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PubMed2006

Role of the physicochemical environment in lung development.

Mechanical forces, exerted on lung tissue via alterations in lung expansion are a major determinant of fetal lung development, having a potent effect on the rate of cellular proliferation, the differentiated state of alveolar epithelial cells and the three-dimensional tissue structure. As a result, much research is currently focused on understanding the molecular mechanisms involved. 2. Although it is likely that mechanical forces exert similar influences on lung development after birth, the types of forces applied to the air-filled lung are very different and more complex. For example, lung aeration causes surface tension to form, which greatly increases lung recoil, leading to a reduction in interstitial tissue and pleural pressures, as well as lung expansion. 3. Because of the loss of the distending influence of lung liquid, the chest wall assumes the role of maintaining resting lung volumes after birth by acting as an external brace that opposes lung recoil. As a result, the distribution of force throughout lung tissue changes markedly. 4. Little is known of how changing the mechanical environment of the lung influences its development after birth, but this has important implications for understanding the impact of assisted ventilation on patients, particularly very preterm infants, who are often ventilated using high positive pressures. 5. Although the application of positive internal distending pressures may, in part, duplicate the fetal environment, the effect of gas versus liquid is unknown and high positive airway pressures are known to adversely affect cardiopulmonary physiology. Understanding the role of mechanical forces in regulating lung development as well as pulmonary physiology in the fetus and newborn is central to improving the care and management of infants suffering respiratory failure.

Adult↗

PubMed2006

Parabronchial smooth muscle cells and alveolar myofibroblasts in lung development.

Epithelial-mesenchymal interactions and extracellular matrix remodeling are key processes of embryonic lung development. Lung smooth muscle cells, which are derived from the mesenchyme, form a sheath around bronchi and blood vessels. During lung organogenesis, smooth muscle differentiation coincides with epithelial branching morphogenesis and closely follows developing airways spatially and temporally. The precise function of parabronchial smooth muscle (PBSM) cells in healthy adult lung remains unclear. However, PBSM may regulate epithelial branching morphogenesis during lung development by the induction of mechanical stress or through regulation of paracrine signaling pathways. Alveolar myofibroblasts are interstitial contractile cells that share features and may share an origin with smooth muscle cells. Alveolar myofibroblasts are essential for secondary septation, a process critical for the development of the gas-exchange region of the lung. Dysregulation of PBSM or alveolar myofibroblast development is thought to underlie the pathogenesis of many lung diseases, including bronchopulmonary dysplasia, asthma, and interstitial fibrosis. We review the current understanding of the regulation of PBSM and alveolar myofibroblast development, and discuss the role of PBSM in lung development. We specifically focus on the role of these cells in the context of fibroblast growth factor-10, sonic hedgehog, bone morphogenetic protein-4, retinoic acid, and Wnt signaling pathways in the regulation of lung branching morphogenesis.

Animals↗

PubMed2005

Similarities and dissimilarities of branching and septation during lung development.

The lungs of small premature babies are at a developmental stage of finalizing their airway tree by a process called branching morphogenesis, and of creating terminal gas exchange units by a mechanism called septation. If the branching process is disturbed, the lung has a propensity to be hypoplastic. If septation is impaired, the terminal gas exchange units, the alveoli, tend to be enlarged and reduced in number, an entity known as bronchopulmonary dysplasia. Here, we review current knowledge of key molecules influencing branching and septation. In particular, we discuss the molecular similarities and dissimilarities between the two processes of airspace enlargement. Understanding of the molecular mechanisms regulating branching and septation may provide perinatologists with targets for improving lung growth and maturation.

Extracellular Matrix↗

PubMed2001

Irx1 and Irx2 expression in early lung development.

We describe a comparative lung expression analysis of the murine Irx1 and Irx2 genes. At embryonic day 8.5 (E8.5), the Irx1 and Irx2 expression starts in the foregut region, where the laryngo-tracheal groove will form. The expression is prominent in the lung epithelium during glandular development. It declines at the end of the canalicular phase. We further compare the Irx1 and Irx2 expression domains to Gli1, 2, 3 and Mash1. Their homologues in Drosophila melanogaster are known as regulative partners of the iroquois complex. The Irx and Gli genes are coexpressed in the developing lungs at the same time. Their transcripts are not localised in the same cells but adjacent to each other in either mesenchymal or epithelial structures. It is thought that the lung development is regulated by the mesenchymal/epithelial interactions.

