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PubMed1985

Perinatal age determines the severity of retarded lung development induced by starvation.

Susceptibility of the lung to caloric restriction is age-dependent, with more permanent damage occurring during the phases of growth and differentiation. Because the guinea pig is born with more well-developed alveoli than are other rodents, the postnatal lung of this species may better resist alveolar hypoplasia than the prenatal lung. Control animals were raised from sows provided food ad libitum during and after normal gestations (66 to 68 days). Starvation groups received 50% rations of control food intakes during 1 of three 21-day periods: prenatal starvation, with sows rationed during their last trimester (Day 45 to term); neonatal starvation, with nursing sows rationed during the 21 days postpartum before weaning; weanling starvation, with animals starved from 21 to 42 days postpartum. Lungs were fixed in situ with glutaraldehyde and analyzed for pulmonary morphometrics. At the end of starvation and before refeeding, lungs of prenatal and weanling starvation groups were significantly reduced for tissue volumes, alveolar and capillary surface areas, and pulmonary diffusing capacity. Recovery with feeding was complete for most parameters in the starved weanlings by maturity, but animals starved prenatally showed residual starvation effects as adults. The neonatally starved animals showed minimal effects of starvation on lung dimensions, both acutely and as adults. Morphologically, the lungs of some prenatally starved neonates were apparently retarded, at least to the saccular phase, and correlated with significant increases in the number of stillborn litters and in neonatal mortality within hours of parturition.

Age Factors↗
PubMed1992

A novel system for the culture of human lung: lung development and the response to injury.

Existing methods of fetal lung organ culture are complicated and require special skills. With the use of a polyester-based plastic sheet, we have developed a simpler human fetal lung organ culture that is viable for 6 wk. This novel method permits the study of growth and differentiation, pulmonary surfactant secretion, and the response of human lung tissue to injury in vitro. Lung tissues, obtained from human fetuses ranging in gestational age from 14 to 18 wk, were cultured on the polyester sheet in Dulbecco's modified Eagle medium supplemented with 15% fetal calf serum and gentamicin. Microscopic study of the fetal lung before culturing revealed round epithelial tubules, lined by glycogen-rich columnar cells and a thick cellular interstitium. After 1 wk in culture, morphological examination showed the development and expansion of alveolar saccules and thinning of the interstitium; type I and II pneumocytes as well as fibroblasts and myofibroblasts were present. Lipid analysis of the tissues, 2 wk after the initiation of the culture, demonstrated a high percentage of dipalmitoyl phosphatidylcholine characteristic of pulmonary surfactant. Treatment of the organ culture with asbestos fibers induced type II cell hyperplasia, increased numbers of collagen fiber bundles within the interstitium, and the accumulation of multi-lamellated surfactant material within the alveolar lumens. We conclude that this organ culture system is suitable for studying lung growth, development, and injury in human tissue.

Asbestos↗
PubMed2000

Effect of immediate versus slow intrauterine reduction of congenital diaphragmatic hernia on lung development in the sheep: a morphometric analysis of term pulmonary structure and maturity.

The incidence of congenital diaphragmatic hernia (CDH) is 1:1,200-5, 000, and the condition is associated with high mortality and morbidity attributed principally to associated pulmonary hypoplasia. One treatment approach has been for intrauterine intervention to induce lung growth to a sufficient level to allow survival at birth. Repair of the hernia in utero has been attempted, using a method of immediate reduction and repair of the hernia (patch) compared to a slow reduction method using a silastic "silo" sewn over the diaphragm defect to contain the hernial contents. In animal studies, this second method has been associated with lower fetal morbidity and mortality. This study, utilizing the sheep model of CDH, focuses on analysis of lung structural development and maturation, comparing the efficacy of the immediate vs. slow methods of hernial repair in preventing/reversing pulmonary hypoplasia. We hypothesized that: a) Both the immediate (patch) and slow (silo) methods of hernia repair performed in the lamb model of CDH will stimulate lung growth and structural development and restore lung structure and maturity towards normal levels by term gestation; b) Effects will be detectable by morphometric measurement of the following parameters: lung volume; parenchyma to nonparenchyma tissue ratio; volume density of connective tissue in nonparenchyma; gas exchange tissue to airspace ratio; gas exchange surface area; capillary loading; alveolar/airspace density; and alveolar perimeter; c) Effects will be seen in all lobes of the lung; and d) There will be no significant difference in lung size or structural parameters between the two groups. Forty-four pregnant ewes were allocated randomly to one of four groups. Fetal lambs in three groups (n = 36) underwent CDH creation at days 72-74 of gestation. Of surviving lambs showing an adequate hernia, 9 were not operated on further, 11 underwent "repair" using a silastic chimney around the hernial contents (slow reduction), and 11 underwent "repair" by a silastic patch over the diaphragmatic defect (immediate reduction). The fourth group were normal controls. All surviving lambs (n = 8 in each group) were delivered by Cesarian section at 141-143 days (term = 145-149 days). Lungs were obtained at autopsy, inflation-fixed, divided into lobes, and sampled, and morphometric analysis was performed. Comparisons were made between these groups and with matched normal controls and CDH untreated animals prepared in conjunction and previously reported. The lungs from the CDH animals treated by both methods of fetal hernia repair showed significant lung growth and structural development and maturation, although they remained significantly hypoplastic compared to normal. There were minor differences in the lung parameters between these two groups, with a tendency for the slow method to provide more normal parameter values. An exception was the increase in lung volume that was greater for the immediate (patch) method, particularly in the left lower lobe. In conclusion, intrauterine hernia repair by both methods is capable of partially reversing total lung and lobar structural hypoplasia and immaturity. The slow reduction method, with reduced potential for mortality and morbidity, is at least as good at reversing pulmonary hypoplasia as the immediate method. Alternative intrauterine interventions to prevent or reverse pulmonary hypoplasia are discussed and compared with the hernia repair methods used in this study.

