[A case of Mycobacterium kansasii lung infection developed after treatment of Mycobacterium gordonae lung infection].
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Drug Therapy, Combination↗
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Lung pathogenesis. VIII. Relationships between alveolar surfactant disorders and development of lung diseases.
The new data concerning the structure and dynamics of the alveolar surfactant, its phospholipid and apoprotein components and their synthesis, storage and secretion by the large granular alveolocytes, the formation and disconnection of lipoprotein complexes, their disorders and pathological relationships were analysed in order to discern the possibility of a more or less important pathogenetic role in the onset and development of lung diseases. Sometimes, surfactant disorders appeared as epiphenomena, like in pulmonary edemas; at other times, they behaved as a turn plate enhancing and centering the development of alveolar lipoproteinosis, microlithiasis alveolaris, hyaline membrane disease of newborns and the adult respiratory distress syndrome. Focusing the pathogenesis on the surfactant disorders and on their causes, a unification of mechanisms became possible with the increase in complexity of processes by the intervention of other complicating factors, mainly the self-perpetuating ones.
Animals↗
Adjuvant radiotherapy for breast cancer as a risk factor for the development of lung cancer.
Women diagnosed with primary breast or lung cancer and recorded between 1972 and 1989 in our tumor registry were identified. Of 4,123 lung cancer patients and 3,537 breast cancer patients, 42 patients with both diagnoses were identified. The two malignancies were diagnosed simultaneously in five patients, lung cancer was diagnosed first in six patients and breast cancer was diagnosed first in 31 (p < 0.001). Nineteen of those 31 patients received adjuvant radiotherapy for breast cancer and developed lung cancer a median of 17 years later. Of the 19 irradiated patients who subsequently developed lung cancer, 15 did so in the ipsilateral lung and only four had lung cancer contralateral to the previously irradiated site (p < 0.001). Adjuvant radiotherapy for breast cancer as delivered decades ago may be an etiologic factor for lung cancer.
Adult↗
Thyroid transcription factor-1, hepatocyte nuclear factor-3beta, surfactant protein B, C, and Clara cell secretory protein in developing mouse lung.
We used immunohistochemical analysis to localize thyroid transcription factor-1 (TTF-1), hepatocyte nuclear factor-3beta (HNF-3beta), prosurfactant proteins B and C (pro-SP-B, pro-SP-C), surfactant protein B (SP-B), and Clara cell secretory protein (CCSP) in developing mouse lung. TTF-1 and HNF-3beta were expressed at the onset of lung morphogenesis (gestational Day 10) and throughout fetal lung development, being detected in the nuclei of airway epithelial cells. TTF-1 was most prominent in distal airway epithelial cells in embryonic lung and HNF-3beta in proximal bronchial and bronchiolar epithelial cells. Pro-SP-B and pro-SP-C were first detected on gestational Day 11, being localized to the cytoplasm of airway epithelial cells. Expression of both pro-proteins was confined to distal airway epithelial cells from gestational Day 12 to Day 16. From gestational Day 17 and thereafter, pro- SP-B was detectable in Type II cells and bronchiolar epithelial cells, whereas pro-SP-C was restricted to Type II cells. SP-B peptide was first detected on gestational Day 17 in the cytoplasm of Type II cells and within the lumen of distal airways. SP-B peptide was detectable only in the cytoplasm of Type II cells in adult lung. CCSP was first detected on gestational Day 17, being localized to the cytoplasm of columnar epithelial cells lining the conducting airways. Pro-SP-B, SF-B, pro-SP-C, and CCSP staining increased before birth. The early expression of TTF-1 and HNF-3beta, preceding and overlapping that of pro-SP-B, mature SP-B, pro-SP-C, and CCSP, supports a regulatory role for TTF-1 and HNF-3beta in lung-specific gene expression.
Animals↗
Developmental expression of glycogenolytic enzymes in rabbit tissues: possible relationship to fetal lung maturation.