Animals↗

PubMed2002

Expression of cytokeratin 18 during pre- and post-natal porcine lung development.

The expression pattern of the intermediate filament protein cytokeratin 18 (CK 18) is described during pre- and post-natal development of the porcine lung using a monoclonal antibody against human CK 18. Lungs from 16 foetuses in pseudoglandular, canalicular, saccular and alveolar stages of lung development and lungs from 12 pigs ranging in age from birth to 49 days after birth were studied by immunohistochemistry. In the early pseudoglandular stage of development (day 70 of gestation) all the columnar epithelial cells lining the tubular endbuds strongly expressed CK 18 predominantly in the apical cell compartment. A modest staining was found in the more cuboidal cells of the canalicular stage (day 80 of gestation) where the labelling occurred as a distinct positive rim at the apical cell membrane in most of the cells lining the canaliculi. In 96- and 100-day-old foetuses, parts of the gas exchanging area were formed as terminal sacs by extreme attenuation of the epithelium. In this stage, CK 18 was clearly detectable in the flat type I as well as in the cuboidal type II alveolar epithelial cells. A marked change of the CK 18 expression pattern occurred during formation of the alveoli by septal outgrowth and maturation of the epithelium in 105- and 111-day-old foetuses. Differentiated type I cells no longer expressed CK 18, whereas type II cells were still labelled. Moreover, a specific change in the subcellular distribution pattern from the luminal periphery in immature porcine type II cells to a cytoplasmic localization in differentiated type II cells could be observed. Our investigation additionally demonstrated that the epithelium of bronchi, bronchioli and terminal bronchioli expressed CK 18 in all pre- and post-natal developmental stages. From the 96 days of gestation onwards the epithelial cells of developing bronchial glands were also labelled. Our results clearly show that during porcine lung development profound changes in the cellular expression pattern of CK 18 occur and that CK 18 can be regarded as a selective marker for differentiated porcine alveolar type II cells from the 105th day of gestation onwards. We also assume that the intermediate filament CK 18 could be of significance in the maturation process of the type II alveolar cells.

Age Factors↗

PubMed1993

Morphometric analysis of fetal rat lung development.

Applying the zone concept described previously, we quantitatively analyzed fetal rat lung development. The zone concept allowed us to coherently define reference spaces in the developing lung, a prerequisite for morphometric analysis. The peripheral zone I corresponds to a zone of growth of yet undifferentiated tissues; zone II arises from zone I and represents a region of structural and cellular differentiation; zones III and IV comprise the conducting airways and vessels. Lungs of fetal rats aged 17-23 days and 20 hours postnatal were fixed with OsO4 and glutaraldehyde and processed for light and electron microscopic morphometry implemented by point and intersection counting. Fetal lung volume grew in proportion to body weight. Zone II being the largest compartment, its volume changes largely determined lung growth rates. Zone II increased in mass owing to differentiation processes at the interface to zone I where the proximal portions of zone I were continuously shifted into zone II by differentiation. New tissue was generated within zone I. Due to these combined processes zone I changed little in volume until it disappeared at the end of the canalicular stage. The presence in the pseudoglandular stage of half of the parenchymal epithelial mass available around birth indicated that parenchymal development started earlier than assumed so far. While the endothelial surface increased most at birth, the epithelial surface grew by more than 600% at day 21, reflecting the onset of canalisation. The study confirmed the usefulness of the zone concept for morphometry and provided some new insights into lung development.

Animals↗

PubMed1997

Cellular distribution of insulin-like growth factor binding protein mRNAs and peptides during rat lung development.

