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PubMed1994

Genetic changes in the development of lung cancer.

Both inherited predisposition and acquired somatic genetic changes contribute to lung tumour development but the former is likely to be the minor component. The relative ease with which lung tumours can be established as cell lines has resulted in extensive cytogenetic analysis, and, this together with molecular techniques which assess loss of genetic material has revealed consistent patterns of genetic damage. Some of these characteristic somatic genetic changes have been traced back to the pre-invasive stage of tumour development and this information may contribute to the future management of this currently intractable disease.

Chromosome Deletion↗
PubMed2000

Early oxidative DNA damages and late development of lung cancer in diesel exhaust-exposed rats.

To demonstrate DNA damages in the early stage of diesel exhaust exposure, an inhalation study of 1 through 12 months was conducted. The lung burden of diesel soot increased with increase in exposure duration. Histologically, hyperplastic foci of alveolar epithelia were found at 6-month exposure and became prominent at the 12th month, with slight nuclear atypia and positive p53 staining. The level of 8-OH-hydroxyguanosine (8-OH-dG) in the exposed rat lungs showed an increase from 1 month of exposure, followed by a gradual increase, reaching almost a plateau level at the 9th month. An in vitro experiment demonstrated significant 8-OH-dG formation when diesel particles and H(2)O(2) were added to the DNA solution. The level of bulky aromatic DNA adducts peaked at the 1st month of exposure, followed by a decrease. By the end of the observation period of 30 months, lung tumors developed even in the 6-month exposure group, and the earliest lung tumors were found only in rats that survived longer than 18 months. In conclusion, persisting oxidative stress on DNA induced in the early phase of diesel exhaust exposure, together with inflammation, seems to play an important role in carcinogenesis at advance ages after a long latent period.

Animals↗
PubMed1996

Expression of Hoxb genes in the developing mouse foregut and lung.

Lung development in the mouse begins at embryonic day 9.5 (E9.5) when lung buds form in the foregut. Subsequently, there is extensive branching and cellular differentiation that depends upon specific epithelial-mesenchymal interactions. Homeobox genes are expressed in specific temporo-spatial patterns in the developing embryo and are known to be involved in axial patterning and specification of regional identity. Using whole mount in situ hybridization and immunohistochemistry, we studied the expression of Hoxb-1, b-2, b-3, b-4 and b-5 in the E9.5-E14.5 foreguts and lungs. Our results show that in E9.5 branchial arches and foregut, Hoxb genes are expressed in overlapping spatial domains and the anterior boundaries of these domains correspond to the position of a particular gene in the cluster-genes on the 3' end of the cluster are expressed more anteriorly in the branchial arches and foregut and those on the 5' end are expressed more posteriorly. Three of the genes, Hoxb-3, b-4, and b-5, are highly expressed in the foregut where the lung buds form. In contrast, in E10.5-E14.5 lung, there are two patterns of Hoxb gene expression. Hoxb-3 and b-4 are expressed in the mesenchyme of the trachea, mainstem bronchi, and distal lung, whereas Hoxb-2 and b-5 mRNA are present only in the mesenchyme of the distal lung buds. These results suggest that specific combinations of Hoxb gene expression are important in lung development and that Hoxb genes may be involved in specifying the differences between proximal (trachea and main bronchi) and distal (lung bud) mesenchyme.

Animals↗
PubMed1981

Uptake and metabolism of biogenic amines in the developing rabbit lung.

Uptake and metabolism of biogenic amines in developing lung were studied in a total of 62 New Zealand White rabbits aged 28 days of gestation to 28 days postnatal. Lungs were perfused in vitro with 5-[14C]hydroxytryptamine (5-HT) or [14C]phenylethylamine (PEA) and coperfused with high-molecular-weight [3H]dextran to assess the vascular space perfused. Patterns of uptake and metabolism of PEA and 5-HT as functions of age were markedly different. PEA uptake and metabolism gradually increased with advancing age. No differences were observed in 5-HT uptake or metabolism within the postnatal age range studied, but the magnitude of each process for 5-HT was significantly lower in premature animals. Functional maturity for both uptake and metabolism of PEA was observed by 14-21 days of age. Inhibition of intrapulmonary monoamine oxidase by semicarbazide and pargyline showed that PEA metabolism was unaffected by the former and moderately reduced by the latter agent only in animals older than 1 wk. Thus the lung of the newborn rabbit effectively takes up and metabolizes PEA and 5-HT, but age-related differences are evident in the development of specific monoamine oxidase subtypes. Reduced 5-HT metabolism in lung of premature animals paralleled changes in the measured vascular space, possibly reflecting difficulty in perfusing premature lungs as well as immature functional status. This study emphasizes the importance of determining functional vascular perfusion (by coperfusion with intravascular markers) when studying the developing lung.

