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PubMed2006

Lung cancer development in primary smelter workers: a nested case-referent study.

OBJECTIVE: The objective of this study was to study the impact of work-related exposure to mainly arsenic and lead versus smoking in primary smelter workers developing lung cancer. METHODS: In a cohort of 3979 primary smelter workers, 46 subjects had contracted respiratory malignancies. They were compared with 141 age-matched male referents by conditional logistic regression analysis. RESULTS: Cases showed a significantly higher smoking rate as compared with referents: odds ratio (OR) = 4.0; 95% confidence interval (CI) = 1.6-10.1; P = 0.003. When restricted to smokers (33 cases, 63 referents), the cumulative air arsenic exposure index, but not the lead exposure indices, was significantly higher among the cases: OR = 1.07; 95% CI = 1.02-1.11; P = 0.005. CONCLUSIONS: Cumulative arsenic exposure and smoking were identified as risk factors for the development of lung cancer; lead exposure, however, was not.

Arsenic Poisoning↗
PubMed2001

Thyroid hormone metabolism and the developing human lung.

Thyroid hormones are involved in the regulation of fetal lung development, and maturation is accelerated in animal models by antepartum exposure to raised concentrations of the receptor-active thyroid hormone triiodothyronine and glucocorticoids. It is essential that the nature of the regulation of the spatial and temporal metabolism of iodothyronines in the human fetus and infant is known before effective therapies can be developed to modify human lung maturation. Thyroid hormone bioavailability to the human fetus is regulated in part by enzymatic deiodination and reversible sulfation of iodothyronines, with contributions from other factors such as fetomaternal and fetoamniotic hormone transfers, fetal thyroid gland production, and the activities of plasma membrane transporters mediating uptake of iodothyronines from plasma into tissues.

Arylsulfatases↗
PubMed1981

The development of the lung in mammals: an analysis of concepts and findings.

To evaluate one model of mammalian-lung development, i.e., division into periods, pre- and postnatal lung development in the CPB-S mouse strain was divided into the currently distinguished periods: the pseudoglandular period, covering establishment of the air-conducting portion; and the canalicular, terminal-sac, and alveolar or postnatal periods, in which the respiratory portion develops. The last three periods would each cover the formation of a different component of the respiratory unit or pulmonary acinus (acinus pulmonaris) (nonalveolated respiratory bronchiole, nonalveolated duct and sac, and alveolar pouch). However, determination of the nature of the relevant structures on the basis of recent findings concerning the epithelia showed that these hypotheses are not tenable. Since the tubule with cuboidal epithelium (appearing in the pseudoglandular and following periods) is the basic structure in the genesis of the pulmonary acinus, the development of the respiratory portion must start in the pseudoglandular period. Likewise, since the definitive components of the acinus are derived from this acinar tubule, their establishment may not be restricted to one of the other periods. Because other postulated divisions of mammalian-lung development were based on similar histological interpretations, they cannot reflect the course of mouse-lung development either. Therefore, a developmental scheme based on the recent findings concerning the epithelia is given as well as a tentative scheme for the human lung. The respiratory portion proved to develop by budding of acinar tubules, the mode of budding being not restricted to any particular pattern.

Animals↗
PubMed2006

Environmental tobacco smoke suppresses nuclear factor-kappaB signaling to increase apoptosis in infant monkey lungs.

RATIONALE: Exposure to environmental tobacco smoke in early life has adverse effects on lung development. Apoptosis plays an essential role in development; however, the molecular mechanisms of pulmonary apoptosis induced by environmental tobacco smoke is unknown. OBJECTIVES: To investigate the mechanistic role of nuclear factor (NF)-kappaB, a critical cell survival pathway, in the developing lungs exposed to environmental tobacco smoke. METHODS: Timed-pregnant rhesus monkeys and their offspring were exposed to filtered air or to aged and diluted sidestream cigarette smoke as a surrogate to environmental tobacco smoke (a total suspended particulate concentration of 0.99 mg/m(3) for 6 h/d, 5 d/wk) from 45-50 d gestational age to 72-77 d postnatal age (n = 4/group). MEASUREMENTS AND MAIN RESULTS: NF-kappaB-DNA binding activity, regulated anti-apoptotic genes, and apoptosis were measured in lung tissues. Exposure to environmental tobacco smoke significantly suppressed NF-kappaB activation pathway and activity. Environmental tobacco smoke further down-regulated NF-kappaB-dependent anti-apoptotic genes and induced activation of caspases, cleavage of cellular death substrates (poly(ADP)-ribose polymerase and caspase-activated DNase) and an increase in the rate of apoptosis in the lung parenchyma. No significant alterations were observed for activator protein 1, p53 or Akt activity. CONCLUSIONS: Our results indicate that exposure to low levels of environmental tobacco smoke during a critical window of maturation in the neonatal nonhuman primate may compromise lung development with potential implications for future lung growth and function. These findings support our hypothesis that NF-kappaB plays a key role in the regulation of the apoptotic process.