A role for IGF binding proteins (IGFBPs) in lung development is suggested by the identification of IGFBPs in lung tissue and production of IGFBPs by fetal lung cells in culture. To characterize the expression of IGFBPs during lung development in the rat in vivo (16 days gestation through adulthood), the expression of IGFBP mRNAs (IGFBP-1 to IGFBP-6) was examined by Northern analysis and in situ hybridization, and IGFBP peptides (IGFBP-2, IGFBP-3, and IGFBP-5) were localized by immunohistochemistry. IGFBP-1 mRNA was not detectable. IGFBP-2 mRNA (1.8 kb) was expressed in both fetal and postnatal life with peak expression during the fetal pseudoglandular stage. IGFBP-2 mRNA was localized mainly to airway epithelium. IGFBP-3 mRNA (2.4 kb) was maximally expressed postnatally in the saccular stage of lung development; it was identified in airway epithelium and interstitium in the fetal lung, but predominantly in airway epithelium after birth. IGFBP-4 (2.6 kb) and IGFBP-5 (6.0 kb) mRNA levels were maximal after birth, from 3 to 21 days postnatal (saccular and alveolar stage). IGFBP-4 mRNA was localized primarily to the interstitium and blood vessels early in development, but was abundant in airway epithelium in the adult. IGFBP-5 mRNA was most abundant in the airway epithelium. IGFBP-3, IGFBP-4, IGFBP-5, and to a lesser extent IGFBP-6 were localized to the large cartilaginous airways in the adult. IGFBP-2, IGFBP-3, and IGFBP-5 peptides were distributed more widely than their respective mRNAs, with a temporal pattern of immunoreactivity following that of their mRNAs. Maximal staining was noted in airway epithelium for IGFBP-2 in the newborn, for IGFBP-3 in the saccular stage (newborn to 3 days postnatal), and for IGFBP-5 in the alveolar stage (5 to 21 days postnatal). Our studies demonstrate that IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 are synthesized and distributed in spatially and temporally different patterns in the developing lung. The widespread distribution of IGFBP immunoreactivity compared with their respective mRNAs suggests that IGFBPs are important paracrine factors in the regulation of IGF action in the developing lung.

Animals↗

PubMed2006

Laminin isoforms and lung development: all isoforms are not equal.

Laminins are a major component of basement membranes. Each laminin molecule is a heterotrimeric glycoprotein composed of one alpha, one beta, and one gamma chain. Fifteen laminin isoforms exist, assembled from various combinations of 5alpha, 3beta, and 3gamma chains. The embryonic lung has abundant laminin isoforms. Increasing evidence suggests that different laminin isoforms have unique functions in lung development. Studies of embryonic lung explants and organotypic co-cultures show that laminin alpha1 and laminin 111 are important for epithelial branching morphogenesis and that laminin alpha2 and laminin 211 have a role in smooth muscle cell differentiation. In vivo studies of laminin alpha5-deficient mice indicate that this laminin chain, found in laminins 511 and 521, is essential for normal lobar septation in early lung development and normal alveolization and distal epithelial cell differentiation and maturation in late lung development. However, not all of the laminin chains present in the developing lung appear to be necessary for normal lung development since laminin alpha4 null mice do not have obvious lung abnormalities and laminin gamma2 null mice have only minimal changes in lung development. The mechanisms responsible for the lung phenotypes in mice with laminin mutations are unknown, but it is clear that multiple laminin isoforms are crucial for lung development and that different laminin isoforms exhibit specific, non-overlapping functions.

Animals↗

PubMed1996

Retinoids in lung development.

The "retinoid revolution" has had considerable impact on research activity in the field of lung development. Postnatal lungs are very sensitive to dietary retinol (R) deprivation. The trachea and the bronchopulmonary tree in R-deficient animals show a striking change in morphology. The columnar epithelium undergoes keratinizing metaplasia, which is reversed when R is supplied. The fetal lung develops postnatally to become one of the most complex organs, characterized by 40 different cell types. The fetal lungs can accumulate retinyl esters. Before birth an unknown signal causes the lowering of these esters, which may be the source of retinoic acid (RA). The administration of glucocorticoids speeds up this process, which in turn is followed by acceleration of lung maturation, ending postnatally. It is not clear what role, if any, the cellular retinoid binding proteins play in this phenomenon. Fetal lung branching leading to the development of the alveolar tree is accelerated by RA, and so is the expression of some fetal genes coding for surfactant proteins and the enzymes that produce their lipid components. It is not clear whether RA influences the development of pulmonary epithelium by interacting directly with the epithelial cells or whether its effects require interaction with other cels like mesenchymal cells. Nuclear RA receptors are intimately involved in lung development. Despite the wealth of evidence on the effect of retinoids on lung development, the application of vitamin A to clinical work has been limited to prematurely delivered infants who have immature lungs. Here attempts are made, by improving their R status, to aid in the development and healing of lungs injured by oxygen therapy.

