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PubMed2001

Overexpression of PDGF-A in the lung epithelium of transgenic mice produces a lethal phenotype associated with hyperplasia of mesenchymal cells.

Transgenic mice expressing platelet-derived growth factor A chain (PDGF-A) in the distal lung epithelium from the surfactant protein C (SPC) promoter were generated to investigate the role of this growth factor in lung development. Expression of the SPC-PDGFA transgene resulted in an enlarged, nonfunctional lung and perinatal lethality caused by failure to initiate ventilation. Histologic analysis of embryonic day (E) 16.5 lungs revealed increased mesenchymal cells and acinar buds and decreased bronchioles and dilated airspaces in SPC-PDGFA transgenic mice. At E18.5, nontransgenic lungs exhibited lung morphology typical of the saccular stage of lung development, including dilated airspaces, thin respiratory epithelium and mesenchyme, and elastin fiber deposition in primary septa. In contrast, E18.5 transgenic lungs retained many features of the canalicular stage of lung development, including undilated airspaces, cuboidal respiratory epithelium, thickened mesenchyme, and lack of parenchymal elastin deposition. These results indicate that PDGF-A is a potent growth factor for mesenchymal cells in the developing lung and that the downregulation of PDGF-A expression that normally occurs in the lung during late gestation is required for transition from the canalicular to the saccular stage of lung development.

Animals↗
PubMed1997

Hoxb-5 expression in the developing mouse lung suggests a role in branching morphogenesis and epithelial cell fate.

Hoxb-5 is one of the few homeobox genes strongly expressed in the developing mouse lung. To explore the hypothesis that Hoxb-5 acts to regulate epithelial cell fate and branching morphogenesis in the developing lung, we studied the temporal, spatial, and cell-specific expression of Hoxb-5 from gestational day (d) 13.5 to postnatal day (P) 2. Immunocytochemistry demonstrated regional localization of Hoxb-5 protein to developing conducting airways and surrounding mesenchyme. The cellular expression pattern changed from diffusely positive nuclei of mesenchymal cells on d13.5 to become more localized to nuclei of subepithelial fibroblasts and some adjacent columnar and cuboidal epithelial cells on d14.5. After d14.5, Hoxb-5 protein expression continued to decrease in mesenchymal cells distal from developing airways, but persisted in fibroblasts underlying conducting airways. Hoxb-5 protein expression persisted in nuclei of columnar and cuboidal epithelial cells on d16.5 and d17.5, with expression in low cuboidal epithelial cells as well from d17.5 to P2. Western blot analysis showed temporal and quantitative changes in Hoxb-5 protein expression with peak expression on d14.5-15.5. We conclude that Hoxb-5 protein is developmentally regulated in a temporal, spatial, and cell-specific manner throughout the pseudoglandular, canalicular, and terminal saccular periods of lung development in the mouse. This localization and expression pattern suggests that Hoxb-5 may influence branching morphogenesis, cell-cell communication, cell fate, and differentiation of conducting airway epithelia.

Animals↗
PubMed2002

Thyroid hormone affects embryonic mouse lung branching morphogenesis and cellular differentiation.

Although thyroid hormone (T(3)) influences epithelial cell differentiation during late fetal lung development, its effects on early lung morphogenesis are unknown. We hypothesized that T(3) would alter embryonic lung airway branching and temporal-spatial differentiation of the lung epithelium and mesenchyme. Gestational day 11.5 embryonic mouse lungs were cultured for 72 h in BGJb serum-free medium without or with added T(3) (0.2, 2.0, 10.0, or 100 nM). Evaluation of terminal bud counts showed a dose- and time-dependent decrease in branching morphogenesis. Cell proliferation was also significantly decreased with higher doses of T(3). Morphometric analysis of lung histology showed that T(3) caused a dose-dependent decrease in mesenchyme and increase in cuboidal epithelia and airway space. Immunocytochemistry showed that with T(3) treatment, Nkx2.1 and surfactant protein SP-C proteins became progressively localized to cuboidal epithelial cells and mesenchymal expression of Hoxb5 was reduced, a pattern resembling late fetal lung development. We conclude that exogenous T(3) treatment during early lung development accelerated epithelial and mesenchymal cell differentiation at the expense of premature reduction in new branch formation and lung growth.