Glycogen can be degraded in mammalian tissues by one of three isozymes of glycogen phosphorylase, termed muscle (M), liver (L) and brain (B) after the tissues in which they are preferentially expressed in adult animals, or by members of the family of alpha-glucosidases. In the current study, we have examined the developmental expression of these enzymes and their respective mRNAs in rabbit tissues, with particular emphasis on the developing lung, a tissue in which glycogen serves as an important source of carbon for surfactant phospholipid biosynthesis. Native gel activity assays and RNA blot hybridization analysis revealed that the B isoform of glycogen phosphorylase predominates in fetal and adult lung tissues, accompanied by a low level of expression of the M isoform. Total B and M phosphorylase activities increased during fetal lung development, with a peak at day 28 of gestation, then decreased to the adult level at term. This peak in activity coincided with the peak period of glycogen degradation in developing lung. While the increase in M isozyme activity was correlated with an increase in the level of its mRNA, B isoform mRNA showed no significant alteration during development, suggesting that the increase in B isoform activity is determined by a posttranscriptional mechanism. Analysis of phosphorylase mRNA levels in developing liver, skeletal muscle, brain and heart revealed a diverse expression pattern. The L isozyme mRNA was predominant at all time points in liver, the M isozyme was predominant at all time points in muscle, the B isozyme was predominant at all time points in brain, and heart contained a mixture of B and M mRNA in roughly equal ratios at all time points. Thus, our studies of phosphorylase mRNA in the rabbit provide no evidence for general predominance of the B isozyme in fetal tissues, or for isozyme 'switching' from the B to the L or M forms during development, as has been suggested by others. In addition to the increase in phosphorylase activity, acid, but not neutral alpha-glucosidase activity was found to increase significantly during fetal lung development, again with a peak at day 28 of gestation. Interestingly, RNA blot hybridization analysis with a probe for lysosomal alpha-glucosidase revealed no change in the level of expression of its 4 kb transcript in developing lung. Instead, we observed induction of a structurally related mRNA of 7.4 kb that peaked at day 28 of gestation. Hybridization with a sucrase/isomaltase-specific oligonucleotide excluded the possibility that the 7.4 kb transcript encodes this protein.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Effect of chronic exposure to NO2 in the developing ferret lung.
The effect of chronic exposure to low (0.5 ppm) and high (10 ppm) concentrations of NO2 on the development of the ferret lung was studied in animals exposed 4 h/day, 5 days/week from age 6 weeks through 20 weeks. Morphometric analysis showed significant changes in alveolar dimensions at both concentrations, compared to air-exposed controls. Thickened alveolar walls, increased cellularity and collagen deposition, increased lung size and the appearance of lesions indicative of oxidant damage indicate that even low concentrations of this gas during lung development may have adverse consequences for adult lung function.
Animals↗
Effects of cis-hydroxyproline on type II cell development in fetal rat lung.
The role of collagen in pulmonary epithelial cell division and differentiation during lung development was investigated by injecting the proline analogue cis-hydroxy-L-proline (cis-HYP) to timed pregnant rats. Lung weight, DNA and 3H thymidine incorporation were unchanged when compared to controls; epithelial cell division, determined by autoradiography, was also unchanged. However air sac development and phospholipid synthesis by epithelial cells were retarded in cis-HYP treated animals. The percentage of epithelial cells containing lamellar bodies was reduced at days 20-22 of gestation and the level of disaturated phosphatidylcholine (DSPC) was also significantly lower in treated rats. A sex-related difference was not eliminated by cis-HYP treatment, lung maturation was still more rapid in females. Non-dialysable hydroxyproline levels were decreased, and morphologically, less fibrillar collagen was seen at the epithelial-interstitial cell interface, though direct cell-cell contacts were not reduced. The results indicate that the injection of cis-HYP did not alter lung growth, but caused a reduction in fibrillar collagen which was associated with reduced surfactant synthesis by Type II epithelial cells.
Animals↗
Small size at birth and greater postnatal weight gain: relationships to diminished infant lung function.
