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PubMed1985

[Biological characterization of a hamster osteosarcoma Os 515--development of lung metastasis].

Biological characterization of a transplantable hamster osteosarcoma Os515 which had been induced by BK virus was attempted, and usefullness of this tumor was confirmed as an experimental model of treatment of osteosarcoma. All the hamsters with this tumor died of spontaneous lung metastasis. The chest X-ray picture of a tumor-bearing hamster visualized diffuse metastasis in the whole lungs 30 days after transplantation. The development of lung metastases was monitored by chest X-ray after marginal excision of subcutaneously transplanted tumors or after radical disarticulation of a tumor-bearing hind limb. Slow-growing nodular lung metastases were seen on X-ray pictures when the subcutaneous tumors were resected 1 or 2 weeks after transplantation, whereas fast-growing diffuse metastases were seen when the tumors were not resected at all or resected 3 weeks after transplantation. Nodular lung metastases occurred in a small number of animals long after the early radical disarticulation of a tumor-bearing leg.

Animals↗
PubMed1996

Identification and developmental expression of two activin receptors in baboon lung.

Activins are members of the transforming growth factor-beta (TGF-beta) superfamily that exert their effects through interacting with specific cell surface TGF-beta superfamily receptors (TSRs). To determine whether activins are involved in lung development, we used a reverse transcription polymerase chain reaction (RT-PCR)-based approach to identify members of the activin receptors from baboon fetal lung mRNAs. Two partial cDNA sequences encoding serine/threonine kinase domains of baboon TSR type I (bTSR1) and type II (bTSR2) were identified by sequencing analysis. bTSR1 displays 96% identity to human activin type I receptor TSR1, whereas bTSR2 shows 80% identity to human activin type II receptor ActRIIB over the kinase domain region. Northern analysis revealed the expression of a 2.1 kb bTSR1 transcript and a 5.0 kb bTSR2 transcript in baboon lung tissues. Both bTSR1 and bTSR2 were expressed throughout embryonic lung development and in adult lung. The expressions of bTSR1 and bTSR2 were developmentally regulated and each had a distinct expression pattern. Furthermore, the expressions of bTSR1 and bTSR2 in fetal baboon lung were altered by oxygen exposure. This study for the first time identifies the presence of the activin receptors in the baboon lung and provides evidence that both bTSR1 and bTSR2 are regulated during lung development, suggesting that activins might play an important role during lung development.

Activin Receptors↗
PubMed2004

Type I and III collagen protein precursors and mRNA in the developing human lung.

Extracellular matrix proteins have a prominent role in both ontogenesis and fibrogenesis in the human lung. The aim of this study was to analyse the expression of newly formed precursor proteins and mRNA of collagen types I and III in developing human lung tissues from 12 to 40 weeks of gestation, and also in neonatal disorders such as respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD). Lung tissues were obtained at autopsy from 60 non-malformed cases. All tissues were analysed by immunohistochemistry and 24 were also investigated by mRNA in situ hybridization. The precursor proteins and mRNA of both collagens were expressed in abundance in pulmonary arteries and veins during all developmental periods. In RDS and BPD, precursor proteins and mRNAs of both collagen types were increased within alveolar walls. The cells in these locations showed alpha-smooth muscle actin, vimentin, and variable desmin immunoreactivity. Collagen I and III precursor proteins and mRNA were also observed in pleura, bronchi, bronchioles, and around chondrocytes during all developmental periods and in diseased lung. In conclusion, collagens I and III were expressed in a similar way in and around various cell types in the developing lung and their expression was increased within alveolar walls in RDS and BPD. Myofibroblast-type cells appeared to produce mRNA for both types of collagen in alveoli.

Actins↗
PubMed1989

An evolutionary link for developing mammalian lungs.