Animals↗
PubMed1992

Expression of aminopeptidase N in fetal rat lung during development.

The ectopeptidase, aminopeptidase N, serves as a cell surface marker of the apical surface of the alveolar type II epithelial cell in adult lung. It is also present in fetal lung before differentiation of morphologically mature type II alveolar epithelial cells, suggesting that it is expressed by precursors of the type II cells. We have examined the mRNA coding for the aminopeptidase in adult and fetal lung and in mature type II cells and determined levels of mRNA and immunoreactive protein during fetal lung development. Comparison of the temporal patterns of steady-state levels of aminopeptidase mRNA and immunoreactive protein during development show that the expression of the protein is developmentally regulated and that expression is regulated, at least in part, at a pretranslational level. Both mRNA and immunoreactive protein levels increase severalfold on the final gestational day, suggesting that the function of the aminopeptidase may be associated with air breathing.

Aging↗
PubMed1995

Uteroglobin gene expression in the rabbit uterus throughout gestation and in the fetal lung. Relationship between uteroglobin and eicosanoid levels in the developing fetal lung.

Uteroglobin (UG) gene encodes a cytokine-like, multifunctional, antiinflammatory protein, with potent phospholipase A2-inhibitory activity. It has been suggested that during implantation this protein protects the embryos from maternal immunological assault, facilitates the maintenance of quiescence in the uterus throughout pregnancy, prevents the onset of premature labor, and helps maintain an inflammation-free respiratory organ. This latter function of UG is suggested to be accomplished by preventing hydrolysis of surfactant phospholipids by a lung-specific phospholipase A2. Using reverse transcription polymerase chain reaction, in situ hybridization, immunofluorescence, and radioimmunoassay, we studied UG gene expression in the rabbit uterus throughout gestation and in the fetal lung. Here, we report that: (a) contrary to previous reports, UG gene expression in the rabbit uterus occurs throughout gestation with a precipitous decline just before parturition; (b) this gene expression is dramatically increased in the fetal lung with increasing gestational age; and (c) while there is an inverse relationship between the levels of UG, PGE2, and PGF2 alpha, a positive correlation was found in that of UG and leukotriene C4 in the fetal lung. Our results raise the possibility that dysregulation of UG gene expression, at least in part, may contribute to the onset of premature labor and the development of inflammatory lung disease in premature neonates.

Animals↗
PubMed2006

Distinct pattern of lung gene expression in the Cftr-KO mice developing spontaneous lung disease compared with their littermate controls.

Cystic fibrosis (CF) is caused by a defect in the CF transmembrane conductance regulator (CFTR) protein that functions as a chloride channel. Dysfunction of the CFTR protein results in salty sweat, pancreatic insufficiency, intestinal obstruction, male infertility, and severe pulmonary disease. Most of the morbidity and mortality of CF patients results from pulmonary complications. Differences in susceptibility to bacterial infection and variable degree of CF lung disease among CF patients remain unexplained. Many phenotypic expressions of the disease do not directly correlate with the type of mutation in the Cftr gene. Using a unique CF mouse model that mimics aspects of human CF lung disease, we analyzed the differential gene expression pattern between the normal lungs of wild-type mice (WT) and the affected lungs of CFTR knockout mice (KO). Using microarray analysis followed by quantitation of candidate gene mRNA and protein expression, we identified many interesting genes involved in the development of CF lung disease in mice. These findings point to distinct mechanisms of gene expression regulation between mice with CF and control mice.

Animals↗
PubMed2006

Lung specific developmental expression of the Xenopus laevis surfactant protein C and B genes.

