organ cultures, inhibition of CD10/NEP with either phosphoramidon or SCH32615 increases thymidine incorporation by 166-182% (P < 0.025). The specific BLP receptor antagonist, [Leu13-psi(CH2NH)Leu14]bombesin abolishes these effects on fetal lung growth, suggesting that CD10/NEP modulates BLP-mediated proliferation. CD10/NEP expression in the growing front of airway epithelium and the effects of CD10/NEP inhibitors in lung explants implicate the enzyme in the regulation of peptide-mediated fetal lung growth.

CD10/neutral endopeptidase 24.11 regulates fetal lung growth and maturation in utero by potentiating endogenous bombesin-like peptides.

Bombesin-like peptides (BLPs) are mitogens for bronchial epithelial cells and small cell lung carcinomas, and increase fetal lung growth and maturation in utero and in organ cultures. BLPs are hydrolyzed by the enzyme CD10/neutral endopeptidase 24.11 (CD10/NEP) which is expressed in bronchial epithelium and functions to inhibit BLP-mediated growth of small cell lung carcinomas. To determine whether CD10/NEP regulates peptide-mediated lung development, we administered a specific CD10/NEP inhibitor, SCH32615, to fetal mice in utero from gestational days e15-17. Fetal lung tissues were evaluated on e18 for: (a) growth using [3H]thymidine incorporation into nuclear DNA; and (b) maturation using: [3H]-choline incorporation into surfactant phospholipids, electron microscopy for type II pneumocytes, and Northern blot analyses for surfactant apoproteins A, B, and C. Inhibition of CD10/NEP stimulated [3H]thymidine incorporation into DNA (70% above baseline, P < 0.005), [3H]choline incorporation into surfactant phospholipids (38% above baseline, P < 0.005), increased numbers of type II pneumocytes (36% above baseline, P = 0.07), and fivefold higher surfactant protein A transcripts (P < 0.05). CD10/NEP-mediated effects were completely blocked by the specific bombesin receptor antagonist, [D-Phe12, Leu14]bombesin. These observations suggest that CD10/NEP regulates fetal lung growth and maturation mediated by endogenous BLPs.

Transforming growth factor beta2 promotes glucose carbon incorporation into nucleic acid ribose through the nonoxidative pentose cycle in lung epithelial carcinoma cells.

The invasive transformation of A-459 lung epithelial carcinoma cells has been linked to the autocrine regulation of malignant phenotypic changes by transforming growth factor beta (TGF-beta). Here we demonstrate, using stable 13C glucose isotopes, that the transformed phenotype is characterized by decreased CO2 production via direct glucose oxidation but increased nucleic acid ribose synthesis through the nonoxidative reactions of the pentose cycle. Increased nucleic acid synthesis through the nonoxidative pentose cycle imparts the metabolic adaptation of nontransformed cells to the invasive phenotype that potentially explains the fundamental metabolic disturbance in tumor cells: highly increased nucleic acid synthesis despite hypoxia and decreased glucose oxidation.

Dihydrotestosterone inhibits fibroblast-pneumonocyte factor-mediated synthesis of saturated phosphatidylcholine by fetal rat lung cells.

Dihydrotestosterone has previously been found to inhibit pulmonary surfactant production in vivo. In the present study, we have investigated the effects of this androgen on the fetal lung fibroblast and type II cell in culture. Addition of 1 X 10(-8) M cortisol to organotype cultures stimulates the synthesis of radiolabelled saturated phosphatidylcholine; however, preincubation of such cultures with 1 X 10(-8) M dihydrotestosterone completely blocks cortisol stimulation of saturated phosphatidylcholine synthesis without affecting basal activity. Cortisol treatment of fetal lung fibroblasts stimulates the production of fibroblast-pneumonocyte factor; pre-treatment with dihydrotestosterone blocks this stimulation. Fibroblast-pneumonocyte factor stimulates the synthesis of saturated phosphatidylcholine by type II pneumonocytes; this effect is also blocked by dihydrotestosterone pre-treatment. I conclude that dihydrotestosterone blocks cortisol-inducible saturated phosphatidylcholine synthesis by inhibiting the production and activity of fibroblast-pneumonocyte factor in vitro.

Parathyroid hormone (PTH) and PTH-related protein stimulate surfactant phospholipid synthesis in rat fetal lung, apparently by a mesenchymal-epithelial mechanism.