Animals↗
PubMed2000

Inhibition of angiogenesis decreases alveolarization in the developing rat lung.

To determine whether angiogenesis is necessary for normal alveolarization, we studied the effects of two antiangiogenic agents, thalidomide and fumagillin, on alveolarization during a critical period of lung growth in infant rats. Newborn rats were treated with daily injections of fumagillin, thalidomide, or vehicle during the first 2 wk of life. Compared with control treatment, fumagillin and thalidomide treatment reduced lung weight-to-body weight ratio and pulmonary arterial density by 20 and 36%, respectively, and reduced alveolarization by 22%. Because these drugs potentially have nonspecific effects on lung growth, we also studied the effects of Su-5416, an inhibitor of the vascular endothelial growth factor receptor known as kinase insert domain-containing receptor/fetal liver kinase (KDR/flk)-1. As observed with the other antiangiogenic agents, Su-5416 treatment decreased alveolarization and arterial density. We conclude that treatment with three different antiangiogenic agents attenuated lung vascular growth and reduced alveolarization in the infant rat. We speculate that angiogenesis is necessary for alveolarization during normal lung development and that injury to the developing pulmonary circulation during a critical period of lung growth can contribute to lung hypoplasia.

Angiogenesis Inhibitors↗
PubMed1993

Expression of immunoreactive cytidine 5'-triphosphate: cholinephosphate cytidylyltransferase in developing rat lung.

The principle rate-limiting enzyme required for phosphatidylcholine production is cytidine 5'-triphosphate:cholinephosphate cytidylyltransferase. Two functional forms of cytosolic cytidylyltransferase have been previously identified: an active high-molecular weight multimer (H-form) and a relatively inactive low-molecular-weight species (L-form). In the present study, we examined the maturational changes in enzyme mass in the subcellular fractions of fetal, neonatal, and adult rat lungs. Total enzyme mass, measured by immunoblotting of total cellular lung homogenates, revealed a large amount of immunoreactive enzyme during the fetal and neonatal periods and relatively low levels of enzyme in the adult lung. A similar developmental profile for enzyme mass was noted in the cytosolic and microsomal fractions. Further, in the fetus, the majority of cytosolic enzyme mass was expressed as an inactive form (L-form). Stimulation of fetal cytosol with phosphatidylglycerol converted the enzyme mass from an inactive form (L-form) to an active form (H-form). In the adult, a substantial portion of the cytosolic enzyme mass was expressed as the active species (H-form). These observations suggest that cytidylyltransferase activity early in lung development is accompanied by an increase in enzyme mass, the majority of which exists as an inactive low-molecular-weight species. In contrast, high levels of enzyme activity are maintained in the adult lung, despite relatively low levels of enzyme mass, because a significantly greater portion of the enzyme mass is expressed as an active high-molecular-weight multimer.

Aging↗
PubMed1983

Light-microscopic immunocytochemical localization of fibronectin in the developing rat lung.

The development of the rat lung is a process of continuing morphological change. Indications from work in other mammalian systems suggest that fibronectin may be important in the control of this process. The present study has examined embryonic, neonatal, and adult lung tissue of the rat by means of the peroxidase-antiperoxidase (PAP) technique to demonstrate fibronectin at the light-microscopic level. Positive reaction was observed with anti-fibronectin serum in all stages examined. Control sections treated with pre-immune serum or no primary serum gave negative results in each case. Fibronectin in adult tissue was localized to the alveolar surface and alveolar basal lamina. Neonatal tissue showed fibronectin on pulmonary tubule walls and in basal lamina while embryonic tissue revealed localization of the protein in the basal lamina and in association with small groups of cells at the base of septal buds. These findings suggest a role for fibronectin in the control of rat lung development. The results are discussed in terms of the known functions of fibronectin as a preliminary matrix for the subsequent deposition of collagenous connective tissue, as a cellular adhesion protein, and as surface-bound material for cellular migration.

Animals↗
PubMed1993

Expression of the epithelial Na+ channel in the developing rat lung.