Animals↗
PubMed1999

Immunocytochemical mapping of the amidating enzyme PAM in the developing and adult mouse lung.

The enzyme PAM is required for activation of many peptide hormones. In adult mouse lung, immunostaining for PAM was located in Clara cells, which constitute most of the epithelial cells of the mouse bronchial/bronchiolar tree. Immunoreactivity appeared for the first time in the epithelium on gestational Day 16, being slight and mostly restricted to the apical cytoplasm. As the lung developed, the labeling became gradually stronger and extended throughout the cell. Smooth muscle of airways and blood vessels, and some parenchymal cells, probably macrophages, also showed PAM immunoreactivity. Of the two enzymatically active domains of PAM, only PHM and not PAL immunoreactivity was found at all stages studied. The early appearance of PAM in developing mouse lung, as well as its presence in a variety of tissues, probably indicates a complex role of this enzyme in pulmonary development and function.

Animals↗
PubMed2001

Branching and differentiation defects in pulmonary epithelium with elevated Gata6 expression.

The transcription factor GATA6 is expressed in the fetal pulmonary epithelium of the developing mouse lung and loss of function studies strongly suggested that it is required for proper branching morphogenesis and epithelial differentiation. We have further investigated the role of GATA6 in this process by utilizing a pulmonary epithelium specific promoter to maintain high levels of GATA6 protein during fetal lung development. Transgenic mice expressing Gata6 cDNA under the control of the human Surfactant Protein-C (SP-C) promoter were generated and their lungs were analyzed during fetal stages. Transgenic lungs exhibit branching defects as early as embryonic day (E) 14.5 and molecular analysis just before birth (E18.5) shows a lack of distal epithelium differentiation whereas proximal epithelium is unaffected. Electron microscopic analysis and glycogen staining confirm the lack of differentiation to mature Type II cells. Thus, elevated levels of GATA6 protein affect early lung development and in analogy to other GATA factors in other tissues, GATA6 also plays a crucial role in the terminal differentiation in this case of the distal pulmonary epithelium.

Animals↗
PubMed2002

Notch1 and Jagged1 expression by the developing pulmonary vasculature.

The molecular mechanisms of pulmonary vascular development are poorly understood. Cell-specific developmental pathways are influenced by cell-cell signaling. Notch signaling molecules are highly conserved receptors active in many cell-fate determination systems. Recent observations of Notch molecules and a Notch ligand, Jagged1, suggest their importance in vascular morphogenesis, and particularly pulmonary vascular development. We performed a systematic evaluation of Notch1/Jagged1 gene and protein expression in the developing mouse lung from embryonic day 11 until adulthood by using quantitative PCR, immunofluorescence, and electron microscopic analysis. mRNA transcripts for Notch1-4 and Jagged1 increased progressively from early to later lung development, accompanied by a simultaneous rise in endothelial cell-specific gene expression, a pattern not seen in other organs. Notch1 mRNA was identified on both epithelial and mesenchymal structures of the embryonic lung. Immunofluorescence staining revealed the progressive acquisition of Notch1 and Jagged1 proteins by the emerging endothelium. Notch1 and Jagged1 were seen initially on well-formed, larger vessels within the embryonic lung bud and progressively on finer vascular networks. Each was also expressed on surrounding nonvascular structures. The localization of Notch1 and Jagged1 on endothelial cell surface membranes within the alveolar microvasculature was confirmed by immuno-electron microscopy. These temporal and spatial patterns in Notch1/Jagged1 gene and protein expression suggest multiple potential paths of cell-cell signaling during lung development and vascular morphogenesis.

Animals↗
PubMed2003

beta-Catenin is required for specification of proximal/distal cell fate during lung morphogenesis.

The lungs are divided, both structurally and functionally, into two distinct components, the proximal airways, which conduct air, and the peripheral airways, which mediate gas exchange. The mechanisms that control the specification of these two structures during lung development are currently unknown. Here we show that beta-catenin signaling is required for the formation of the distal, but not the proximal, airways. When the gene for beta-catenin was conditionally excised in epithelial cells of the developing mouse lung prior to embryonic day 14.5, the proximal lung tubules grew and differentiated appropriately. The mice, however, died at birth because of respiratory failure. Analysis of the lungs by in situ hybridization and immunohistochemistry, using molecular markers of the epithelial and mesenchymal components of both proximal and peripheral airways, showed that the lungs were composed primarily of proximal airways. These observations establish, for the first time, both the sites and timing of specification of the proximal and peripheral airways in the developing lung, and that beta-catenin is one of the essential components of this specification.