Efforts to characterize the mechanisms underlying early lung development have been confounded by the absence of a model that permits study of lung development prior to the onset of endodermal differentiation. Since Xenopus laevis development occurs in an extrauterine environment, we sought to determine whether the classical molecular markers of lung development and function, surfactant protein genes, are expressed in X. laevis. Surfactant protein C (SP-C) is a specific marker for lung development, expressed early in development and exclusively in the lung. Surfactant protein B (SP-B) expression is essential for life, as its absence results in neonatal death in mice and gene mutations have been associated with neonatal respiratory failure in humans. Here, we report the cloning of the first non-mammalian SP-C and SP-B genes (termed xSP-C and xSP-B) using the Xenopus model. The processed mature translated regions of both xSP-C and xSP-B have high homology with both human and mouse genes. xSP-C and xSP-B are both expressed throughout the lung of the X. laevis swimming tadpoles soon after the initiation of lung development as assessed by RT-PCR and whole mount in situ hybridization. The temporal expression patterns of xSP-C and xSP-B are consistent with the expression patterns in mammalian models of lung development. In both the tadpole and the adult X. laevis, xSP-C and xSP-B are expressed only in lung. Knowledge of the sequence and expression pattern of these two surfactant proteins in Xenopus might allow for use of this organism to study early lung development.

Amino Acid Sequence↗
PubMed1999

Glucose transporter expression in developing fetal lungs and lung neoplasms.

Glucose uptake and metabolism are essential for proliferation and survival of cells, and are supposed to be enhanced in actively proliferating cell systems such as embryonic and cancer tissues. Glucose uptake is usually carried out through glucose transporters. In the developing fetal lung, metabolism of glucose is thought to be an important process in cell proliferation, differentiation and maturation. Active glucose uptake could result in accumulation of glycogen in epithelial cells, and utilization of glycogen could be a critical phenomenon for lung epithelial development. In hamsters, although facilitative glucose transporter isoform 1 (GLUT1) and isoform 4 (GLUT4) are not detected in adult lungs, expression of them is detected with immunohistochemical and Western blot analyses in the developing fetal lungs. In human lung carcinomas, GLUT1 expression is seen in most cases of lung carcinoma, and is seen especially frequently in squamous cell carcinoma. GLUT1 expression in adenocarcinoma of the lung is correlated with reduced cell differentiation, larger tumor size and positive lymph node metastasis. A few cases of lung carcinoma show positive staining for GLUT3 and GLUT4. Thus, expression of some facilitative glucose transporter isoforms is detected in developing fetal epithelium and in lung carcinomas. Overexpression of them could enhance uptake of glucose into these cells, and the increased influx of glucose could be involved in active cell proliferation, which is a common character of the developing lung epithelium and carcinoma.

Animals↗
PubMed2005

Control mechanisms of lung alveolar development and their disorders in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that occurs in very premature infants and is characterized by impaired alveologenesis. This ultimate phase of lung development is mostly postnatal and allows growth of gas-exchange surface area to meet the needs of the organism. Alveologenesis is a highly integrated process that implies cooperative interactions between interstitial, epithelial, and vascular compartments of the lung. Understanding of its underlying mechanisms has considerably progressed recently with identification of structural, signaling, or remodeling molecules that are crucial in the process. Thus, the pivotal role of elastin deposition in lung walls has been demonstrated, and many key control-molecules have been identified, including various transcription factors, growth factors such as platelet-derived growth factor, fibroblast growth factors, and vascular endothelial growth factor, matrix-remodeling enzymes, and retinoids. BPD-associated changes in lung expression/content have been evidenced for most of these molecules, especially for signaling pathways, through both clinical investigations in premature infants and the use of animal models, including the premature baboon or lamb, neonatal exposure to hyperoxia in rodents, and maternal-fetal infection. These findings open therapeutic perspectives to correct imbalanced signaling. Unraveling the intimate molecular mechanisms of alveolar building appears as a prerequisite to define new strategies for the prevention and care of BPD.

Animals↗
PubMed2004

Prior lung disease and risk of lung cancer in a large prospective study.