The adult mature fetal, but not immature fetal, lung is capable of actively transporting Na+ from the alveolar space. The reason for the impaired Na+ transport in the immature lung is not known; however, the apical membrane Na+ channel is the rate-limiting step for epithelial Na+ transport. This study determined whether transcripts coding for the adult rat colonic epithelial Na+ channel (alpha rENaC) were present in the fetal and adult lung and whether they were developmentally regulated. Similarly sized alpha rENaC transcripts were identified in RNA isolated from fetal and adult whole rat lung, primary cultures of fetal and adult alveolar epithelium, and adult rat whole kidneys, suggesting that the lung alpha rENaC is a similar transcript to that found in the salt-deprived rat colonic epithelium. There were low mRNA levels in 17- to 18-day gestational age (GA) fetal lungs and epithelium (term GA = 22 days), but these levels increased markedly during the saccular stage of lung development (20 days GA) and remained high in adult lungs. The combined administration of thyroid-releasing hormone and dexamethasone to pregnant rats between 16 and 18 days GA induced the expression of lung alpha rENaC in their fetuses. We conclude that alpha rENaC is expressed in mature fetal and adult alveolar epithelium and that it is influenced by hormones known to alter maturation of the fetal lung.

Aging↗
PubMed2002

Lung tumor development in mice exposed to tobacco smoke and fed beta-carotene diets.

In human clinical trials it was found that the putative chemopreventive agent beta-carotene not only failed to protect active smokers against the carcinogenic action of tobacco smoke, but actually increased their risk of developing lung cancer. In preclinical animal studies, beta-carotene had been effective against some chemically induced cancers, but not against tumors in the respiratory tract. We exposed male strain A/J mice to tobacco smoke at a concentration of 140 mg/m(3) of total suspended particulate matter, 6 h a day, 5 days a week, for either 4 or 5 months, followed by a recovery period in air for 4 or 5 months, or for 9 months without recovery period. beta-carotene was added in the form of gelatin beadlets to the AIN-93G diet either during or following tobacco smoke exposure at concentrations of 0.005, 0.05 and 0.5%. In the supplement-fed animals, plasma and lung levels of beta-carotene were higher than they were in animals fed control diets. Exposure to tobacco smoke increased rather than decreased plasma beta-carotene levels, but had no significant effect on lung levels. After 9 months, lung tumor multiplicities and incidence were determined. Tobacco smoke increased both lung tumor multiplicities and incidences, but beta-carotene failed to modulate tumor development under all exposure conditions. Animal studies in a model of tobacco smoke carcinogenesis would thus have predicted the absence of any beneficial effects of beta-carotene supplementation in current or former smokers, but would have failed to anticipate the increase in lung cancer risk.

Animals↗
PubMed1998

Expression of smooth muscle markers in the developing murine lung: potential contractile properties and lineal descent.

Contractile cells in the mammalian lung develop in close association with the outgrowing stem bronchi. Fully differentiated smooth muscle cells are typically found in proximal regions, residing in the substantial muscular walls of the major airways and blood vessels. More distally, cells expressing markers of differentiated smooth muscle cells to a variable degree, and which may therefore possess contractile properties, are to be found scattered around the interstitium. We have investigated the temporal and spatial distribution of smooth muscle lineage markers (smooth muscle myosin mRNA) and of those indicative of contractile function (metavinculin mRNA) in the murine lung. In the smooth muscle layers of the bronchi and major blood vessels, these genes are expressed from the onset of pulmonary budding, concurrently with the appearance of alpha-smooth muscle actin and calponin proteins. During fetal development, smooth muscle-associated genes and proteins are restricted to this committed smooth muscle population. The first signs of myofibroblast or pericyte differentiation become manifest perinatally, when their expression of alpha-smooth muscle actin escalates. In the adult lung, such cells may be readily pin-pointed by their positive reaction for metavinculin mRNA, but, at maturity, they do not always coexpress alpha-smooth muscle actin.

Actins↗
PubMed1985

The ultrastructural study of glycogen and lamellar bodies in the development of fetal monkey lung.

Developing fetal monkey lung tissues were studied at the gestational period of 135-145 days. In general, glycogen is distributed throughout the cytoplasm of the type II pneumocytes at this gestational period. It is of interest that we found a structural relationship between glycogen particles and lamellar body formation in the type II pneumocytes. The glycogen particles were found inside the electron-dense pre-granules and the immature lamellar bodies. Some of the fully matured lamellar bodies also contained glycogen. This phenomenon has not been observed previously, and it supports the evidence that there is a close and direct structural relationship between glycogen and the development of lamellar bodies at this stage of lung development in the type II pneumocytes.