Animals↗
PubMed1994

Regulation of lung branching morphogenesis by bombesin-like peptides and neutral endopeptidase.

The expression of bombesin-like peptides (BLPs) by pulmonary neuroendocrine cells is transiently upregulated during lung development. A functional role for BLPs is supported by their ability to stimulate lung growth and maturation both in vitro and in vivo during the late stages of lung development. In addition, the cell membrane-associated enzyme CD10/neutral endopeptidase 24.11 (CD10/NEP), which inactivates BLPs and other regulatory peptides, is also expressed by developing lungs and modulates the stimulatory effects of BLPs on lung growth and maturation. We hypothesized that, in addition to expressing BLPs and CD10/NEP, embryonic lungs must express BLP receptors, and that BLPs may also regulate processes that occur during early lung development such as branching morphogenesis. Using reverse transcriptase-polymerase chain reaction and oligonucleotide primers designed for amplifying a BLP receptor originally isolated from Swiss 3T3 mouse fibroblasts, we found that embryonic mouse lungs express a similar BLP receptor mRNA during the pseudoglandular stage of lung development when branching morphogenesis take place. Subsequently, we evaluated the effects of ligands for this BLP receptor using embryonic mouse lungs in an in vitro model of lung branching morphogenesis. We found that, in comparison with control lungs, treatment with bombesin (1 to 100 nM) resulted in a modest increase in clefts or branching points. In contrast, embryonic mouse lungs treated with the BLP analog [Leu13-psi(CH2NH)Leu14]bombesin (1 microM), which also binds to this BLP receptor but has predominantly antagonistic effects, demonstrated fewer branching points.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Influence of the donor lung on development of early infections in lung transplant recipients.

Infection of the lung allograft is the greatest cause of morbidity and mortality after heart-lung transplantation. To better understand the pathogenesis of these infections, we compared the results from cultures of the donor tracheas with the type and prevalence of early intrathoracic infections in the recipients. In the last 37 recipients, intrathoracic infections occurred within 2 weeks of operation in 16 (43%). Organisms isolated from the donor tracheal cultures were different from those associated with early infections, except for three of four recipients with heavy growth of Candida in donor tracheal cultures, in whom fatal invasive candidiasis developed caused by the same species of Candida isolated from the donor culture. Comparisons were made between recipients with (n = 16) and without early infection (n = 21) for age of donors and recipients, ischemic time, length of donor stay in an intensive care unit, donor arterial oxygen pressure, duration of recipient intubation, sterile donor tracheal culture or culture with presence of mouth flora, bacterial pathogens, or Candida, method of lung preservation, and antibiotic prophylaxis of donor. The only factor significantly associated with the onset of early infection was the presence of mouth flora in the donor tracheal culture (p = 0.004, Fisher's exact test, two sided). Multiple logistic regression was performed to test the additional contribution of other covariates after adjusting for the presence of mouth flora. None of the other covariates contributed to the occurrence of early infection. Recipients with early infection had a significantly lower survival compared with those without early infection (p = 0.04) by the Kaplan-Meier survival analysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed2005

Hypoxia-induced mitogenic factor modulates surfactant protein B and C expression in mouse lung.

Previous studies have demonstrated a robust pulmonary expression of hypoxia-induced mitogenic factor (HIMF) during the perinatal period, when surfactant protein (SP) synthesis begins. We hypothesized that HIMF modulates SP expression and participates in lung development and maturation. The temporal-spatial expression of HIMF, SP-B, and SP-C in developing mouse lungs was examined by immunohistochemical staining, Western blot, and RT-PCR. The expression and localization of SP-B and SP-C were investigated in mouse lungs after intratracheal instillation of HIMF in adult mice. The effects of HIMF on SP-B and SP-C transcription activity, and on mRNA degradation, were investigated in mouse lung epithelial (MLE)-12 and C10 cells using the promoter-luciferase reporter assay and actinomycin D incubation. The activation of Akt, extracellular signal-regulated kinase (ERK)1/2, and p38 mitogen-activated protein kinase was explored by Western blot. Intratracheal instillation of HIMF resulted in significant increases of SP-B and SP-C production, predominantly localized to alveolar type II cells. In MLE-12 and C10 cells, HIMF enhanced SP-B and SP-C mRNA levels in a dose-dependent manner. Meanwhile, HIMF increased transcription activity and prevented actinomycin D-facilitated SP-B and SP-C mRNA degradation in MLE-12 cells. Incubation of cells with LY294002, PD098059, or U0126 abolished HIMF-induced Akt and ERK1/2 phosphorylation and suppressed HIMF-induced SP-B and SP-C production, whereas SB203580 had no effect. These results indicate that HIMF induces SP-B and SP-C production in mouse lungs and alveolar type II-like cell lines via activations of phosphatidylinositol 3-kinase/Akt and ERK1/2 mitogen-activated protein kinase, suggesting that HIMF plays critical roles in lung development and maturation.