Lungs of the human infant and those of other mammals are filled with fluid immediately prior to birth. Studies of the ionic composition of this fluid indicate that active ionic transport processes occur in the epithelial cells of the potential airspaces. The purpose of this study was to see if these active ion pumps were present in developing species other than mammals thus providing a possible evolutionary link to mammals. A series of samples of lung liquid, amniotic fluid, and plasma were taken from embryonic marine turtles gathered from clutches incubating in the beach at Mon Repos, Queensland, Australia during the summer of 1986-87. The concentrations of sodium, potassium and chloride ions and protein measured in these liquids indicated that active pumping processes similar to that seen in the mammalian lung were present in the developing lungs of these marine reptiles and further, circumstantial evidence was gathered to suggest that this liquid was partially reabsorbed prior to hatching. The results support the notion that processes responsible for the normal development of the human lung and lungs of other mammals are also present in the hollow lungs of marine turtles. Thus there is an evolutionary counterpart controlling lung development in more ancient species. It may be possible to generalize this observation to the development of hollow lungs of other species.

Animals↗
PubMed1999

Lung cancer, tobacco, and environmental factors in the African population of the Northern Province, South Africa.

DESIGN: Case-control study among incident African patients with cancer. Questionnaire assessment of exposure to tobacco, occupation, and place of birth. SETTING: Northern Province, South Africa. SUBJECTS: Between 1993 and 1995, 288 men and 60 women with lung cancer and 183 male and 197 female controls (consisting of patients newly diagnosed with cancers other than those known to be associated with smoking) were interviewed. Unmatched, unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) of developing lung cancer in relation to a number of variables. MAIN OUTCOME MEASURE: Risk of developing lung cancer related to exposure to tobacco, indoor pollution, dusty work environment, and residential exposure to asbestos. RESULTS: There was a significant increase in the risk of developing lung cancer through smoking. In men, the ORs were 2.2 (95% CI = 1.0 to 4. 6) in ex-smokers, 9.8 (95% CI = 5.9 to 16.4) in light smokers (0-14 g/day), and 12.0 (95% CI = 6.5 to 22.3) in heavy smokers. In women, the ORs were 5.8 (95% CI = 1.3 to 25.8) in ex-smokers and 5.5 (95% CI = 2.6 to 11.3) in current smokers. Work in a dusty industry showed an elevated risk (OR = 3.2, 95% CI = 1.8 to 5.8) for lung cancer only in men. Male residents of areas where asbestos was shipped for distribution (termed moderately polluted asbestos areas) had a 2.5-fold increase (95% CI = 1.0 to 4.4) in the risk (OR) of developing lung cancer, and residents of areas where asbestos was mined (termed heavily polluted asbestos areas) had a 2.8-fold increase in risk (95% CI = 0.7 to 10.4). Female residents of heavily polluted asbestos areas showed elevated risks of 5.4 (95% CI = 1.3 to 22.5) of developing lung cancer. CONCLUSION: The data suggest that tobacco smoking is the most important risk factor for the development of lung cancer in this setting. Risks for lung cancer are reminiscent of those observed in Western countries in the 1960s and 1970s. However, environmental exposure to asbestos, a dusty occupation (in men), and perhaps indoor air pollution may also contribute to the development of lung cancer in this province.

Adult↗
PubMed2003

Significance of p63 amplification and overexpression in lung cancer development and prognosis.

The fight against lung cancer is greatly compromised by the lack of effective early detection strategies. Genomic abnormalities and specifically the amplification of chromosomal region 3q26-3qter in lung cancer represent a major signature of neoplastic transformation. Here, we address the significance of p53 homologue p63 mapping to 3q27 in lung tumorigenesis. We analyzed p63 gene copy number (CN) by fluorescence in situ hybridization and expression by immunohistochemistry in tissue microarrays of 217 non-small cell lung cancers (NSCLCs) and correlated them with survival. We additionally characterized our findings in a subset of 24 NSCLCs by reverse transcription-PCR and Western blotting. We analyzed p63 CN and protein expression in 41 preinvasive squamous lesions. The p63 genomic sequence was amplified in 88% of squamous carcinomas, in 42% of large cell carcinomas, and in 11% of adenocarcinomas of the lung. The predominant splice variant of p63 expressed was DeltaNp63alpha. Western analyses revealed DeltaNp63alpha expression in normal bronchus and squamous carcinomas but not in normal lung or in adenocarcinomas. Furthermore, p63genomic amplification and protein staining intensity associated with better survival. We found a significant increase in CN in preinvasive lesions graded severe dysplasia or higher. Our data demonstrate that there is early and frequent genomic amplification of p63 in the development of squamous carcinoma of the lung and that patients with NSCLC showing amplification and overexpression of p63 have prolonged survival. These observations suggest that p63 genomic amplification has an early role in lung tumorigenesis and deserves additional evaluation as a biomarker for lung cancer progression.