Recent evidence suggests that impaired lung development is linked with diminished lung function and an increased risk of chronic obstructive airway disease in adulthood. To examine environmental influences on early lung development, we measured lung function in 131 normal-term infants aged 5-14 weeks. Adjusting for age at measurement, FEV at 0.4 seconds fell by 4.4% for each standard deviation decrease in birth weight (p = 0.047); when adjusted for FVC, FEV at 0.4 seconds was not related to birth weight but fell by 3.2% per standard deviation increase in infant weight gain (p = 0.001). Age- and sex-adjusted total respiratory system compliance fell by 7.0% per standard deviation decrease in birth weight (p < 0.001) but was not related to infant weight gain. In univariate analyses, age-adjusted forced expiratory flow at functional residual capacity was not related to birth weight, but decreased by 11.0% per standard deviation increase in infant weight gain (p = 0.007). The respiratory rate rose by 5.1% per standard deviation increase in infant weight gain (p = 0.001). Lung function measurements were not related to infant feeding. The observations suggest that lower rates of fetal growth and higher rates of early infancy weight gain are associated with impaired lung development.
Anthropometry↗
Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia.
Pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH) remains a major therapeutic problem. Moreover, the pathogenesis of pulmonary hypoplasia in case of CDH is controversial. In particular, little is known about early lung development in this anomaly. To investigate lung development separate from diaphragm development we used an in vitro modification of the 2, 4-dichlorophenyl-p-nitrophenylether (Nitrofen) animal model for CDH. This enabled us to investigate the direct effects of Nitrofen on early lung development and branching morphogenesis in an organotypic explant system without the influence of impaired diaphragm development. Epithelial cell differentiation of the lung explants was assessed using surfactant protein-C and Clara cell secretory protein-10 mRNA expression as markers. Furthermore, cell proliferation and apoptosis were investigated. Our results indicate that Nitrofen negatively influences branching morphogenesis of the lung. Initial lung anlage formation is not affected. In addition, epithelial cell differentiation and cell proliferation are attenuated in lungs exposed to Nitrofen. These data indicate that Nitrofen interferes with early lung development before and separate from (aberrant) diaphragm development. Therefore, we postulate the dual-hit hypothesis, which explains pulmonary hypoplasia in CDH by two insults, one affecting both lungs before diaphragm development and one affecting the ipsilateral lung after defective diaphragm development.
Animals↗
The components of VARA, a nutrient-metabolite combination of vitamin A and retinoic acid, act efficiently together and separately to increase retinyl esters in the lungs of neonatal rats.
Retinoic acid (RA), produced from vitamin A (VA, retinol), is required for normal lung development and postnatal lung maturation. The concentration of retinyl ester (RE), the major storage form of retinol, decreases in the lungs in the perinatal period. Previously, we tested VARA, a nutrient-metabolite combination of VA and RA (10:1 molar ratio), on lung RE formation in postnatal rats and showed that the components of VARA acted synergistically to increase lung RE, as compared with the effects of equal amounts of VA and RA given alone. In this study, we first determined the equivalency of orally administered VARA in comparison to a standard oral supplement of VA, with respect to lung and liver RE storage. In a dose-dilution study, VARA was 4 times as effective as the standard dose of VA (VARA-25% did not differ from VA-100%). The synergistic effect of VARA was selective for the lungs, compared with the liver, in which VA and VARA had equal effects. Secondly, we tested whether the 2 components of VARA must be coadministered to exert their synergistic effect on lung RE content. RA and VA and were administered separately and together as VARA. Although RA alone had no effect on lung RE in this 24-h experiment, RA synergized with VA administered either 12 h before RA or 12 h after RA, as well as when coadministered as VARA. We infer that VA and RA are both limiting for lung RE formation in neonates. Given the importance of bioactive retinoids in cell differentiation and lung development, assuring an adequate lung RE content postnatally could be of benefit for lung maturation.
Animals↗
Primary structure of hepatocyte nuclear factor/forkhead homologue 4 and characterization of gene expression in the developing respiratory and reproductive epithelium.