Animals↗
PubMed1992

Cyclic adenosine 3',5'-monophosphate increases beta-adrenergic receptor concentration in cultured human fetal lung explants and type II cells.

cAMP regulates the maturation of many biochemical processes that occur during normal lung development, including the changing levels of surfactant proteins and phospholipids. We examined the effect of cAMP on the beta-adrenergic receptor concentration in the developing human lung. Isobutylmethylxanthine, a cAMP phosphodiesterase inhibitor, increased both the tissue cAMP content and beta-adrenergic receptor concentration in treated explants above those in untreated explants. 8-Bromo-cAMP treatment also elevated the beta-adrenergic receptor concentration of lung explants compared to that in untreated controls. These data indicate the ability of elevated cAMP to increase the beta-adrenergic receptor concentration. Both lung cAMP and beta-adrenergic receptor concentrations increase spontaneously in culture. To test for a possible causal relationship, we cultured explants with protein kinase inhibitors. We found that H-8, a preferential inhibitor of the cAMP-dependent protein kinase [protein kinase-A (PKA)], but not H-7, which inhibits PKA and protein kinase-C with similar potency, blocked the spontaneous rise in beta-adrenergic receptor concentration in human fetal lung explants, indicating that PKA activity is required for this rise in beta-adrenergic receptor concentration. Type II cells isolated from cultured lung treated with H-8 had fewer beta-adrenergic receptors than cells isolated from untreated explants. These studies show that cAMP increases the beta-adrenergic receptor concentration in human fetal lung and specifically in type II cells through a PKA-dependent mechanism, consistent with a role for cAMP in beta-adrenergic receptor regulation during normal lung development.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1986

Oligohydramnios-induced lung hypoplasia: the influence of timing and duration in gestation.

We drained amniotic fluid for periods of 5 and 10 days at various times in gestation between days 40 and 55 in the guinea pig (term is 67 days). We analyzed the impact of this procedure on fetal lung growth and used untouched littermate fetuses as controls. During the canalicular stage of lung development, total lung DNA per gram of fetal weight was significantly reduced after only 5 days of oligohydramnios and the percent change did not vary between the two consecutive 5-day periods studied (period A, days 40 to 45, delta of -0.047 mg, p = 0.004; period B, days 45 to 50, delta of -0.042 mg, p = 0.002). The impact of the same duration of oligohydramnios on lung growth later in gestation, during the terminal sac stage of lung development, was less (period C, days 50 to 55, delta of -0.027 mg, p = 0.097). This reduction in effect between period A or B and C was significant at the 0.05 level using a one-way analysis of variance. Two overlapping 10-day periods were also studied. In both experiments, the percent changes in lung DNA per gram of fetal weight between experimental and littermate controls were significant (period D, days 40 to 50, delta of -0.072 mg, p = 0.001; period E, days 45 to 55, delta of -0.047 mg, p = 0.001). The inhibitory effect of oligohydramnios on lung growth was more marked in period D than E (significant at the 0.05 level).(ABSTRACT TRUNCATED AT 250 WORDS)

Amniotic Fluid↗
PubMed2006

Defective lung vascular development in endothelial nitric oxide synthase-deficient mice.

Normal blood vessel formation is required for the development of nearly all organs during embryogenesis, including lung. Neonatal diseases such as persistent pulmonary hypertension of the newborn and alveolar capillary dysplasia are thought to result in large part from a failure of normal lung vascular development. Therefore, in the past decade, there has been increasing interest in studying the mechanisms underlying the development of the lung circulation to better understand the pathogenesis of these often lethal neonatal lung diseases. It has now been well accepted that in addition to its protean roles in the maintenance of vascular homeostasis, endothelium-derived nitric oxide also plays a pivotal role in postnatal angiogenesis, mediating downstream signaling in response to classic angiogenic factors. Recent findings in endothelial nitric oxide synthase (eNOS)-deficient mice point to a novel and previously unrecognized role of eNOS-NO pathway in fetal lung vascular development and lung morphogenesis. The lung phenotype of eNOS mutants closely resembles alveolar capillary dysplasia in humans, a universally fatal form of persistent pulmonary hypertension of the newborn that presents with defective lung vascular development and respiratory distress in newborn. We anticipate that these new insights into the basic mechanisms of lung vascular development may lead to novel therapeutic strategies for neonatal lung diseases.