Animals↗

PubMed1998

Distribution of integrins during human fetal lung development.

Interactions between epithelial cells and the extracellular matrix through integrins play a key role in the development of the lung by modulating branching morphogenesis, epithelial cell polarization, and differentiation. To determine the role of integrins during the different stages of lung development, we investigated the distribution of eight integrin subunits in the trachea and lung from human fetuses. In distal airways, during the early pseudoglandular stage of development, the alpha2-, alpha5-, alpha6-, alphav-, and beta1-subunits were detected in all epithelial cell plasma membranes, and polarized but undifferentiated tracheal epithelial cells expressed alpha3-, alpha6-, and beta1-subunits in the plasma membrane of the cells facing the basement membrane. The alpha6- and beta4-chains were detected along the basal plasma membrane of the basal cells in differentiated tracheal epithelia. The alpha4-subunit was detected in all respiratory cells throughout fetal development. In the submucosal glands, myoepithelial cells expressed the integrin subunits found in the undifferentiated cells of the developing airways, whereas the secretory cells expressed only alpha2-, alpha3-, alpha4-, alpha6-, and beta1-subunits. These results demonstrate differential expression of integrins during lung development and suggest that integrins may play multiple roles in organogenesis and maturation of respiratory surface epithelium and glands.

Antigens, CD↗

PubMed2005

Normal lung development in RAIG1-deficient mice despite unique lung epithelium-specific expression.

RAIG1, 2, and 3 and GPCR5d represent a new subfamily of orphan G protein-coupled receptors. RAIG1 is expressed abundantly and specifically in the lung during development and in adult mice. During lung development, RAIG1 expression is initiated at E14.5 and gradually increases, reaching its highest levels at E18. High levels of expression are maintained in adult lungs. Given its abundant lung-specific expression and role in retinoic acid signaling, we hypothesized that RAIG1 plays a role in epithelial cell differentiation during lung development. To determine RAIG1 function and track endogenous RAIG1 spatial expression, a null allele of Raig1 was generated and the lacZ gene was "knocked-in." Although expression was detected in both proximal and distal epithelium during embryogenesis, it became restricted to type I and type II pneumocytes and the most distal bronchiolar cells in postnatal lungs. This is the first gene known to have this unique epithelial cell expression pattern. Despite this high level of expression, targeted inactivation of Raig1 did not cause significant developmental defects. Epithelial cell differentiation was normal and lung structure was intact. Analysis of other family members demonstrated some overlapping embryonic expression of RAIG3 mRNA that could have led to functional redundancy in the single RAIG1 null mutant mouse.

Animals↗

PubMedDate not supplied

Morphogenesis and pathogenesis of chronic lung diseases. XI. Histoenzymatic study of the experimentally developing lung granulomas.

The development of lung granulomas induced in rabbits by an intravenous injection of the complete Freund adjuvant containing dog pulmonary proteins was followed by histologic and histoenzymatic methods. By comparison with normal rabbit lungs. the developing structures of the induced lung granulomas showed an increase of all tested enzymes at 15 days, and a secondary intensity decrease of the activity of malic dehydrogenase, of acid and alkaline phosphatases, and of alanyl-aminopeptidase at 30 days. Only the hydroxyproline-epimerase showed at these intervals an increasing activity in the lung granulomas. The developed reticulinic fibrils appeared to have a highly intense alkaline phosphatase activity.

Animals↗

PubMed1995

Histological and immunohistochemical analysis of lung development, with particular reference to lung hypoplasia.

