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At least 757 records · Page 42Linked to original sources
PubMed2001

The ex vivo differential expression of apoptosis signaling cofactors in the developing perinatal lung: essential role of oxygenation during the transition from placental to pulmonary-based respiration.

The signaling pathways implicated in regulating apoptosisin the perinatal developing lung are not well characterized. We have previously shown that apoptosis signaling cofactors in the fetal alveolar epithelium are redox-sensitive and differentially expressed in response to oxyexcitation (Haddad and Land, Biochem. Biophys. Res. Commun. 271, 257-267, 2000). In this report we investigated the role of oxygenation during the transition period from placental to pulmonary-based respiration in regulating the differential expression of apoptosis cofactors ex vivo. The antiapoptotic proto-oncogene, Bcl-2, exhibited suppressed abundance commencing after birth, an effect which was partially restored at a later stage of development. Oxygenation-mediated down-regulation of Bcl-2 was accompanied by suppression of Bax, such that Bcl-2/Bax equilibrium ratio remained steadily constant postnatally. Analysis of whether a Bax-independent pathway is involved in cell death in the perinatal lung revealed a novel role for p53, whose abundance predominated that of Bcl-2 and Bax at different stages of gestational development. We conclude that apoptosis ex vivo is partly Bax-insensitive and mediated by suppression of Bcl-2 in a p53-dependent mechanism.

Actins↗
PubMed2006

Contribution of inflammation to lung injury and development.

Inflammation interferes with lung development in model systems and is present chronically in the lungs of preterm infants who develop bronchopulmonary dysplasia (BPD). Antenatal inflammation is very commonly associated with preterm deliveries, but there is generally minimal information about the duration, intensity, or organisms associated with chorioamnionitis. In preterm lamb models, chorioamnionitis causes a lung injury similar to BPD and also causes clinical lung maturation. Continuous exposure of the developing lung before and after delivery to inflammation may be central to the development of BPD.

Animals↗
PubMed2002

Increased epithelial cell proliferation in very premature baboons with chronic lung disease.

Coordinated proliferation of lung cells is required for normal lung growth and differentiation. Chronic injury to developing lung may disrupt normal patterns of cell proliferation. To examine patterns of cell proliferation in injured developing lungs, we investigated premature baboons delivered at 125 days gestation (approximately 67% of term) and treated with oxygen and ventilation for 6, 14, or 21 days (PRN). Each PRN treatment group contained 3 or 4 animals. During normal in utero lung development, the proportion of proliferating lung cells declined as measured by the cell-cycle marker Ki67. In the PRN group, the proportion of proliferating lung cells was 2.5-8.5-fold greater than in corresponding gestational controls. By 14 days of treatment, the proportion of cells that expressed pro-surfactant protein B (proSP-B) was ~2.5-fold greater than in gestational controls. In the PRN group, 41% of proliferating cells expressed proSP-B compared with 5.8% in the gestational controls. By 21 days of treatment, proliferation of proSP-B-expressing epithelial cells declined substantially, but the proportion of proliferating non-proSP-B-expressing cells increased approximately sevenfold. These data show that the development of chronic lung disease is associated with major alterations in normal patterns of lung-cell proliferation.

Animals↗
PubMed1984

Perinatal rat lung retinol (vitamin A) and retinyl palmitate.

The potential role for retinol (vitamin A alcohol) in the differentiation of the developing lung prompted this study in the perinatal rat. High performance liquid chromatography was used to separate, detect, and quantitate retinol and retinyl palmitate in lipid extracts of tissue and serum. Fetal and maternal blood showed the presence of retinol, whereas no retinyl palmitate was detected. On the other hand, fetal and postnatal lungs contained retinyl palmitate as well as retinol. Considerable changes in the content of lung retinyl palmitate were found during lung development. Fetal lungs (17-21 days of gestation) contained 2.3 +/- 0.36 micrograms/g wet weight (mean +/- SD) of retinyl palmitate and 0.14 +/- 0.05 micrograms/g of retinol. Lungs of pups (1-10 days old) contained much less retinyl palmitate, 0.63 +/- 0.20 micrograms/g, whereas the amount of retinol was the same as in fetal lungs. The surprisingly high content of retinyl palmitate in fetal lung and its depletion after birth may be functionally related to retinol action in the developing lung.

Animals↗
PubMed2000

Effects of retinoic acid on airspace development and lung collagen in hyperoxia-exposed newborn rats.

