It has been proposed that thyroid hormones may have a role in the regulation of lung development and the maturation of the surfactant system. The purpose of this study was to examine the effects of exogenous thyroxine (T,) on rat lung development and to investigate possible interactions of this hormone with the glucocorticoids, other hormones implicated in the regulation of lung development.A number of different experimental protocols were utilized: T, was administered to day 17 and 18 rat fetuses from untreated animals as well as from animals which had been adrenalectomized or treated with the 11-P-hydroxylase inhibitor, Metopirone; replacement hydrocortisone was administered to some groups. Sham-operated and untreated animals were included as controls. Animals were sacrificed from days 19-22 (term, day 22-23) of gestation and the fetal lungs were examined. Accelerated lung development was observed in all experimental groups receiving T,. Alveolar epithelial cells were more differentiated in comparison to controls. Glycogen deposits were diminished, cell flattening was more advanced, mitochondria, Golgi complexes and rough endoplasmic reticulum were more prominent, and lamellar bodies, storage sites for pulmonary surfactant, were greatly increased in number. Secretion of lamellar bodies into the alveolar space was also stimulated. The results also indicated that T, and glucocorticoids act together in the acceleration of lung development. Under conditions of decreased glucocorticoids (Metopirone treatment and adrenalectomy), stimulatory effects of T, were still evident but less pronounced; hydrocortisone replacement increased the observed stimulation. Maximal acceleration of lung development was observed subsequent to T, and uncontrolled surgical stress. These results demonstrate that T, can accelerate rat lung development and that this acceleration is maximal in the presence of glucocorticoids.It is now well established that immaturity of the lung, leading to deficient pulmonary surfactant stores a t birth, is one of the major etiologic factors leading to the respiratory distress syndrome (RDS) of the newborn (for reviews, see Comroe, '77; Farrell and Avery, '75; Gluck, '72; King, '74; Scarpelli, '68; Tierney, '74). This finding has led to many investigations concerning the factors which may control the maturation of the lung as well as the initiation and regulation of the synthesis of '76) and its subsequent release onto the alveolar surface.Since the possibility that adrenal glucocorticoids might influence lung maturation was initially suggested (Buckingham et al., '68) and subsequently supported in studies by Liggins ('691, a large body of morphologic, biochemical and physiologic data has accumulated indicating that glucocorticoids can ac- celerate lung development and the maturation of the surfactant system (for reviews, see Avery, '75; Ballard and Ballard, '76; Ballard et al., '77; Farrell, '77). Though less well established as a regulatory factor, a number of experimental studies have indicate...

The in vitro metabolism of SDZ HDL 376, a thiocarbamide developed for the treatment of atherosclerosis, was investigated in rat, dog, monkey, and human liver microsomes, as well as in rat and human liver slices. [14C]SDZ HDL 376 was extensively metabolized in all the species except human. In rat liver microsomes an S-oxide was the major metabolite. In human and monkey microsomes, carbon hydroxylation was favored. The NADPH-dependent oxidation of SDZ HDL 376 resulted in covalent binding to microsomal protein. Addition of GSH to the incubations decreased protein binding in a concentration-dependent manner and resulted in a novel SDZ HDL 376-GSH adduct. Adduct formation required NADPH and was mediated predominantly by cytochrome P450. Inhibition of cytochrome P450 by 1-aminobenzotriazole resulted in a 95% decrease in adduct formation, while heat inactivation of flavin-containing monooxygenases resulted in a 10% decrease. Unlike other thiocarbamides which form disulfide adducts with GSH, the SDZ HDL 376 adduct contained a thioether linkage as characterized by LC/MS/MS and reference to a synthetic standard. Reactions performed with [35S]GSH resulted in a [35S]SDZ HDL 376-GSH adduct, demonstrating the sulfur was derived from GSH. Adduct formation was faster in rat microsomal reactions compared to human microsomes. Other structurally unrelated thiocarbamides (phenylthiourea, methimazole, 2-mercaptobenzimidazole, 2-mercaptoquinazoline, and 2-propyl-6-thiouracil) did not form similar adducts in rat liver microsomes supplemented with GSH. Therefore, the GSH adduct of SDZ HDL 376 is unique for this type of thiocarbamide. These results suggest that the bioactivation and detoxification of SDZ HDL 376 differ significantly from other thiocarbamides. Furthermore, the in vitro formation of S-oxides and GSH adducts in rat hepatic tissue, and ring hydroxylation and glucuronidation in human hepatic tissue, suggests rats may be more susceptible to the toxicity of SDZ HDL 376 compared to humans.