Animals↗
PubMed2005

Modulation of IGF-binding protein-2 and -3 in hyperoxic injury in developing rat lung.

Retinoids play an important role in lung development and repair. We showed that retinoic acid (RA) inhibits O(2)-induced fibroblast proliferation in rat lung explants. IGF-1, which enhances the proliferation of human fetal lung fibroblasts and stimulates collagen production during lung injury, has an important role in the lung injury/repair process. Interactions of IGF-1 with its receptor are modulated by IGF-binding proteins IGFBPs. We hypothesized that RA alters IGFBP-2 and -3 in hyperoxia-exposed neonatal lung and alters collagen production. Neonatal rat lungs were cultured in room air or 95% O(2) and 5% CO(2) for 3 d with or without RA. IGFBP-2 and -3 were measured both in culture medium and in lung tissue. Type I collagen and procollagen propeptide were analyzed in the lung tissue. Hyperoxia induced an increase in type I collagen that was significantly inhibited in the presence of RA. IGFBP-2 and IGFBP-3 in the lungs were decreased in hyperoxia but significantly increased in hyperoxia plus RA. In the culture medium, IGFBP-2 and -3 were not increased with hyperoxia but significantly increased in the presence of RA plus hyperoxia. There was no increase in IGFBP-3 RNA transcript after RA treatment in either room air or O(2) exposure. In conclusion, RA modulates the secreted IGFBP-2 and -3 during O(2) exposure and inhibits the increase in collagen that occurs during lung injury. We speculate that RA protects against O(2)-induced neonatal lung injury through modulation of the IGFBPs.

Animals↗
PubMed2003

[Retinoic acid and regeneration therapy of the lung diseases].

Retinoic acid is the bioactive metabolite of vitamin A and considerable evidence implicates retinoic acid as important signaling molecule during normal lung development and retinoid signaling elements, such as receptors and binding proteins have been described in the developing lung. Alveolization, or the formation of alveoli during lung development, is essentially completed in the neonatal period, and little neo-alveolization occurs in the adult lung. Recently, several studies have shown that retinoic acid is effective in promoting alveolization in neonatal rats, in adult rats with elastase-induced emphysema. However, the exact mechanism governing this regeneration is still unknown. Recent advanced technologies will clarify the role of retinoic acid in alveolization and even how alveolization occurs, leading to regeneration therapy for the devastating lung diseases, such as emphysema and fibrotic disorders.

Animals↗
PubMed2004

Developing rat lung has a sided pacemaker region for morphogenesis-related airway peristalsis.

Prenatal airways from diverse species are capable of spontaneous peristaltic contractions in each trimester. The function of this smooth muscle activity is unknown. We demonstrate that peristalsis of the embryonic airway originates from a sided pacemaker focus, is stimulated in a calcium-dependent fashion by the pulmonary morphogen fibroblast growth factor-10 (FGF-10), and appears coupled to lung growth. Airway peristalsis may be crucial for lung development (thereby providing a physiologic role for airway smooth muscle) and play a hitherto unanticipated role in reported transgenic mutant lung phenotypes.

Animals↗
PubMed1997

Comparison of the ontogeny of protein gene product 9.5, chromogranin A and proliferating cell nuclear antigen in developing human lung.

Pulmonary neuroendocrine cell products, especially bombesin-like peptides, are important modulators of fetal lung growth, morphogenesis and maturation. In the present study, we describe the ontogeny of protein gene product 9.5 (PGP 9.5) in 28 midtrimester human fetal lungs, in comparison to chromogranin A (CGA), a marker of differentiated neuroendocrine cells, and proliferating cell nuclear antigen (PCNA), which is expressed by actively dividing cells. PGP 9.5 immunostaining colocalized with CGA in many cells, although the peak abundance of PGP 9.5 preceded that of CGA by 4 to 6 weeks. In addition, a novel staining pattern was noted for PGP 9.5: diffuse cytoplasmic staining of undifferentiated epithelial cells, which was demonstrated by all of the airways before 15 weeks gestation. After gestational week 15, only the smallest airways demonstrated this pattern. PCNA immunostaining demonstrated age-dependent regional variation. All samples had approximately 25% epithelial cells immunopositive for PCNA. Between 11 and 14 weeks gestation over 50% of the mesenchymal cells were PCNA positive. This mesenchymal staining decreased after 14 weeks, and was rare by week 19. There was no definite correlation between the immunostaining for PGP 9.5 and that for PCNA, although PGP 9.5 positive cells were usually PCNA negative. These observations suggest that other growth factors produced by non-neuroendocrine epithelial cells also participate in lung development.