We examined the effects of parathyroid hormone (PTH) and PTH-related protein (PTHrP) on rat fetal lung fibroblast and pneumocyte cell signalling. We also studied the effects of PTH and PTHrP on surfactant phospholipid synthesis to determine whether these peptides can modulate pulmonary maturation. Exposure of fibroblasts (gestational days 18-21) to PTH(1-34) or PTHrP(1-34) produced time- and dose-dependent stimulations of cAMP and inositol phosphate accumulation. Maximal stimulation of cAMP accumulation occurred with 1 x 10(-8) M of either peptide. These effects upon cAMP accumulation were competitively inhibited by the PTH antagonist, [Nle8, Nle18, Tyr34]bPTH(3-34)amide. Maximal stimulation of fibroblast inositol phosphates was reached at 1 x 10(-7) M of either peptide. In contrast, PTH and PTHrP at these concentrations produced no changes in cAMP or inositol phosphate metabolism in isolated type II pneumocytes. When pneumocytes were exposed to PTH or PTHrP and pulse-labelled with [methyl-3H]choline chloride, no hormone-stimulated changes in saturated phosphatidylcholine (PC) synthesis were detected. However, PTH and PTHrP stimulated saturated PC synthesis in rat fetal lung explants (gestational day 19-20) by 46% and 106%, respectively. When fibroblasts and pneumocytes were co-cultured, PTH and PTHrP again stimulated saturated PC synthesis by 45% and 73%, respectively. Taken together, these findings suggest that PTH and PTHrP may be endocrine and/or paracrine regulators of fetal lung development.

The cell as the mechanistic basis for evolution.

The First Principles for Physiology originated in and emanate from the unicellular state of life. Viewing physiology as a continuum from unicellular to multicellular organisms provides fundamental insight to ontogeny and phylogeny as a functionally integral whole. Such mechanisms are most evident under conditions of physiologic stress; all of the molecular pathways that evolved in service to the vertebrate water-land transition aided and abetted the evolution of the vertebrate lung, for example. Reduction of evolution to cell biology has an important scientific feature­it is predictive. One implication of this perspective on evolution is the likelihood that it is the unicellular state that is actually the object of selection. By looking at the process of evolution from its unicellular origins, the causal relationships between genotype and phenotype are revealed, as are many other aspects of physiology and medicine that have remained anecdotal and counter-intuitive. Evolutionary development can best be considered as a cyclical, epigenetic, reiterative environmental assessment process, originating from the unicellular state, both forward and backward, to sustain and perpetuate unicellular homeostasis.

Androgens delay human fetal lung maturation in vitro.

The mature lung produces pulmonary surfactant, a lipid-protein complex that prevents lung alveoli from becoming atelectatic. The prenatal surge of surfactant production in preparation for birth occurs between 28-34 weeks gestation and is triggered by glucocorticoids, which stimulate surfactant synthesis by alveolar epithelial cells through a series of biochemical steps mediated by mesenchymal-epithelial interactions. In contrast to this, when explanted midgestation human fetal lung tissue is maintained in serum-free medium, there is a spontaneous increase (40%) in de novo saturated phosphatidylcholine (SPC) synthesis on the fifth day in culture. Addition of dexamethasone (DEX; 1 x 10(-8) M) to the culture medium causes the increased synthesis in SPC to occur earlier (day 4) and to a greater extent (87%). Addition of an equimolar concentration of dihydrotestosterone (DHT) to the medium delays both the spontaneous and DEX-stimulated increases in SPC synthesis by 24 h. Weak fetal adrenal androgens are also able to block both spontaneous and DEX-stimulated SPC synthesis. Addition of DHT to the explant cultures at daily intervals reveals that inhibition of the DEX effect occurs within the first 24 h after exposure. The antiandrogen flutamide neutralizes the effect of DHT, indicating that it acts through the androgen receptor to block the glucocorticoid. Therefore, the human fetal adrenal cortex may time lung development through both inhibitory and stimulatory mechanisms.

Glucocorticoid dependence of fetal lung maturation in vitro.