Animals↗
PubMed1984

Preparation for birth into an O2-rich environment: the antioxidant enzymes in the developing rabbit lung.

To determine if some specific "preparation for birth" occurs in the developing lung to help assure its successful adaptation to a comparatively O2-rich world at birth, we measured the activities of the antioxidant enzymes in the developing lungs of rabbit fetuses from 10 d before parturition to several days after birth. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GP) activities showed similar maturational patterns with significant increases in activity, compared with earlier gestational levels, during the last 3-5 d before birth. During the final days in utero, SOD and CAT activities increased by approximately 110% and lung GP activity by approximately 200%. There were no parallel changes in lung O2 consumption demonstrable over this same prenatal period.

Adaptation, Physiological↗
PubMed1992

Ontogeny of reactivity to endothelial cell markers during development of the embryonic and fetal rat lung.

The reactivity of endothelial cells to putative endothelial cell-specific markers varies with species, with vessel size and with the organ studied. To determine their value in studies of fetal rat lung, and whether organ immaturity would also influence reactivity, we studied endothelial cell immunoreactivity to antibodies against Factor VIII/von Willebrand factor (VIII/vWF), and binding reactivity to Bandeiraea (Griffonia) simplicifolia 1 lectin (BSL 1) during rat fetal lung development. Using an indirect immunofluorescent technique to detect Factor VIII/von Willebrand factor (VIII/vWF), endothelial cells lining the aortic arches were identified as early as day 11 of gestation (term = 22 days), prior to lung development. Immunoreactivity to VIII/vWF was subsequently localized to intrapulmonary endothelial cells and was not dependent on vessel size. In contrast, binding reactivity of FITC-conjugated BSL 1 was observed to both endothelial cells and to the basement membrane of developing airways, thus limiting its value as endothelial cell marker. During very early lung development solitary angioblasts could not be identified by reactivity to either VIII/vWF antibodies or to BSL 1, and neither marker appears to be of value for studies of early angiogenic events.

Animals↗
PubMed1989

Short-term perinatal 10% O2 alters postnatal development of lung alveoli.

We studied the effect of breathing 10% O2 for less than or equal to 9 h by rat dams during the last day of gestation and (with their pups) for 1-2 h immediately after birth on the development of the lung's gas exchange region in the pups. Our major finding is that this brief stress resulted in substantially altered lung development noted at age 7 days and still partially present at age 30 days. In particular, perinatal hypoxia slowed the postnatal increase of lung volume, delayed septation of the large gas exchange saccules, diminished the increase of the gas exchange surface area, but accelerated thinning of the wall of the gas exchange structures. The changes produced by briefly breathing 10% O2 had as great an effect on these aspects of lung development as the same prenatal exposure to 10% O2 plus continuous postnatal exposure to 10% O2 for 7 days. Breathing 10% O2 had a particularly strong effect on alveolar wall thinning, since 2 h of breathing 10% O2 immediately after birth, without prenatal hypoxia, accelerated thinning of the alveolar wall.

Aging↗
PubMed2005

Vascular endothelial growth factor co-ordinates proper development of lung epithelium and vasculature.

The vasculature forms an intrinsic functional component of the lung and its development must be tightly regulated and coordinated with lung epithelial morphogenesis. Vascular endothelial growth factor (VEGF) and its receptors are highly expressed in a complementary pattern in the lungs during embryonic development. VEGF is expressed by epithelium and the receptors in the surrounding mesenchyme. To determine the function of VEGF in lung formation, we inhibited its activity using a soluble receptor in lung renal capsule grafts. Inhibition of VEGF results in inhibition of vascular development and significant alteration in epithelial development. Epithelial proliferation is inhibited, sacculation is impaired, and the epithelium undergoes apoptosis. Interestingly, when VEGF is attenuated, epithelial differentiation still proceeds, as shown by acquisition of both proximal and distal markers. These data show that VEGF co-ordinates epithelial and vascular development. It is required for the development of the lung vasculature and the vasculature is necessary for epithelial proliferation and morphogenesis, but not for cell differentiation.

Animals↗