Chromogranin A↗
PubMed1997

CFTR gene transduction in neonatal rabbits using an adeno-associated virus (AAV) vector.

Patients with cystic fibrosis develop lung disease after birth, therefore CFTR gene replacement therapy should be most efficacious in the neonatal period prior to the onset of pulmonary damage. An adeno-associated virus (AAV) vector, SA306 (Flotte TR et al Proc Natl Acad Sci USA 1993; 90: 10613-10617), which contains the AAV inverted terminal repeats flanking the human CFTR cDNA linked to an amino-terminal epitope tag, was used to transduce a human CFTR fusion protein into neonatal New Zealand white rabbits. Vector inocula of 1 x 10(5) to 5 x 10(10) particles were given by intratracheal instillation on day 3 of life and the rabbit lungs were studied at 3 or 4 days, 2-6 weeks, or 6 months after infection; the 2-6 week time-point corresponds to the completion of the alveolar phase of lagomorph lung development. Vector DNA was detected by an in situ polymerase chain reaction (PCR) using vector-specific primers at up to 6 weeks after inoculation. Human CFTR mRNA was detected by Northern analysis at up to 2 weeks after vector inoculation, and by a reverse transcriptase PCR assay at up to 3 weeks after infection. Epithelial expression of the human CFTR fusion protein was detected using antisera to both the human CFTR R domain and the amino-terminal epitope at up to 6 weeks after vector inoculation. Vector DNA, mRNA, or human CFTR immunoreactivity were not observed at the 6 month time-point. Rabbits infected with SA306 were clinically indistinguishable from their uninfected litter mates. These data indicate that CFTR gene transduction using an AAV vector is feasible in the neonatal rabbit, and that expression of vector-derived CFTR persists throughout the alveolar phase of lung development. The apparent lack of vector persistence after the alveolar phase may reflect dilution of transduced cells by further lung growth or a lack of transduction of pulmonary epithelial stem cells.

Animals↗
PubMed2001

Functional overexpression of wild-type p53 correlates with alveolar cell differentiation in the developing human lung.

At 15 weeks after conception (a.c.), the human pulmonary acinus is lined by distal low-columnar and more proximal cuboidal cells that are successive stages in alveolar type II cell differentiation (pseudoglandular period of lung development). From 16 weeks a.c. onward, there are also 'flatter' cells that are intermediate stages in the differentiation of cuboidal type II cells into squamous type I cells (canalicular period). We investigated the role of wild-type p53 protein and the proliferation marker Ki-67 in the differentiation of type II and type I cells in these two periods. Serial sections from fetal lungs (n = 30) were immunoincubated with antibodies against p53 and Ki-67. The presence of prospective type II and type I cells was confirmed using immunohistochemistry for surfactant protein SP-A as a differentiation marker and light and electron microscopy. The p53 and Ki-67 positive nuclei were quantified per alveolar cell phenotype (i.e., low-columnar; cuboidal; flatter). The occurrence of cell apoptosis was studied using propidium iodide (PI) and 4',6'-diamino-2-phenylindol dihydrochloride (DAPI) staining. The combined increase in p53 expression and decrease in Ki-67 expression during alveolar epithelial cell differentiation suggests that wild-type p53 protein plays a role in the differentiation of alveolar type II and type I cells in the human lung, and that this function is mediated through cell cycle arrest. The rare incidence of apoptotic nuclei in alveolar type II cells, together with their absence in alveolar type I cells, supports the view that p53 is involved in the differentiation, rather than the death, of alveolar epithelial cells.

Apoptosis↗
PubMed2001

Expression of Tcf/Lef and sFrp and localization of beta-catenin in the developing mouse lung.

Recent evidence that Wnts and other genes in the Wnt signaling pathway are expressed in embryonic and adult mouse lung suggests that this pathway is important for cell fate decisions and differentiation of lung cell types. We therefore examined the expression and protein distribution of several Wnt pathway components during prenatal mouse lung development using whole-mount in situ hybridization and immunohistochemistry. Between embryonic days 10.5 and 17.5 (E10.5-E17.5), beta-catenin was localized in the cytoplasm, and often also the nucleus, of the undifferentiated primordial epithelium (PE), differentiating alveolar epithelium (AE; present from E14.5 onward), and adjacent mesenchyme. Tcf1, Lef1, Tcf3, Tcf4, sFrp1, sFrp2 and sFrp4 were also expressed in the PE, AE, and adjacent mesenchyme in specific spatio-temporal patterns.

Animals↗