Alternative Splicing↗
PubMed2005

Early developmental origins of impaired lung structure and function.

Epidemiological studies show that exposure to factors that restrict fetal growth or lead to low birthweight can alter lung development and have later adverse effects on lung function and respiratory health. The major causal factors include reduced nutrient and oxygen availability, nicotine exposure via maternal tobacco smoking and preterm birth, each of which can affect critical stages of lung development. Experimental studies show that these environmental insults can permanently alter lung structure and hence lung function, increasing the risk of respiratory illness and accelerating the rate of lung aging. Further studies are required that address the molecular and cellular mechanisms by which these factors adversely affect lung development and whether such effects can be blocked or reversed. Ultimately however, a major goal should be to prevent prenatal compromises through clinical monitoring, and in the case of smoking through education, thereby ensuring that each fetus has the best possible environment in which to develop.

Adult↗
PubMed1991

Platelet-derived growth factor and growth-related genes in rat lung. I. Developmental expression.

The autocrine, paracrine, or systemic growth factors responsible for fetal lung cell growth are not completely defined. The progression-type insulin-like growth factors and epidermal growth factor, or transforming growth factor-alpha acting through the epidermal growth factor receptor, appear to act on the developing lung epithelium. The competence factors that facilitate the actions of progression factors during lung growth are unknown. Fetal rat lung cells in vitro synthesize a platelet-derived growth factor (PDGF)-like polypeptide, which we have hypothesized may play a paracrine role in normal lung development. Slot blot and Northern blot analyses of fetal rat lung mRNA have been used to determine if there is a relationship between expression of message for PDGF-A or PDGF-B chains, or their cognate receptors, and periods of maximal growth during late fetal rat lung development. Whole lung mRNA was extracted on 18, 19, 20, 21, and 22 days of gestation (term = 22 days). The peak of DNA synthesis, as assessed by expression of message for DNA polymerase alpha, histone 3, and the proto-oncogenes c-fos and c-myc, which are stimulated by binding of growth factors including PDGF, occurred during the canalicular stage of lung development on days 19 and 20 of gestation. Expression of message for PDGF-A and PDGF-B chains was low during the pseudoglandular stage on day 18, peaked during the canalicular stage on days 19 and 20, then fell again during the saccular stage at days 21 and 22 of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Transferrin gene expression and transferrin immunolocalization in developing foetal rat lung.

In previous studies we have shown that transferrin (Tf) specifically stimulates dermatan- and chondroitin-sulphate proteoglycan accumulation around lung cells, and in the extracellular matrix of lung tissue, in vitro. The aim of this study was to determine whether the gene for Tf was activated in specific lung cells during development, and whether the protein product showed evidence of association with extracellular matrix. The expression of the gene in developing lung was shown by the hybridization of a Tf cDNA to a 2.4 kb (kilobase) mRNA species in total RNA extracts of foetal lung. The expression of the Tf gene in comparison to a control gene (GAPD, glyceraldehyde phosphate dehydrogenase) was greatest in 19, 20 and 21 day foetal lung, rising from low levels on day 18 and decreasing markedly at term (day 22). Extracts of RNA from primary cultures of mesenchymal fibroblasts and type II epithelial cells were also analysed for Tf mRNA. These experiments indicated that Tf gene expression was predominantly confined to the mesenchymal compartment. The presence of Tf in histological sections of foetal lung was demonstrated by immunohistochemistry and showed a distinct pattern, with intense staining of the alveolar and the capillary basement membranes. The matrix surrounding the mesenchymal fibroblasts was stained in a diffuse network while epithelial cells were unstained. The staining was low from days 12-16 of gestation, increased to a maximum at days 19-20 but decreased markedly toward term. The Tf staining did not co-localize with transferrin receptor, also demonstrated by immunohistochemistry. These results suggest that Tf is not only present at specific sites in the developing lung, but also is synthesized according to a strict developmental schedule of gene expression.