OBJECTIVES: While 75-90% of people who develop lung cancer are smokers, only a small proportion of smokers develop lung cancer. Identifying factors that increase a smoker's risk of developing lung cancer may help scientists to better understand the etiology of lung cancer and more effectively target high-risk groups for screening. METHODS: Information on physician-diagnosed non-malignant lung diseases [asbestosis, asthma, chronic bronchitis or emphysema (CB/E), pneumonia, and tuberculosis] was obtained at baseline from 17,698 men and women involved in CARET, a randomized lung cancer prevention trial of beta-carotene and vitamin A among heavy smokers and asbestos-exposed workers. Hazard ratios for lung cancer were estimated through Cox regression models, after controlling for potential confounding factors, included smoking. Analyses were restricted to former and current smokers. RESULTS: During a median follow up of 9.1 years, 1028 cases of lung cancer occurred. Those who developed lung cancer were more likely to report a history of CB/E than controls (adjusted HR = 1.29, 95% CI: 1.09-1.53). In subgroup analyses, the association between a history of CB/E and lung cancer was stronger for those who were younger at diagnosis/reference, men in the heavy smoker cohort, former smokers, and those with squamous cell carcinomas. There was little association between a history of other lung diseases and lung cancer. CONCLUSIONS: Smokers with a history of CB/E may be at higher risk of developing lung cancer, independent of their smoking history.

Adult↗
PubMed1997

Re-emergence of a fetal pattern of insulin-like growth factor expression during hyperoxic rat lung injury.

Chronic injury to the developing lung results in cell proliferation and characteristic architectural changes. It is likely that growth factors produced and acting locally are important to these processes. Insulin-like growth factors I and II (IGF-I and IGF-II) are peptide growth factors expressed by lung cells. Roles for IGF-I and IGF-II in lung injury are suggested by their expression during lung development and by studies showing changes in IGF-I expression by activated alveolar macrophages, and increases in IGF-II peptide in oxidant arrested alveolar epithelial cells. To investigate whether the expression of IGF-I and IGF-II are changed with hyperoxic exposure, newborn rats were exposed to 80-90% oxygen for up to 6 wk and Northern hybridization analyses, in situ hybridization histochemistry, immunohistochemical staining, and reverse transcription-polymerase chain reaction (RT-PCR) studies were performed. Northern hybridization analyses of RNA extracted from whole lung showed increases in IGF-I and IGF-II mRNAs with prolonged hyperoxia. In situ hybridization histochemistry and immunohistochemical staining demonstrated spatial patterns of IGF-I and IGF-II expression similar to those seen during fetal lung development. In addition, alveolar macrophages express IGF-I and type II epithelial cells express IGF-II in control and oxygen-injured lung. These results suggest that in lung injury resident lung cells may re-express IGFs in a manner reminiscent of fetal development, and activated inflammatory cells may contribute to the proliferative response through autocrine and paracrine mechanisms.

Animals↗
PubMed1990

[Status of lung transplantation: developments, indications and results].

Lung transplantation has proven to be a successful treatment for selected patients with end stage pulmonary disease. The indications are restrictive, chronic obstructive or infective lung diseases and diseases associated with high pulmonary resistance. The choice of the appropriate operation as single lung transplantation, double lung transplantation or heart-lung transplantation is based on the various end stage lung diseases. From 1983 till april 1989 76 single lung and 49 double lung transplants were performed in different centers with an actual survival rate of 60% for single and 57% for double lung transplants.

Animals↗
PubMed2003

Lung growth and development.

The organogenesis of lung involves several complex mechanisms, including interactions between cells originating from two germ layers--endoderm and mesoderm. Regulation of lung branching morphogenesis with reference to its architecture, growth pattern, differentiation, interactions between epithelium and mesenchyme and / or endothelium, as well as genes regulating these processes have been addressed by the pulmonary biologists through careful molecular biology and genetic experimental approaches. The mammalian lung develops by outpouching from the foregut endoderm as two lung buds into the surrounding splanchnic mesenchyme. Several different regions of the foregut are specified to develop into different thoracic and visceral organs. The lung-buds further elongate and branch, and the foregut longitudinally gets separated into esophagus and trachea. In rodents (mice and rats), this occurs around embryonic day 11, where the right lung bud develops into four different lobes and left lung develops as a single lobe. In humans, these processes occur by 3-4 weeks of embryonic development, where the right lung is a trilobar lung and the left lung is a bilobar lung. Several generations of dichotomous branching occur during embryonic development, followed by secularization and alveolarization pre- and post-natally, which transform a fluid-filled lung into an air-breathing lung able to sustain the newborn. During these different developmental stages from embryonic to newborn stage, the lung architecture undergoes profound changes, which are marked by a series of programmed events regulated by master genes (e.g., homeobox genes), nuclear transcription factors, hormones, growth factors and other factors. These programmed events can be altered by undesirable exposure to overdoses of hormones/vitamins/growth factors, synthetic drugs, environmental toxins, radiation and other agents. In the recent years molecular techniques have opened avenues to study specific functions of genes or their products (proteins) in vivo or in vitro at a cellular or an organelle level, some of these include targeted disruption, knock-in / knock-out genes, in vitro mutagenesis, use of sense and anti-sense oligonucleotides. Some of these aspects with reference to regulation of normal lung development and growth and a specific example of pulmonary hypoplasia as an abnormal lung formation are discussed in this review.