Members of the winged helix/forkhead family of transcription factors are believed to play a role in cell-specific gene expression. A cDNA encoding a member of this family of proteins, termed hepatocyte nuclear factor/forkhead homologue 4 (HFH-4), has been isolated from rat lung and rat testis cDNA libraries. This cDNA contains an open reading frame of 421 amino acids with a conserved DNA binding domain and several potential transactivating regions. During murine lung development, a single species of HFH-4-specific transcript (2.4 kb long) is first detected precisely at the start of the late pseudoglandular stage (embryonic day 14.5) and, by in situ hybridization, is specifically localized to the proximal pulmonary epithelium. The unique temporal and spatial pattern of HFH-4 gene expression in the developing lung defines this protein as a marker for the initiation of bronchial epithelial cell differentiation and suggests that it may play an important role in cell fate determination during lung development. In addition to expression in the pulmonary epithelium, RNA blot analysis reveals 2.4-kb HFH-4 transcripts in the testis and oviduct. By using mice with genetic defects in spermatogenesis, HFH-4 expression in the testis is found to be associated with the appearance of haploid germ cells and in situ hybridization studies indicate that HFH-4 expression is confined to stages I-VII of spermatogenesis. This pattern of HFH-4 gene expression during the early stages of differentiation of haploid germ cells suggests that HFH-4 may play a role in regulating stage-specific gene expression and cell-fate determination during lung development and in spermatogenesis.
Aging↗
Fetal lung mRNA levels of Hox genes are differentially altered by maternal diabetes and butyrate in rats.
Diabetes is known to be associated with delayed lung development in humans and in experimental animals. This includes delayed expression of surfactant apoproteins. An important component of the metabolic abnormalities in diabetes is elevated levels of analogs of butyric acid, and the effects of diabetes on surfactant apoproteins can be reproduced by exposure of fetal rat lung explants to butyrate. Dexamethasone has the opposite effects on lung development. In humans, antenatal exposure to dexamethasone results in a lower incidence of RDS, whereas in experimental animals, dexamethasone increases the expression of surfactant apoproteins. A subset of Hox genes are expressed in developing lung, and their level of expression decreases with advancing gestation. We hypothesized that: 1) lungs of fetuses of rats with streptozotocin-induced diabetes would have altered levels of expression of Hox genes, 2) the effect would be mediated in part through elevated levels of butyrate, and 3) dexamethasone would reverse the effect. We tested our hypotheses in vivo using fetuses from streptozotocin-treated rats and in vitro by treating lung explants from normal rats with sodium butyrate. Streptozotocin treatment increased expression of Hoxb-5 at 18 d of gestation, but did not affect Hoxa-5 expression. This was associated with a 20-fold increase in alpha-aminobutyrate levels. Dexamethasone tended to reverse this effect. In contrast, butyrate treatment of explants decreased the expression of Hoxa-5 and Hoxb-5. We conclude that diabetes alters expression of Hox genes, but that the effect of butyrate on lung development, and in particular on surfactant apoprotein expression, is independent of its effects on Hox genes.
Animals↗
Biochemical and physiological development of fetal rhesus lung.
Study of 17 fetal rhesus monkeys (Macaca mulatta) revealed a sequential rise in lung phosphatidylcholine (PC) concentration due to elevations in both disaturated (DSPC) and unsaturated constituents. The % DSPC in lung tissue clinical abruptly at 145 days of gestation prior to significant increases in PC or DSPC concentration but in association with improved lung deflation stability (% V10). This suggests that the DSPC-to-PC ratio may be a sensitive biochemical indicator of surfactant phospholipid production in lung parenchyma. Phosphatidyl-glycerol content did not increase significantly until after 155 days gestation, which was coincident with maximizing pulmonary distensibility (V max). Declining levels of phosphatidylethanolamine and sphingomyelin in lung tissue at 162 days support the hypothesis that preferential synthesis of PC occurs during late gestation. A serial decline in lung glycogen content with advancing gestation may reflect glycogen utilization as a substrate for lung phospholipid production. Comparison of biochemical and physiological data confirms the impression that discordances occur among lung maturational events. Lastly, a relationship between rising fetal blood cortisol levels and indices of fetal lung development was not demonstrated.