Impaired septal formation and decreased alveolarization are often caused by hyperoxic injury to the developing lung and are characteristic features of bronchopulmonary dysplasia. Dexamethasone, frequently administered to infants during oxygen exposure, also inhibits septal formation in the newborn lung. Vitamin A administration reduces the incidence of bronchopulmonary dysplasia in vitamin A-deficient premature infants, and retinoic acid improves alveolarization in newborn rats treated with dexamethasone, indicating that retinoic acid may be useful in preventing hyperoxia-induced impaired septation in bronchopulmonary dysplasia. To investigate whether treatment with retinoic acid during exposure to hyperoxia would improve septal formation, newborn rats exposed to > or =90% O(2) from d 3 of life to d 14 were treated with retinoic acid (d 3-13 of life) and/or dexamethasone (d 4-13 of life). In contrast with the effects of retinoic acid on dexamethasone-induced inhibition of alveolarization, we found that retinoic acid did not improve septal formation or decrease airspace size in animals exposed to hyperoxia alone or to hyperoxia plus dexamethasone. Retinoic acid did, however, increase collagen in airspace walls as demonstrated by staining and immunohistochemistry. There was no increase in procollagen mRNA by Northern hybridization analysis, indicating that retinoic acid-associated increases in lung collagen are likely due to posttranscriptional regulation. There was a trend toward increased survival in hyperoxia in animals treated with retinoic acid to the extent that combined therapy with retinoic acid and dexamethasone resulted in the greatest improvement in animal survival. These results suggest that although retinoic acid may be of benefit in hyperoxia-induced lung injury and may have important effects on lung matrix, it does not prevent impairment of septation or induce alveolar formation during exposure to hyperoxia.

Animals↗
PubMed1998

Connexin 26 expression in human and ferret airways and lung during development.

Coordinated microscopic and molecular biological studies were used to document gap junction expression during postnatal development in ferret tracheal epithelium and lung and in fetal and adult human airway and lung. Expression of connexin 26 (Cx26) in the ferret airways was limited to the epithelial layer and was observed only during the newborn interval. In contrast, we found Cx26 expressed in the alveolar epithelium of the ferret lung by in situ hybridization, Northern blotting, RT-PCR amplification, and immunocytochemical labeling at all ages examined. This finding was further confirmed by documentation of gap junctional plaques upon ultrastructural examination of freeze-fracture replicas of adult ferret lung tissue. Parallel studies of developing human fetal lung and airway suggested connexin expression in the airways only in the first trimester but, as in the ferret, persistent expression was observed in both fetal and adult lung. These studies suggest that the transient expression of Cx26 is a reliable early indicator of airway epithelial development and differentiation in the airways. In contrast, Cx26 expression persists throughout life in the lung, suggesting that gap junctions serve more perennial intercellular communication functions in the peripheral lung.

Animals↗
PubMed2000

Computer simulations of particle deposition in the developing human lung.

An age-dependent theoretical model has been developed to predict PM dosimetry in children's lungs. Computer codes have been written that describe the dimensions of individual airways and the geometry of branching airway networks within developing lungs. Breathing parameters have also been formulated as functions of subject age. Our computer simulations suggest that particle size, age, and activity level markedly affect deposition patterns of inhaled air pollutants. For example, the predicted lung deposition fraction is 38% in an adult but is nearly twice as high (73%) in a 7-month-old for 2-micron particles inhaled during heavy breathing. Tracheobronchial (TB) and pulmonary (or alveolated airways, P) deposition patterns may also be calculated using the model. Due to different clearance processes in the TB and P airways (i.e., mucociliary transport and macrophage action, respectively), the determination of compartmental dose is important for PM risk assessment analyses. Furthermore, the results of such simulations may aid in the setting of regulatory standards for air pollutants, as the data provide a scientific basis for estimating dose delivered to a designated sensitive subpopulation (children).

Adolescent↗
PubMedDate not supplied

Composition of the pulmonary interstitium during normal development of the human fetus.

Normal lung development is dependent on epithelial-mesenchymal interactions. This study was undertaken to examine the structure of the interstitium of the developing human fetal lung, concentrating particularly on the first and second trimesters. Lung tissue was obtained at autopsy from nonmalformed, nonmacerated cases of spontaneous abortion (n = 15), stillbirth (n = 9), and very early neonatal death (n = 5) (range of gestations, 10-42 weeks). Paraffin-embedded tissue sections were examined using immunohistochemical methods to determine expression of collagens I, III, IV, V, and VI; the glycoproteins fibronectin and laminin; and the intermediate filaments vimentin, alpha-smooth muscle actin (alphaSMA), and desmin. Collagens III and VI and cells expressing alphaSMA were present consistently at points of airway branching and secondary crest formation, indicating a role for these components in the initiation and stabilization of airway branches in the developing lung. Desmin expression by stromal cells succeeded alphaSMA temporally, and may represent a marker of terminal smooth muscle differentiation within the airway; it was not detected in the vascular tree. Other components were widely expressed throughout the extracellular matrix, including basement membranes, at all gestations. The spatial and temporal patterns of expression of components of the lung interstitium provide clues to the mechanisms underlying normal human lung development and possible insights into the pathogenesis of fetal and neonatal lung disease.