Earlier studies of the fetal lung in tissue culture have led to the conclusion that its maturation is autonomous. We have studied the role of the small amount of cortisol supplied by the serum routinely added to culture media. It was observed that 28-day-old fetal rabbit lung cells continued to grow and differentiate in culture medium supplemented with 10% calf serum (2.2 X 10(-8) M cortisol). However, when these cells were propagated in medium supplemented with calf serum which was charcoal stripped or from adrenalectomized animals, growth and differentiation were prevented (<1 X 10(-12) M cortisol). The addition of cortixol (1 X 10(-10) to 1 X 10(-5) M) to such media restored the ability of these cells to grow and differentiate in culture. Other classes of steroid hormones failed to restore such activity even with a 10-fold excess of cortisol. We conclude that maturation of the 28-day-old fetal rabbit lung in vitro is dependent upon the presence of cortisol.

Sex differences in avian embryo pulmonary surfactant production: evidence for sex chromosome involvement.

Sex differences in fetal pulmonary surfactant production have been shown in mammalian species, with the female at an advantage. A relationship between fetal sexual differentiation and the development of pulmonary surfactant production has been proposed. We hypothesized that if sex chromosomal factors play a role in causing the surfactant sex difference, then a reversal in the sex karyotype would be associated with a reversal in the surfactant sex difference and in some sex-specific responses to hormonal regulators of fetal surfactant production. To test this, we measured the surfactant-related phospholipids phosphatidylcholine and saturated phosphatidylcholine (SPC) in lung homogenates of avian embryos in which the male sex karyotype is homozygous (ZZ) and the female heterozygous (ZW). The following experimental groups were monitored: untreated controls on days 15 through 21 of gestation; embryos injected with 250 micrograms 17 beta-estradiol or of the antiestrogen CI 628; embryos injected with 250 micrograms testosterone or of the antiandrogen Flutamide; and embryos injected with 0.75 micrograms dexamethasone or 100 micrograms 11-deoxycortisol. Untreated controls exhibited significantly higher PC/milligram lung weight and SPC/milligram lung weight ratios in male embryos at gestation days 15 through 19. Hormone treatments also produced sex-specific effects. Dexamethasone significantly accelerated the male lung SPC concentration (35% over control) without affecting that of females. Glucocorticoid inhibition with 11-deoxycortisol significantly reduced the lung SPC concentration of both males and females, each by 19%. Testosterone significantly increased the female lung SPC concentration by 23%, and Flutamide significantly lowered this in the females by 24%. Estrogen reversed the sex difference by producing a relatively small (16%) decrease in the male lung SPC content while significantly increasing that of the females by 32%. CI 628 produced a modest and proportionate reduction of the lung SPC content in both sexes. These data provide evidence for a male advantage in fetal pulmonary surfactant production in the avian system, the reverse to that observed in humans, rabbits, rats, and mice. The known sex-specific responses of the developing surfactant system to glucocorticoids and to androgens are also reversed in the chick embryo as compared to the mammal. This gives additional support to the proposed link between the process of fetal sexual differentiation and the dimorphism in fetal pulmonary surfactant production and suggests that the sex chromosomes play an important regulatory role in the dimorphism of fetal surfactant production.

The rabbit fetal lung as a glucocorticoid target tissue.

Fetal lung cells from 28 day gestation rabbits cultured in the presence of cortisol (5.5 times 10 - minus 6M) or dexamethasone (5.5 times 10- minus 8M) incorporated [3-H] choline into lecithin to a significantly greater extent than did control cultures. 11-Deoxycortisol, 21-deoxycortisol and 11beta-hydroxyprogesterone, at a concentration of 5.5 times 10- minus 5 M, had no effect on lecithin synthesis. However, when lung cells were simultaneously exposed to these steroids and to cortisol at the concentrations quoted, [3-H] choline incorporation was reduced to control values. Cortisone (5.5 times 10- minus M) also enhanced lecithin synthesis, the activity of the steroid likely being related to the capacity of the lung cells to convert cortisone to cortisol. This hypothesis was supported by the observations that 11-ketoprogesterone (1.3 times 10- minus 5M), which totally inhibited the conversion of cortisone to cortisol and which had no effect of its own on [3-H] choline incorporation, inhibited the effect of cortisone on lecithin synthesis but not that of cortisol. These data support the view that glucocorticoids affect lung cell maturation in a manner comparable to the interaction of other steroid hormones with their target tissues. The capacity of the fetal lung to convert cortisone to cortisol may be physiologically significant in light of the high concentration of 11-oxo-steroids in the fetal circulation throughout pregnancy.