Using immunohistochemical (IH) staining for epithelial membrane antigen (EMA), keratin, Leu-7, Ca 19-9, secretory component (SC) and surfactant protein A (SPA) on formalin-fixed, paraffin-embedded autopsy cases of stillbirth and early neonatal death, the normal profile of IH-positive cells in the airway of the developing fetal lung was clarified. IH-positive cells first appeared in the proximal region of the lung, and then in the distal region. Keratin-positive cells and EMA-positive cells were abundant at the 10th gestational week (10 GW), the earliest stage observed in this study. Cells positive for Leu-7 and Ca 19-9 appeared during the time when bronchial branches developed, and were abundant at around 16 GW, the time of completion of bronchial branching. On the other hand, SPA- and SC-positive cells appeared after the completion of bronchial branching, and were abundant around 29 GW and 34 GW, respectively. Acinous structural development was observed in terms of radial alveolar count (RAC). Cases of lung hypoplasia defined as a lung weight to body weight ratio of under 0.012 at > or = 28 GW or under 0.015 at < 28 GW showed a rather high tendency of abnormalities of cellular differentiation revealed by IH staining.

Bronchi↗

PubMed1998

Hepatocyte growth factor (HGF) acts as a mesenchyme-derived morphogenic factor during fetal lung development.

Mesenchymal-epithelial tissue interactions are important for development of various organs, and in many cases, soluble signaling molecules may be involved in this interaction. Hepatocyte growth factor (HGF) is a mesenchyme-derived factor which has mitogenic, motogenic and morphogenic activities on various types of epithelial cells and is considered to be a possible mediator of epithelial-mesenchymal interaction during organogenesis and organ regeneration. In this study, we examined the role of HGF during lung development. In situ hybridization analysis showed HGF and the c-met/HGF receptor gene to be respectively expressed in mesenchyme and epithelium in the developing lung. In organ cultures, exogenously added HGF apparently stimulated branching morphogenesis of the fetal lung. In contrast, HGF translation arrest or neutralization assays resulted in clear inhibition of epithelial branching. These results suggest that HGF is a putative candidate for a mesenchyme-derived morphogen regulating lung organogenesis. We also found that HGF is involved in epithelial branching, in collaboration with fibroblast growth factor (FGF) family molecule(s). In mesenchyme-free culture, HGF alone did not induce epithelial morphogenesis, however, addition of both HGF and acidic FGF (aFGF) or keratinocyte growth factor (KGF), ligands for the KGF receptor, induced epithelial branching more extensively than that was observed in explants treated with aFGF or KGF alone. In addition, the simultaneous inhibition of HGF- and FGF-mediated signaling using neutralizing antibody and antisense oligo-DNA resulted in drastic impairment of epithelial growth and branching. Possible interactions between HGF and FGFs or other growth factors in lung development is given consideration.

Animals↗

PubMed1976

Phospholipid content, composition and biosynthesis during fetal lung development in the rabbit.

The phospholipid content and composition of lung wash and lung tissue as well as the activities of the enzymes involved in the synthesis of phosphatidylcholine and phosphatidylglycerol (the major surface active components of pulmonary surfactant) were studied in the rabbit during fetal lung development. In lung wash the amount of phospholipid increased four-fold during the period 27-31 day's gestation. There was a further ten-fold increase following the onset breathing. During the same period the amount of phosphatidylcholine in lung wash increased from 29% of the total phospholipid to 80% while the amount of sphingomyelin decreased from 38% to 2%. The amount of phosphatidylcholine in lung tissue also increased during development but to a much lesser extent. During fetal lung development the activities of choline kinase and cholinephosphate cytidyltransferase changed little, cholinephosphotranserase decreased while lysophosphatidic acid acyltransferase and lysolecithin acyltransferase increased. There was a postnatal increase in the activities of cholinephosphate cytidyltransferase, cholinephosphotransferase and both acyltransferases. The amount of phosphatidylglycerol, as a percentage of the total phospholipid, in lung wash and lung tissue as well as the activity of pulmonary glycerolphosphate phosphatidyltransferase did not change appreciably during development.

Animals↗

PubMed2006

Abnormal lung development precedes oligohydramnios in a transgenic murine model of renal dysgenesis.