Animals↗
Spatial and temporal distribution of insulin-like growth factors I and II during development of rat lung.
Insulin-like growth factors (IGF) I and II genes are expressed in developing lung tissue, but the details of distribution during different stages of lung development have not been delineated. To define the role of IGFs in lung development, the expression of IGF-I and IGF-II mRNAs and peptides was examined in rat lungs from 16-day gestation through adulthood. The expression of stable IGF mRNAs was investigated by Northern analysis, IGF mRNAs were localized by in situ hybridization histochemistry, and IGF peptides were localized by immunohistochemistry. Four IGF-II transcripts (3.5, 2.2, 1.8, and 1.0 kb) were identified; IGF-II mRNA levels were highest early in fetal life (day 16-18) and decreased gradually until 28 days postnatal. Four IGF-I transcripts (7.8, 4.4, 2.1, and 0.6 kb) were detected but were of low abundance. IGF-II mRNA was localized mainly in mesenchymal cells but was also identified in the airway epithelium, with peak expression in the perinatal lung. IGF-II peptide was prominent in late fetal life and for 5 days after birth and was identified in both mesenchymal and epithelial cells. In contrast, there was little evidence of IGF-I mRNA and peptide until after birth: IGF-I was most easily identified between 5 and 14 days postnatal (the height of alveolar multiplication and formation), when both mRNA and peptide were localized to mesenchymal and epithelial cells. Our studies demonstrate that IGF-I and IGF-II are synthesized and distributed in spatially and temporally different patterns in the developing lung. IGF-I and IGF-II peptides are more widely identified than their respective mRNAs, suggesting a paracrine distribution in the developing lung.
Aging↗
Degradation of type IV collagen during the development of fetal rat lung.
Lung structure undergoes rapid remodeling during late gestation as a functional respiratory unit is formed. To determine the role of collagen turnover in this process, particularly the basement membrane component, we studied the degradation of collagen in a series of fetal rats from day 18 of gestation to full term. During the period of rapid cell proliferation to day 20, the collagen level per milligram of lung did not change though the rate of synthesis increased. More than 40% of new collagen was rapidly degraded. At the end of the growth phase, collagen synthesis rose rapidly as the total collagen content increased in the lung. Over this period, little Type I collagenase activity could be detected, but degradation of Type IV collagen was readily measured and was maximal at 18 to 20 days. The enzyme(s) was almost all present in the active form, and evidence for dissolution of the subepithelial basement membrane was also found by electron microscopy. Using isolated fetal epithelial cells and fibroblasts, supernatants of both cell types showed degradative activity for Type IV collagen, particularly at days 18 to 20. The major enzyme involved appears to be a 72 kD collagenase, as shown by zymography and by mRNA expression in both cell types. The results demonstrate that rapid degradation of Type IV collagen occurs during the growth phase of late fetal lung development, and that both epithelial and stromal cells contribute to collagenolytic activity.
Animals↗
[Studies on adequate components and amounts of transfusion solution after hepatectomy from the viewpoint of the development of lung edema].
