[Lung development and malformations].
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This study has been aimed at showing the influence of tobacco smoke, together with low protein diet on the lungs of newborn rats. The studied animals were Wistar rats. They were exposed to the tobacco smoke for 11 weeks (6 weeks before mating, 12 days during mating, and 21 days of pregnancy). Morphological analysis and interpretation of 48 one-day old rats was based on observation under the light and electron microscope. The study showed atelectasis of the lungs: the lung tissue was insufficiently extended, the alveoli were geometrically irregular and the alveolar septa were thick. Many extravasated erythrocytes and edema (latent as well as overt) were also present. The II type pneumocytes and their surfactant were poorly developed. Tobacco smoke caused the serious pathological effects and together with poor protein diet all changes worsened. For comparison, the lungs of control group were studied (lack of exposure to tobacco smoke); they were well aerated and their structure well-developed.
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The core fucosylation (alpha1,6-fucosylation) of glycoproteins is widely distributed in mammalian tissues, and is altered under pathological conditions. To investigate physiological functions of the core fucose, we generated alpha1,6-fucosyltransferase (Fut8)-null mice and found that disruption of Fut8 induces severe growth retardation and death during postnatal development. Histopathological analysis revealed that Fut8(-/-) mice showed emphysema-like changes in the lung, verified by a physiological compliance analysis. Biochemical studies indicated that lungs from Fut8(-/-) mice exhibit a marked overexpression of matrix metalloproteinases (MMPs), such as MMP-12 and MMP-13, highly associated with lung-destructive phenotypes, and a down-regulation of extracellular matrix (ECM) proteins such as elastin, as well as retarded alveolar epithelia cell differentiation. These changes should be consistent with a deficiency in TGF-beta1 signaling, a pleiotropic factor that controls ECM homeostasis by down-regulating MMP expression and inducing ECM protein components. In fact, Fut8(-/-) mice have a marked dysregulation of TGF-beta1 receptor activation and signaling, as assessed by TGF-beta1 binding assays and Smad2 phosphorylation analysis. We also show that these TGF-beta1 receptor defects found in Fut8(-/-) cells can be rescued by reintroducing Fut8 into Fut8(-/-) cells. Furthermore, exogenous TGF-beta1 potentially rescued emphysema-like phenotype and concomitantly reduced MMP expression in Fut8(-/-) lung. We propose that the lack of core fucosylation of TGF-beta1 receptors is crucial for a developmental and progressive/destructive emphysema, suggesting that perturbation of this function could underlie certain cases of human emphysema.
A 36-year-old Russian patient had been exposed to severe nuclear radiation during the Tschernobyl accident and developed Cushing's syndrome in September 1991. After bilateral adrenalectomy a small centrally localized lung tumor in the left segment S6 was diagnosed, and the syndrome was correlated to primary lung cancer. Thoracotomy and resection of the segments S6 revealed a primary ACTH-producing lung tumor of the cell type of a paraganglioma. The patient lost his symptoms after curative tumor resection. The case is discussed under the aspects of tumor etiology, its clinical course and immunohistochemical findings.
The amiloride-sensitive epithelial Na(+) channel (ENaC), the rate-limiting step in epithelial Na(+) transport, consists of three subunits: alpha, beta, and gamma. The abundance of mRNA encoding the alpha-subunit far surpasses the amount for other subunits, and considerably exceeds the predicted subunit protein stoichiometry. We evaluated 5'-untranslated region (UTR) expression and found that fetal rat lung uses alternative 5'UTRs for alpha-ENaC during development. Sucrose density gradient analysis of postnuclear supernatants from fetal rat lung homogenates demonstrated that all three ENaC subunits were associated with high molecular weight polysomes, indicating active translation of the mRNAs, but translational efficiency was much lower for the alpha-subunit. Sucrose density gradient distributions were comparable for the endogenously expressed alpha-ENaC 5'UTRs in rat lung at Fetal Day 20 or Postnatal Day 1 using Northern analysis. Although birth resulted in a global decrease in lung mRNA translation, the loading of ribosomes on ENaC subunit mRNAs was largely unaffected. Evaluation of cytokeratin 18 and vimentin mRNAs in these gradients suggested a cell-specific effect. We conclude that there are different translational efficiencies for ENaC subunits and that perinatal processes globally modulate lung mRNA translation.
Somatomedins/insulinlike growth factors (Sm/IGFs) are peptide growth factors that are synthesized in multiple tissues and have been implicated in organ growth. Poly(A +)RNAs from lungs of fetal and postnatal rats were examined by dot and Northern blot analyses to investigate the local synthesis of IGFs during lung organogenesis. Blots were successively hybridized with 32P-labeled human IGF-II and mouse Sm-C/IGF-I cDNAs followed by human ubiquitin cDNAs (a control). Multiple IGF-II mRNA species of 4.7, 3.9, 3.1, 2.2, 1.75, and 1.2 kb were observed. Prenatally, the 3.9 kb species was predominant. In adult lung, the 4.7 kb species was the major species, and the 1.2 kb species was not detectable. Multiple Sm-C/IGF-I mRNA species of estimated sizes 7.5, 4.7, 1.7, and 1.0 kb were observed and their relative abundance did not change discernibly throughout development. Densitometric quantification revealed that IGF-II mRNAs were 7-20 fold more abundant in fetal lung than adult lung. In addition, they were 5-8 times more abundant than Sm-C/IGF-I mRNAs in embryonic lung, and were slightly less abundant than Sm-C/IGF-I mRNAs in adult lung. These data suggest synthesis of both Sm-C/IGF-I and IGF-II throughout lung organogenesis. Developmental changes in IGF-II mRNA abundance during lung organogenesis imply regulation at the level of gene transcription and/or mRNA stability.
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In this overview on the role of PAF in reproductive biology, we have emphasized its relationship to fetal lung maturation and the initiation and maintenance of parturition. In addition, we have discussed the role of this autacoid in certain complications of premature delivery. It should be pointed out, however, that it is our view that other mediators and cytokines also play a role in these processes. In the past, many investigators have suggested a central role for one of these mediators that serves as the "trigger" of these biologic events. It is our view that these systems are regulated by a number of effectors, among which PAF may play an important role.
A single course of antenatal steroids is widely used during preterm labor to promote fetal lung maturation. However, little is known regarding efficacy and safety of multiple courses of antenatal steroids. In animal models and clinical trials, treatment with glucocorticoids can inhibit growth. The present study of single- vs multiple-course steroids in pregnant ewes analyzes the effects of steroids vs placebo on fetal lung histopathology. Single-course groups received dexamethasone (Dex) 6 mg or normal saline every 12 hr for 48 hr at 104-106 days of gestation (term = 150 days). Multiple-course groups received the first course at 76-78 days; this was repeated weekly for 5 weeks. At 108 days, lungs were analyzed using immunohistochemistry for alpha-smooth muscle actin, a myofibroblast marker and proliferating cell nuclear antigen. Cell injury/death was evaluated using TdT-mediated dUTP digoxigenin nick end labeling (TUNEL) analysis. Although fetal growth was restricted by either single or multiple courses of Dex, alveolar development was accelerated as measured by mean linear intercepts. Alveolar walls were thinner, developing septa were longer, and septal myofibroblasts were increased for both Dex groups compared with controls. Cell proliferation increased following multiple steroid courses, especially in the distal parenchyma, with a corresponding decrease in apoptosis. These observations suggest that Dex promotes alveolarization, whether given in single or multiple courses.