Animals↗
PubMed2004

Role of oxygen and vascular development in epithelial branching morphogenesis of the developing mouse lung.

Recent investigations have suggested an active role for endothelial cells in organ development, including the lung. Herein, we investigated some of the molecular mechanisms underlying normal pulmonary vascular development and their influence on epithelial branching morphogenesis. Because the lung in utero develops in a relative hypoxic environment, we first investigated the influence of low oxygen on epithelial and vascular branching morphogenesis. Two transgenic mouse models, the C101-LacZ (epithelial-LacZ marker) and the Tie2-LacZ (endothelial-LacZ marker), were used. At embryonic day 11.5, primitive lung buds were dissected and cultured at either 20 or 3% oxygen. At 24-h intervals, epithelial and endothelial LacZ gene expression was visualized by X-galactosidase staining. The rate of branching of both tissue elements was increased in explants cultured at 3% oxygen compared with 20% oxygen. Low oxygen increased expression of VEGF, but not that of the VEGF receptor (Flk-1). Expression of two crucial epithelial branching factors, fibroblast growth factor-10 and bone morphogenetic protein-4, were not affected by low oxygen. Epithelial differentiation was maintained at low oxygen as shown by surfactant protein C in situ hybridization. To explore epithelial-vascular interactions, we inhibited vascular development with antisense oligonucleotides targeted against either hypoxia inducible factor-1 alpha or VEGF. Epithelial branching morphogenesis in vitro was dramatically abrogated when pulmonary vascular development was inhibited. Collectively, the in vitro data show that a low-oxygen environment enhances branching of both distal lung epithelium and vascular tissue and that pulmonary vascular development appears to be rate limiting for epithelial branching morphogenesis.

Animals↗
PubMed2000

Differential frequencies of p16(INK4a) promoter hypermethylation, p53 mutation, and K-ras mutation in exfoliative material mark the development of lung cancer in symptomatic chronic smokers.

PURPOSE: The aim of this study was to investigate the frequency of three (epi)genetic alterations (p53 and K-ras mutations and p16(INK4a) promoter hypermethylation) in symptomatic chronic smokers compared with patients with lung cancer and to evaluate the use of exfoliative material for such analyses. PATIENTS AND METHODS: Fifty-one patients with histologically confirmed lung cancer and 25 chronic smokers (> 20 pack-years) were investigated for mutations in the K-ras (codon 12) and p53 (codons 248, 249, and 273) genes and for allelic hypermethylation of the p16(INK4a) gene. DNA was isolated from sputum and bilateral bronchial lavage, and brushings were taken at bronchoscopy. RESULTS: Forty-one genetic lesions were detected within exfoliative material from the group of 51 patients with lung cancer and 10 lesions in the chronic smoker group. K-ras mutations occurred exclusively in the lung cancer group, whereas p53 mutations and p16(INK4a) promoter hypermethylation were also found in chronic smokers. Three of eight chronic smokers who harbored an (epi)genetic alteration were subsequently diagnosed with lung cancer. Analysis of sputum yielded information equivalent to that of samples obtained during bronchoscopy. CONCLUSION: p16(INK4a) promoter hypermethylation and p53 mutations can occur in chronic smokers before any clinical evidence of neoplasia and may be indicative of an increased risk of developing lung cancer or of early disease. K-ras mutations occur exclusively in the presence of clinically detectable neoplastic transformation. Molecular analysis of sputum for such markers may provide an effective means of screening chronic smokers to enable earlier detection and therapeutic intervention of lung cancer.