The effect of hormones on developmental events is not a new area of scientific investigation. However, in the last decade, the developing lung has been the focus of an increasing amount of basic and applied research. Inadequate development of the newborn's respiratory system precludes extra-uterine existence; indeed, such respiratory inadequacy has been a leading cause of death in premature infants. Tremendous strides have been made in understanding the basic cell biology of the developing lung. Much has been learned about the source, composition, and function of pulmonary surfactant, a surface-active material produced by the lung and essential to alveolar stability. Deficient stores of this material is a major etiologic factor in the respiratory distress syndrome of the newborn (RDS). This fact, coupled with observations that certain hormones can accelerate lung development and the consequent availability of adequate stores of pulmonary surfactant, has led to a large body of literaturae dealing with the effects of hormones (and other agents) on lung development. It is the purpose of this literature review (1) to discuss the various kinds of investigations which have linked surfactant synthesis to the type II pulmonary epithelial cell; and (2) to review the current status of research dealing with the effects of glucocorticoids and thyroid hormones on lung maturation.

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The type II pulmonary epithelial cell is the recognized state of surfactant synthesis and storage. Results of recent studies indicate that the thyroid hormones, triiodothyronine (T3) and thyroxine (T4), may be important regulators of surfactant production and/or release. Direct and indirect immunofluorescence techniques were used in an attempt to demonstrate binding of T3 and T4 in monolayer cultures of isolated type II cells. These cultured epithelial cells are clonally-derived from adult rat lung, retain a diploid karyotype through 35 population doublings in vitro, contain granular inclusions (lamellar bodies) in the perinuclear cytoplasm, and synthesize phosphatidylcholine via the CDP-choline pathway. In isolated type II cells, either of two fluorescent patterns was observed: (a) nuclear fluorescence accompanied by a reticular perinuclear network; or (b) diffuse cytoplasmic accumulations with concentrations around perinculear cytoplasmic inclusions. Ultrastructurally these inclusions had the typical appearance of lamellar bodies. Histochemical studies demonstrated that these inclusions contained surfactant-associated nonspecific esterases and stained with Nile blized markers for pulmonary surfactant indicate that these inclusions are indeed lamellar bodies, the putative sites of surfactant synthesis and/or storage. These findings suggest that the type II pulmonary epithelial cell contains specific binding sites for thyroid hormones, and support the hypothesis that thyroid hormones are regulators of surfactant metabolism.

Direct and indirect immunofluorescence techniques were used to localize the thyroid hormones triidothyronine (T3) and thyroxine (T4) in adult rat thyroid gland. Optimum dilutions of the antisera were established and four tissue fixatives were investigated for usefulness in this technique. Use of antibodies specific for either T3 or T4 resulted in brilliant fluorescence in the colloid pools and apical cytoplasm of follicular cells. In all cases, the adjacent parathyroid gland was devoid of fluorescence. This report demonstrates that these dipeptide hormones can be localized by using immunofluorescence techniques.

Adult rats were injected intravenously with [125I]-3,5,3'-triiodothyronine (T3) of [125I]-thyroxine (T4). Others were similarly treated, except for the addition of a 500-fold excess of the appropriate unlabeled hormone. Light microscopic autoradiography of semi-thin sections of liver from these animals demonstrated high affinity, low capacity binding of T3 and, to a much lesser extent, T4 to the nuclei of the liver cells. Labeling over the cytoplasmic portion of the cells was greater than that over the nucleus with either hormone, but was not decreased significantly with the addition of unlabelled hormone, suggesting the absence of specific binding sites in this location.