Animals↗
PubMed2000

Correlation between lung injury score and serum albumin levels in patients at risk for developing acute lung injury.

This is a prospective observational study of 100 consecutive patients who were at risk for developing acute lung injury and were admitted into the surgical intensive care unit. We found a highly significant correlation between an increase in serum albumin levels and a fall in lung injury score and vice versa (r = -0.51, P = 0.000). A highly significant association was also found between mortality, fall in serum albumin levels, rise in lung injury score, and a higher simplified acute physiology score at admission (P = 0.000).

Critical Care↗
PubMed1998

Factors influencing the development of lung fibrosis after chemoradiation for small cell carcinoma of the lung: evidence for inherent interindividual variation.

PURPOSE: Clinical observations often reveal individual differences in the severity of lung fibrosis after definitive radiation therapy for lung cancer. Recent experimental studies suggest that the risk of developing lung fibrosis may be genetically controlled. The present study was undertaken to examine the magnitude of individual variation in the incidence and severity of lung fibrosis in a well-defined patient population treated by concurrent chemoradiation for limited small-cell lung carcinomas (LSCLC). MATERIALS AND METHODS: Between 1989 and 1994, 56 patients with LSCLC were enrolled in one of two controlled prospective studies of concurrent chemotherapy and concomitant conventional (45 Gy in 25 fractions q.d. over 5 weeks) or accelerated (45 Gy in 30 fractions b.i.d. over 3 weeks) radiotherapy. Chemotherapy consisted of cisplatin and etoposide (PE) or PE plus ifosfamide and mesna (PIE). Of the 56, a group of 25 patients who had serial computerized tomography (CT) examinations of the chest and were deemed to have unequivocal radiographic complete responses were selected for this study. The severity of lung fibrosis was recorded for each patient from the CT images using an arbitrary scale (0 to 3) at 1 year after treatment. Radiographic fibrosis scores were recorded on 1-3 CT slices in 3 different dose-areas (20-30 Gy; 30-40 Gy; and >40 Gy) that were defined using the corresponding CT slices from the patient's CT treatment plan. Of these patients, 23 (92%) had at least 2 slices scored; 11 patients had all 3 slices scored. RESULTS: Among the clinical and treatment parameters investigated (including type of chemotherapy), only total dose and fractionation schedule were identified as significant and independent determinants of lung fibrosis. Radiographic fibrosis scores were higher in high-dose areas and among patients treated with the accelerated schedule. Using a fit of the proportional odds (PO) model based on the total dose and fractionation schedule, fibrosis score residuals were calculated for each patient. The residual for each score is defined as the difference between the observed and expected score based on the dose and treatment schedule received. Average residuals varied significantly among patients (p = 0.005, Kruskal-Willis test). Using a modified version of the PO model, the coefficient of variation in patient heterogeneity was estimated to be 10.1% (95% confidence interval: 6.2-14.9%). Inclusion of the heterogeneity factor, in addition to total dose and fractionation schedule, improved the fit of the PO model to an extremely high level of significance (p < 10(-7)). CONCLUSIONS: Our data indicate that the risk and severity of lung fibrosis analyzed radiographically on CT images increases with total dose and with the use of an accelerated radiation schedule, for patients treated with chemoradiation for small-cell lung cancer. There was also demonstrable patient-to-patient heterogeneity, suggesting that the risk of lung fibrosis is strongly affected by inherent factors that vary among individuals.