Aged↗
PubMed2001

Dexamethasone and epinephrine stimulate surfactant secretion in type II cells of embryonic chickens.

Pulmonary surfactant (PS), a mixture of phospholipids and proteins secreted by alveolar type II cells, functions to reduce the surface tension in the lungs of all air-breathing vertebrates. Here we examine the control of PS during lung development in a homeothermic egg-laying vertebrate. In mammals, glucocorticoids and autonomic neurotransmitters contribute to the maturation of the surfactant system. We examined whether dexamethasone, epinephrine, and carbamylcholine hydrochloride (agonist for acetylcholine) increased the amount of PS secreted from cultured type II cells of the developing chicken lung. In particular, we wanted to establish whether dexamethasone would increase PS secretion through a process involving lung fibroblasts. We isolated and cocultured type II cells and lung fibroblasts from chickens after 16, 18, and 20 days of incubation and from hatchlings (day 21). Epinephrine stimulated phosphatidylcholine (PC) secretion at all stages, whereas dexamethasone stimulated secretion of PC at days 16 and 18. Carbamylcholine hydrochloride had no effect at any stage. This is the first study to establish the existence of similar cellular pathways regulating the development of surfactant in chickens and eutherian mammals, despite the vastly different birthing strategies and lung structure and function.

Adrenergic Agonists↗
PubMed1992

Development of lung function in relation to increased degree of bronchial responsiveness.

To study the relationship between development of lung function and bronchial responsiveness, we examined 106 subjects recruited from a random sample of 527 subjects, aged 8-18 years, from Copenhagen. Lung function and bronchial responsiveness to inhaled histamine were measured at two occasions, in 1986 and 1988. The participating subjects (n = 106) were divided into three groups: (a) 20 asthmatics with bronchial hyperresponsiveness (BHR), (b) 42 nonasthmatic subjects with BHR in 1986, and (c) 44 controls without BHR. In 1986, FEV1 expressed as percentage of predicted value, was found to be similar in the three groups (91%, 94%, and 99%, respectively). The increase in height during the observation period was found to be 5, 6, and 6 cm, respectively, in the three groups. However, at the second examination, in 1988, FEV1 was found to be significantly reduced in both asthmatics (87%) and nonasthmatic subjects (85%) compared with the controls (103%). In 1988, 16 asthmatics (80%) and 24 (57%) nonasthmatic subjects were found to have BHR, whereas none of the controls were found to have BHR. A multiple regression analysis was used to determine the correlation between change in FEV1 and potential factors of importance. The change in FEV1 was highly correlated with the presence of BHR in 1986, however, no correlation was found between change in FEV1 and change in bronchial responsiveness. In conclusion, nonasthmatic subjects with former BHR showed signs of airflow obstruction and less increase in lung function during growth irrespective of the change in level of bronchial responsiveness, which may suggest a risk for subsequent development of obstructive lung disease.

Adolescent↗
PubMed2000

Isolation and localization of type IIb Na/Pi cotransporter in the developing rat lung.

Differential display analysis of rat lung at different developmental stages identified a fragment, HG80, which appeared on embryonic day 16.5 and thereafter. A full-length cDNA derived from a cDNA library of newborn rat lung probed with HG80 was the rat counterpart of sodium-dependent phosphate transporter type IIb and was designated rNaPi IIb. In situ hybridization showed that rNaPi IIb was expressed in type II alveolar cells, suggesting a role in the synthesis of surfactant in the alveoli. The time-dependent changes in localization of this gene in the developing lung and its possible use as a type II pneumocyte marker are discussed.

Animals↗
PubMed1982

Fetal zinc deficiency as a mechanism for cadmium induced toxicity to the developing rat lung and pulmonary surfactant.