Collagen↗
PubMed2004

The effects of dietary myoinositol on lung tumor development in tobacco smoke-exposed mice.

The purpose of these experiments was to investigate whether a diet containing myoinositol could prevent the development of tobacco smoke-induced lung tumors in strain A/J mice. In a positive control experiment, 1% and 3% of myoinositol in AIN-93 diet reduced the development of lung tumors induced by NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] by 69% and 75%. In animals exposed for 5 mo, 6 h/day, 5 days/wk, to a mixture of tobacco sidestream and mainstream smoke, and then fed myoinositol-containing diets once smoke exposure had ceased, no chemopreventive effect was observed. When animals were fed myoinositol during both tobacco smoke exposure and the recovery period, a slight but statistically not significant reduction in tumor multiplicities was found. It was concluded that myoinositol has less chemopreventive activity against the full complex mixture of tobacco smoke than it has against selected constituents such as NNK or benzo[a]pyrene.

Animals↗
PubMed1997

Combined genetic polymorphism and risk for development of lung cancer.

Susceptibility to lung cancer has been shown to be modulated by host specific factors. Inheritance of different polymorphic cytochrome P450s (CYPs) and the glutathione S-transferases (GSTs) which affect metabolism of environmental toxicants may play a key role in individual susceptibility. Although individual polymorphic genes have been reported to be associated with development of lung cancer, little is known about the combined effects of several genes in carcinogenesis. From our study of 54 lung cancer patients and 50 matched controls, we observed that a combination of several versions of 'unfavorable' metabolizing genes (CYP2D6, CYP2E1, GSTM1 and GSTT1) is strongly associated with lung cancer. The relative risk for the different combinations of these genotypes ranged between 1.3 and 14, with higher risk involving the activating genes. The duration and intensity of heavy smoking (expressed in pack-years) are the most important determinant for the development of lung cancer. For example, the estimated risk for development of lung cancer associated with smoking > 30 pack-years is represented by an odds ratio = 6.65; 95% CL = 2.3-19.9 irrespective of an individual's genotype, whereas for smoking between > 30 and < 50 pack years, odds ratio = 4.5; 95% CL = 1.37-15; and for smoking > 50 pack-years, odds ratio = 30; 95% CL = 5.7-114. On the other hand, smoking of less than 30 pack-years is associated with an increased risk in the presence of the polymorphic genes (odds ratio = 2.5; 95% CL = 0.32-54). The results of our study indicate that the inheritance of multiple 'unfavorable' genotypes, especially activating genes, is a crucial predisposing factor for the development of lung cancer from cigarette smoking. In addition, the genes may cause moderate smokers who would normally outlive the deleterious effects of smoking to develop lung cancer. The information can therefore be used to target individuals for prevention of health problems.

Adult↗
PubMed2003

Is maternal copper supplementation during alveolarization protecting the developing rat lung against the adverse effects of maternal nicotine exposure? A morphometric study.

In a previous study, it was shown that maternal nicotine exposure during gestation and lactation interfered with alveolarization and resulted in gradual deterioration of the lung parenchyma, resulting in microscopic emphysema. The aim of this study was thus to investigate the long-term effects of maternal nicotine exposure (1 mg/kg body weight/day, subcutaneous [sc] from the onset of the phase of rapid alveolarization, which occur from postnatal day 4 in rats, on (1) the development of the gas-exchange area of the lungs of the offspring and, (2) whether maternal copper supplementation (1 mg/kg body weight/day, SC) during the same period of time will prevent the effect of maternal nicotine exposure on the development of the neonatal rat lung. Nicotine administration lasted until weaning on postnatal day 21. The day of birth was designated day 0. The offspring were exposed to nicotine via the mother's milk only. The experimental animals received no nicotine or copper after postnatal day 21. The lung tissue of the neonates was collected on postnatal days 14, 21, and 42 and prepared for morphometry. The results obtained show that maternal nicotine exposure had no influence on body weight, chest circumference, crown-rump length, and lung volume, but resulted in bigger alveolar volumes and suppressed alveolarization in the lungs of the offspring. Copper supplementation during this period of lung development reduced the adverse effect of maternal nicotine exposure on neonatal lung development. Even though copper reduced the adverse effects of maternal nicotine exposure during this phase of lung development, it did not prevent the induction of microscopic emphysema.