PURPOSE: Renal development regulates prenatal lung growth by maintaining fetal urine output and liquor volume. However, shared signaling pathways underpinning renal and lung morphogenesis indicate that lung hypoplasia in the presence of renal dysgenesis may not result from oligohydramnios alone. We used a transgenic model of renal agenesis/anuria to test whether lung hypoplasia precedes any possible influence of oligohydramnios. MATERIALS AND METHODS: E12 lung primordia from normal and gamma1III4 deficient murine embryos (fetal anuria and renal agenesis-dysgenesis) were cultured for 72 hours. Morphological lung development was measured at 24, 48 and 78 hours by bud counting and tracings of lung epithelial contour using image analysis software and photomicrographs. Genotyping was performed by a separate blinded investigator. RESULTS: E12 homozygous mutant lungs branched but had significant decreases in bud count, epithelial area and perimeter compared to heterozygous or WT controls. These changes presented prior to oligohydramnios and persisted in isolation from the developing renal tract throughout the 72-hour culture period. CONCLUSIONS: Lethal lung hypoplasia seen at term in this model is present from the earliest stages of development, persists in vitro and, therefore, it is not consequent on renal dysfunction. These data implies that 1) fetal interventions for severe prenatal uropathies may have variable success for protecting future lung function and 2) patients with fetal uropathies may warrant greater scrutiny of prenatal lung growth and long-term postnatal lung function.

Animals↗

PubMedDate not supplied

Lifetime probability of developing lung cancer, by smoking status, Canada.

Life table methodology was used to estimate the probability of developing lung cancer by smoking status. Lifetime risks of developing lung cancer were estimated for six hypothetical cohorts (males, females, male current smokers, male never smokers, female current smokers, and female never smokers). Estimates of smoking mortality and incidence rates were calculated based on Canadian rates observed over the period 1987 to 1989. It was found that 172/1,000 of male current smokers will eventually develop lung cancer; the similar probability among female current smokers was 116/1,000. For those who never smoked on a regular basis the lifetime risk was substantially reduced. Only 13/1,000 males and 14/1,000 females in this category will develop lung cancer. When smoking status is not adjusted for, the lifetime risk of developing lung cancer is approximately 96/1,000 and 43/1,000 for males and females respectively.

Actuarial Analysis↗

PubMed1988

Stage-specific expression of SSEA-1-related antigens in the developing lung of human embryos and its relation to the distribution of these antigens in lung cancers.

The localization of three carbohydrate antigens, Lex, Ley, and sialylated Lex-i, which are closely related to stage-specific embryonic antigen 1, in the lung of developing human embryos was investigated using specific monoclonal antibodies. In the 38-day-old embryo, when the primitive lung bud has appeared and developed into two lung sacs, only Ley antigen was specifically positive in the proliferating cells in the terminal portion of lung bud. In the 50-53-day-old embryos, the future bronchi were actively developing from the bronchial buds. At this stage, the Ley antigen was maximally expressed and the Lex antigen appeared in the bud cells. In the lung of the 12-week-old embryo, buds for the future bronchioles were lined by simple cuboidal epithelial cells, which were strongly positive for Lex antigen, weakly positive for Ley antigen, and still completely negative for sialylated Lex-i antigen. Sialylated Lex-i antigen finally appeared in 18-week-old embryos, in the cells of the terminal buds for the future alveoli. At this stage, the Lex and Ley antigens were already beginning to disappear and were only weakly positive in cells of terminal buds. At 20 weeks, only sialylated Lex-i antigen was weakly detected in the cells in the terminal buds; after 8 months, all three antigens were essentially not detected in the respiratory cells in most of the embryos examined in this study. Formation of bronchial glands was detected at 18 weeks, where the developing gland cells were specifically positive for sialylated Lex-i antigen. Ciliation of the bronchial epithelial cells started at 12 weeks and propagated thereafter. The ciliation was accompanied by the reappearance of Ley and Lex antigen in the epithelial cells. These findings collectively indicated that the three antigens all have a physiological significance as stage-specific developmental antigens of the human lung; those antigens were specifically present in the bud cells at each important step of the morphogenesis of the human lung, such as cells in the lung buds, bronchial buds, and terminal buds for the formation of the alveolus, and cells differentiating into bronchial gland cells. The three antigens gradually disappear in the later stage of development along with the maturation process of the lung. Stage-specific embryonic antigen 1 and related antigens are known to be associated with various human cancers, including lung cancers. We suggest that the expression of these antigens in the lung cancer cells is the result of the retrodifferentiation of the cancer cells to the stages of immature embryonic lung cells.

Adenocarcinoma↗