Maternal exposure to cadmium alters lung and pulmonary surfactant development in the rat fetus. A toxic property of cadmium is its biological interaction with the essential trace metal zinc. The present study was undertaken to determine the role of zinc in the induction of fetal anomalies by cadmium. Pregnant rats were injected with 8 mg/kg cadmium chloride alone or with 12 mg/kg zinc chloride on gestation days 12-15 and sacrificed on gestation day 21. Controls received injections of saline and zinc chloride. Pulmonary surfactant phospholipids were isolated from fetal lungs and quantified. Concentrations of cadmium and zinc in maternal and fetal tissues and placenta were measured. Cadmium treatment caused embryonic death, lung hypoplasia and diminished quantity of the major pulmonary surfactant phospholipid, phosphatidylcholine. Zinc treatment alone did not alter normal fetal development. Coadministration of zinc with cadmium prevented all of the previously observed cadmium-induced fetotoxicity. The placenta appeared to act as a barrier to cadmium movement, as cadmium was found in the placenta but not in fetal tissues. However, cadmium treatment decreased fetal zinc content. Simultaneous injection of zinc with cadmium maintained the fetal zinc concentration at the control level. Thus cadmium appears to exert its fetotoxic effects indirectly, through a fetal zinc deficiency.

Animals↗
PubMed1998

Genetics and pulmonary medicine. 7. Somatic mutations in the development of lung cancer.

Lung cancers exhibit complex heterogeneous karyotypes and to date sequencing the serial somatic mutations which give rise to malignant change has proved difficult. Cigarette smoke causes a field change in the respiratory mucosa with mutations demonstrable even in histologically normal areas. After smoking cessation many of these mutations seem to persist indefinitely so that the risk of an ex-smoker developing lung cancer never reverts to that of a life-long non-smoker. Demonstration of specific somatic mutations in biopsy or sputum samples may eventually provide a useful method of screening for lung cancer. Somatic mutations give useful information about prognosis in non-small cell lung cancer and they are the key to exciting future retroviral and monoclonal antibody mediated therapies.

Humans↗
PubMed2003

Lung development-the effects of chronic hypoxia.

Chronic hypoxia compromises the development of both airways and pulmonary vasculature following exposure before or after birth. It also impairs adaptation to extrauterine life. The immediate morbidity and mortality is high, and long-term sequelae in terms of lung structure, and thus function, are common, particularly in premature infants. Chronic lung disease or bronchopulmonary dysplasia can develop with or without cor pulmonale. The extensive fibrotic disease of classical bronchopulmonary dysplasia has become uncommon with the development of improved treatment strategies, but the development of the lung periphery can still be compromised as more immature babies survive. This article highlights the landmarks of normal lung development together with the principal established and newly recognized features of exposure to chronic hypoxic in the young. In doing so, it indicates promising areas for research activity.

Chronic Disease↗
PubMed1978

Changes in the structural and metabolic heterogeneity of phosphatidylcholines in the developing rat lung.

In the present study the developmental profiles of the structural and metabolic heterogeneity of rat lung phosphatidylcholine are presented. The individual molecular species of phosphatidylcholine at different stages of the developing rat lung were analyzed as diacylglycerol derivatives. The metabolic heterogeneity of rat lung phosphatidylcholine was also studied by incubation using lung slices with radioactive precursors. The results obtained were as follows: 1. A significant increase of lung phosphatidylcholine during perinatal development (up to 1 day after birth) was found to be largely due to the increase of dipalmitoyl species. The percentage of palmitoyl-palmitoleoyl species also increased from --4 to --1 day of gestation, while palmitoyl-oleoyl species were found to decrease during development. Other molecular species showed no significant changes. 2. The incorporation of [1-14C]palmitoyl lysophosphatidylcholine into saturated phosphatidylcholine was relatively low at the earlier stage of fetal development, but it increased significantly in the last stage and reached its maximum at one day prior to birth and one day prior to the marked accumulation of dipalmitoylphosphatidylcholine occurring in the lung. In contrast, the incorporation of [3H]glycerol into saturated phosphatidylcholine remained, without showing a marked alteration during development. These results suggest that the lysophosphatidylcholine pathway which is mainly attributed to transacylation mechanism between 2 molecules of lysophosphatidylcholine may contribute to the marked production of dipalmitoylphosphatidylcholine in the lung in the last stage of gestation.

Aging↗