Animals↗
PubMed1998

Effects of fluoxetine on the development of lung metastases induced by operative stress in rats.

Experiments were performed in order to evaluate the effects of fluoxetine, a selective inhibitor of neural serotonin transporter antidepressant, on the development lung metastases in rats subjected to laparotomy and injected (i.v.) with 10(4) Walker 256 (W-256) carcinosarcoma cells. The number of metastatic nodules on the surface of the lungs, as well as the percentage-area of metastases in the frontal section through pulmonary hilus were increased in rats subjected to sham-surgery or laparotomy. Treatment with fluoxetine (5 mg/kg) partially reversed those adverse effects of surgery, but the difference was clearer when it was administered before surgery was performed. Survival periods were also assessed and fluoxetine was found to decrease the lethality of rats exposed to surgery.

Animals↗
PubMed2001

Immunolocalization of sonic hedgehog (Shh) in developing mouse lung.

Expression of sonic hedgehog (Shh) is required for normal development of the lung during embryogenesis. Loss of Shh expression in mice results in tracheoesophageal fistula, lung hypoplasia, and abnormal lung lobulation. To determine whether Shh may play a role later in lung morphogenesis, immunostaining for Shh was performed in mouse lung from embryonic day (E) 10.5 to postnatal day (PD) 24. Shh was detected in the distal epithelium of the developing mouse lung from E10.5 to E16.5. From E16.5 until PD15, Shh was present in epithelial cells in both the peripheral and conducting airways. Although all cells of the developing epithelium uniformly expressed Shh at E10.5, Shh expression was restricted to subsets of epithelial cells by E16.5. Between E16.5 and PD15, non-uniform Shh staining of epithelial cells was observed in the conducting airways in a pattern consistent with the distribution of non-ciliated bronchiolar cells (i.e., Clara cells) and the Clara cell marker CCSP. Shh did not co-localize with hepatocyte nuclear factor/forkhead homologue-4 (HFH-4), beta-tubulin, or with the presence of cilia. These results support the concept that Shh plays a distinct regulatory role in the lung later in morphogenesis, when it may influence formation or cytodifferentiation of the conducting airways.

Animals↗
PubMed2007

Incidence and risk factors for the development of lung tumors after liver transplantation.

Tobacco and immunosuppression are risk factors for developing upper aerodigestive and lung tumors after transplantation. This study comprises 701 adult recipients who survived more than 2 months after transplant: 276 patients underwent orthotopic liver transplantation (OLT) for alcoholic cirrhosis (AC) and 425 for nonalcoholic disease. The aim is to analyze the incidence, clinical characteristics, risk factors, and outcome of patients who develop lung malignancies after OLT. Incidence of lung cancer was 2.1% (15 patients): 4.3% (12 patients) in the alcoholic group and 0.7% (three patients) in the nonalcoholic group (P < 0.001). Mean time from OLT to tumor diagnosis was 86 months. Thirteen patients were smokers; 12 patients were heavy drinkers; and 11 were drinkers and smokers. Squamous cell carcinoma was diagnosed in nine patients, large cell carcinoma in three, adenocarcinoma in two, and broncoalveolar in one. Tumor staging: 10 patients at stage IV; three at stage IIIB; and two at stage IIB. Tumor resection was performed in one patient, and three also received chemotherapy. Mean survival after tumor diagnosis was 5.4 months. There is a higher risk of lung cancer in smoker patients who have undergone OLT for AC, and have a very poor prognosis because tumors are diagnosed at advanced stages.

Adolescent↗
PubMed2004

Defective lung vascular development and fatal respiratory distress in endothelial NO synthase-deficient mice: a model of alveolar capillary dysplasia?

Endothelium-derived NO plays a critical role in the regulation of cardiovascular function and structure, as well as acting as a downstream mediator of the angiogenic response to numerous vascular growth factors. Although endothelial NO synthase (eNOS)-deficient mice are viable, minor congenital cardiac abnormalities have been reported and homozygous offspring exhibit high neonatal mortality out of proportion to the severity of these defects. The aim of the present report was to determine whether abnormalities of the pulmonary vascular development could contribute to high neonatal loss in eNOS-deficient animals. We now report that eNOS-deficient mice display major defects in lung morphogenesis, resulting in respiratory distress and death within the first hours of life in the majority of animals. Histological and molecular examination of preterm and newborn mutant lungs demonstrated marked thickening of saccular septae, with evidence of reduced surfactant material. Lungs of eNOS-deficient mice also exhibited a striking paucity of distal arteriolar branches and extensive regions of capillary hypoperfusion, together with misalignment of pulmonary veins, which represent the characteristic features of alveolar capillary dysplasia. We conclude that eNOS plays a previously unrecognized role in lung development, which may have relevance for clinical syndromes of neonatal respiratory distress.