Adult↗
PubMed2006

Influence of air pollution on respiratory health during perinatal development.

The respiratory system is a highly ordered structure composed of over 40 cell types involved in a multitude of functions. Development of the lungs spans from embryogenesis to adult life, passing through several distinct stages of growth. 2. Oxidant gases, airborne particles and environmental tobacco smoke are common air pollutants that could have a significant impact on the lungs during both pre- and postnatal periods of life. Although the specific target cells for exposure to these pollutants are not clearly identified, these cells are likely to affect critical signals or mediators expressed during distinct stages of lung development. 3. Neonatal susceptibility to environmental pollutants may be caused by either direct or indirect hits on several cell types to influence cell differentiation, proliferation and/or maturation. Air pollutants may also alter the normal developmental pattern for metabolic, immune and neurological functions that are constantly changing during in utero and postnatal growth. 4. The sensitivity of neonatal cells to environmental insults is likely to be completely different from these same cell types found in the adult. Delivery of an environmental toxicant to the respiratory system is also dramatically different during the fetal compared with the postnatal period. Passage and interaction of environmental factors through other organ systems and the vasculature, as well as maternal influences, must be taken into consideration when evaluating the impact of an environmental toxicant during early life. 5. To understand the heath outcomes of exposure to a variety of environmental factors in the respiratory system of children requires careful consideration that lung development is a multistep process and cannot be based on studies in adults.

Adult↗
PubMed2006

FGF-10 is decreased in bronchopulmonary dysplasia and suppressed by Toll-like receptor activation.

Many extremely preterm infants continue to suffer from bronchopulmonary dysplasia, which results from abnormal saccular-stage lung development. Here, we show that fibroblast growth factor-10 (FGF-10) is required for saccular lung development and reduced in the lung tissue of infants with bronchopulmonary dysplasia. Although exposure to bacteria increases the risk of bronchopulmonary dysplasia, no molecular target has been identified connecting inflammatory stimuli and abnormal lung development. In an experimental mouse model of saccular lung development, activation of Toll-like receptor 2 (TLR2) or Toll-like receptor 4 (TLR4) inhibited FGF-10 expression, leading to abnormal saccular airway morphogenesis. In addition, Toll-mediated FGF-10 inhibition disrupted the normal positioning of myofibroblasts around saccular airways, similar to the mislocalization of myofibroblasts seen in patients with bronchopulmonary dysplasia. Reduced FGF-10 expression may therefore link the innate immune system and impaired lung development in bronchopulmonary dysplasia.

Animals↗
PubMed1997

Preneoplasia-associated expression of calcyclin and of binding sites for synthetic blood group A/H trisaccharide--exposing neoglycoconjugates in human lung.

Development of preneoplastic lesions in human lung is supposed to be accompanied with alterations of distinct biochemical features which might functionally be crucial for this alteration. To contribute to the definition of such determinants in peripheral lung parenchyma, the files of the Department of Pathology, Thoraxklinik, (a total of 2890 cases) were screened for respective tissue specimens. Seventy one cases with complete clinical documentation were found and an age-, sex-, and disease-matched control group was formed. When compared to control group patients, especially the tumor free cases with preneoplastic aberrations revealed a history of exposure to external noxes. Several probes with assumed relevance were tested with the panel of specimens for both groups, focussing on comparative analysis of alveolar lining cells. In addition to labelled neoglycoconjugates which include tissue lectin-seeking probes that expose mono-, di- and blood group-related trisaccharides, presence of calcium- and annexin-binding calcyclin, of complement component C5b, of the lymphokine macrophage migration inhibitory factor, and of ligands of the serum amyloid P component was evaluated. Compared to normal cells at the alveolar surface in controls, the preneoplastic cells displayed an apparent down-regulation of expression of A/H-trisaccharide-specific binding sites and an upregulation of expression of calcyclin. These three characteristics correlated with the phenotypic alterations and encourage further studies to elucidate the functional significance of reduced expression of the glycoligand-specific sites and the presence of this member of the S100-family of Ca(2+)-binding proteins.

Adult↗