The purpose of this study was to evaluate the mechanism of development of lung edema and to determine adequate components and amounts of transfusion solution after major hepatic resection in normal and Dimethylnitrosamine (DMNA)-induced cirrhotic dogs. The dogs were administered maintenance dose (1-2 ml/kg/h) or large volumes (10-20 ml/kg/h) of lactated Ringer's solution (RL), 10% Dextrose or Dextran 40 (D40) after surgery. 1) In the groups transfused with maintenance dose or large volumes of RL, or large volumes of D40 after 80% and 70% hepatectomy in normal dogs and 40% hepatectomy in DMNA-induced cirrhotic dogs, the extravascular lung water (EVLW) increased with a high incidence of the development of lung edema. On the other hand, in the groups transfused with maintenance dose or large volumes of 10% Dextrose, or maintenance dose of D40, EVLW did not increase, thus preventing the development of lung edema. 2) The lower the functional reserve of the remaining liver and reticuloendothelial function, the more the volume of EVLW increased. The increments in plasma endotoxin titers through the spill over phenomenon, due to the decline of reticuloendothelial function after hepatectomy, caused an increase in the permeability of lung capillaries. Moreover, the decrease of colloid hydrostatic pressure gradient (CHPG) also caused an increase in EVLW. It is clear that both the permeability of lung capillaries and CHPG contribute to the development of lung edema after hepatectomy.
Animals↗
Expression patterns of laminin alpha1 and alpha5 in human lung during development.
Laminins are trimeric glycoprotein components of basement membranes. Each laminin has three structurally similar chains, designated alpha, beta, and gamma. Five laminin alpha chains are now known. In previous studies using monoclonal antibody 4C7, laminin alpha1 was thought to be present in basement membranes of human lung throughout development and in the adult, but recent expression studies have demonstrated that 4C7 identifies laminin alpha5 rather than alpha1. To determine the temporal and spatial patterns of laminin alpha1 and laminin alpha5 in developing human lung, we prepared complementary DNA probes specific for laminin alpha1 and alpha5 messenger RNAs (mRNAs). By Northern analysis, laminin alpha1 mRNA was prominent in first-trimester fetal lung, but was not detectable at 23 wk or at later times. In contrast, laminin alpha5 mRNA was readily detected in early fetal lung and remained present thereafter. Immunohistochemical staining demonstrated laminin alpha1 only in early fetal lung, whereas laminin alpha5 was persistent from the early fetal period. In situ hybridization localized laminin alpha1 expression to distal epithelium in the first-trimester lung, and laminin alpha5 to all epithelium and developing pulmonary arteries from the first trimester through the perinatal period. These studies indicate that laminin alpha1 expression is restricted to early human lung morphogenesis, whereas the expression of laminin alpha5 in human lung is continuous from early lung development through adult life. It is evident that laminin alpha1 and laminin alpha5 have different roles in the development of the human lung.
Blotting, Northern↗
Development of fetal lamb lung and kidney in obstructive uropathy: a preliminary report.
Oligohydramnios, whatever the cause, results in lungs that are 'hypoplastic' or at least smaller than normal. The fine structure in such lungs has not been reported previously. Three fetal lambs had both ureters ligated at 60, 72 and 58 days of gestation. They were sacrificed at 117, 143 and 142 days of gestation. The lungs were fixed by tracheal perfusion at 15 mm Hg. Individual lobar volumes were determined, and the lungs were sampled for electron microscopy. Total lung volumes for 2 of the lambs were very close to those previously reported for lungs of equivalent gestation with diaphragmatic hernia. The third lamb had a twin that had been unrecognised at the time of the original procedure. This lamb's lung volumes were normal. The morphological appearances of the lungs at the electron microscopy level are not normal but dramatically different from those previously reported in lambs with diaphragmatic hernia, phrenic nerve avulsion, and fetal tracheostomy. The lungs of the lamb with bilateral ureteric ligation and a normal twin were essentially normal. These preliminary findings point to the need for more studies of lung structure in oligohydramnios/obstructive uropathy models. However, the normal lungs in a lamb with grossly dysplastic kidneys and a normal twin argue against any important renal trophic factor in lung development in the fetal lamb. An interesting sidelight to this investigation was the unequivocal demonstration that early ureteric ligation results in true renal dysplasia in the fetal lamb. The kidneys of the lamb sacrificed at 117 days were smaller than normal and grossly dysplastic. The kidneys of the lambs that underwent ureteric ligation at 60 and 72 days were structurally different, with the ureters ligated at 60 days being small and dysplastic, while those with the ureters ligated at 72 days were larger and appeared almost polycystic.
Animals↗