Animals↗
PubMed1996

Effects of K-ras gene mutations in the development of lung lesions induced by 4-(N-methyl-n-nitrosamino)-1-(3-pyridyl)-1-butanone in A/J mice.

The relationship between the development of peripheral lung lesions induced by tobacco-specific 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and K-ras gene mutation in A/J mice, and the correlations between histological alterations and the course of lung lesion development after NNK treatment and K-ras gene mutation were investigated. The acquisition of a selective growth advantage by the lung lesions with mutations was also examined using immunohistochemical labeling with bromodeoxyuridine. Thirty female 5 weeks old A/J mice were each injected intraperitoneally with a single dose of NNK (100 mg/kg body weight) and subdivided into 6 groups according to the time after NNK treatment. The lung lesions were characterized histologically as alveolar/bronchiolar hyperplasia, adenoma and adenocarcinoma, and point mutations in codons 12 and 61 of the K-ras gene were detected by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) and dideoxy sequencing methods. K-ras gene mutations were identified in 7 (58.3%) of 12 hyperplasias, 42(75.0%) of 56 adenomas and 3 (75.0%) of 4 adenocarcinomas. The most frequent K-ras gene mutation was a G-to-A transition at the second base of codon 12 and this accounted for 86.5% of all the mutations detected. Neither the frequency of activation of this gene nor the specific mutation was affected by the time after NNK treatment and there was no positive correlation between the proliferative activity of lung lesions and the presence of K-ras gene mutations. Thus, K-ras gene mutation is closely associated with the development of NNK-induced peripheral lung lesions in A/J mice, but it plays no role in the selective growth advantage of these lesions.

Animals↗
PubMed2005

Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases during normal human pulmonary development.

AIMS: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are thought to be involved in lung development because they play an important role in the turnover of the extracellular matrix. Although limited data on MMP and TIMP expression are available from animal studies during prenatal pulmonary development, little is known about their expression during human fetal lung development. The aim of this study was to investigate the expression of MMP-1, -2, -9, TIMP-1, -2 and -3 in human fetal lungs from 9 to 42 weeks of gestation. METHODS AND RESULTS: Forty-five normal human fetal lung samples were analysed by immunohistochemistry. MMP-1, -9, TIMP-1, -2 and -3, but not MMP-2, were expressed in the epithelium at all gestational ages. The endothelium of all vessels and the arterial smooth muscle cells expressed MMP-1, -2, -9, TIMP-2 and -3, but not TIMP-1, at all developmental stages. CONCLUSION: The extensive distribution of MMPs and TIMPs throughout all stages of human lung development suggests that they play a significant role in the remodelling that occurs in the interstitium and epithelial basement membrane during lung development and in pulmonary vascular development. These data will serve as a base line for comparison with neonatal lung pathology, including pulmonary hypertension.

Fetus↗
PubMed2002

Defective pulmonary development in the absence of heparin-binding vascular endothelial growth factor isoforms.

Development of the airways, alveoli, and the pulmonary vasculature in the fetus is a process that is precisely controlled. One of the growth factors involved, vascular endothelial growth factor (VEGF), is so critical for embryonic development that in the mouse, elimination of just a single allele is lethal. In the early stages of lung development, the mouse VEGF gene expresses three isoforms (120, 164, and 188) in a distinct temporo-spatial pattern, suggesting a specific function for each. We engineered mice that express only VEGF 120, to study the role of VEGF isoforms in lung development. Lung vessel development in these mice was studied by scanning electron microscopy of Mercox casts of lung vasculature. Airway and air-blood barrier development was analyzed by light microscopy, transmission electron microscopy, immunohistochemistry, and morphometry. In all VEGF120/120 fetuses and pups, lung vascular casts were smaller and less dense compared with 120/+ and wild-type littermates. Although the generation count of pre-acinar vessels was similar in all three genotypes, the most peripheral vessels were dilated and were more widely separated in 120/120 fetuses of all ages, compared with 120/+ and wild-type littermates. In addition, 120/120 animals had fewer air-blood barriers and a decreased airspace-parenchyma ratio compared with 120/+ and wild-type littermates. We concluded that the absence of VEGF 164 and 188 isoforms impairs lung microvascular development and delays airspace maturation, indicating an essential role for heparin-binding VEGF isoforms in normal lung development.

Alternative Splicing↗