Animals↗
PubMed2002

Perinatal corticosteroids and the developing lung.

A significant number of infants are born prematurely each year, many of whom will develop respiratory disease and require ventilation. A substantial number of these infants will die and many of the survivors will subsequently develop chronic inflammatory lung disease. Administration of corticosteroids to women prior to a premature delivery is associated with a significant reduction in mortality and in the incidence of respiratory distress syndrome and intracranial haemorrhage in their infants once born. Postnatal administration of corticosteroids to the infant who develops chronic lung disease has been widely practised for many years. Recent meta-analyses have suggested that benefit may be limited. Treatment is also associated with a range of different side-effects but it has been assumed that the cost-benefit ratio favoured treatment. Recent evidence of permanent and highly significant long-term adverse effects has questioned the validity of this judgement.

Adrenal Cortex Hormones↗
PubMed1985

The responses of glutathione and antioxidant enzymes to hyperoxia in developing lung.

Total glutathione levels and the activity of enzymes associated with antioxidant protection in neonatal lung are increased in response to hyperoxia. Glutathione levels in developing rat lung decreased from 24 nmol/mg protein on day 19 of gestation to approximately 12 nmol/mg protein at birth. The initial decrease in glutathione may be due to emergence of other antioxidant systems. Newborn rats placed in 100% oxygen showed a rapid and sustained increase in total glutathione levels which was primarily due to an increase in reduced glutathione. Explants obtained from 16-wk gestation human fetal lung or from 17- to 18-day fetal rat lung also showed increased total and reduced glutathione when cultured in 95% oxygen, 5% CO2 as compared with explants cultured in room air. Type II cells isolated from neonatal rats maintained in oxygen for 6 days also showed glutathione levels twice those found in cells isolated from animals in room air. The activity of antioxidant enzymes (glucose-6-phosphate dehydrogenase, glutathione peroxidase, glutathione reductase) was increased in lungs of newborn rats exposed to 100% oxygen either at birth or 2 days of age. Antioxidant enzyme activity of lung explants cultured in 95% oxygen, 5% CO2 was also higher than in explants maintained in room air. These results suggest that the increases in glutathione and of antioxidant enzymes in vivo and in vitro are a direct effect of oxygen exposure in lung and that the increase of both glutathione and antioxidant enzyme activity is intrinsic to the lung cell itself. It is likely that increases in glutathione in lung represent an important protective mechanism against oxidant injury.

Animals↗
PubMed1998

Distribution of the CD15 epitope in the mammalian developing lung is opposite in mouse compared with human.

The distribution of the expression of the CD15 epitope was characterized by immunohistochemistry in the developing mouse and human lung on embryonic days E9.5-E19 and gestational weeks GW7-GW25, respectively. In the earliest stages in the mouse, the tracheal epithelial cells expressed CD15 on their apical and lateral cell membranes and, in the more proximal regions, also showed a faint cytoplasmatic CD15 expression. Only very few epithelial cells in the bronchial bud regions expressed CD15 on their apical surfaces. In later stages (E12-E17), cells in the proximal parts of the bronchi and bronchioli expressed CD15 on their apical, but also on their lateral membranes, and increasing numbers of cells expressed CD15 cytoplasmatically. Cells in the distal, presumably proliferating, areas of the bud regions were CD15 negative. This distribution pattern of CD15 was consistent until the latest embryonic stages. These results are completely opposite to those found in human developing lung where up to GW20 bronchial and bronchiolar bud regions were CD15 positive, while in the proximal parts of the airways the vast majority of cells were CD15 negative. After GW20, CD15 immunoreactivity in the bud regions vanished and was completely absent on GW25. This difference between human and mouse adds further evidence to profound species differences in the expression of CD15 in various organs, e.g., in the cerebellum or the retina, and should be taken into account when considering functional roles of CD15 and also when relating results from a (transgenic) mouse model to the respective human organ system.

Animals↗
PubMed1985

Distribution of secretory component and immunoglobulins in the developing lung.

The distribution of secretory component and immunoglobulins, IgA, IgG, and IgM in developing human lungs, ranging in age from 12 gestational weeks to 8 yr, was studied using the indirect peroxidase-labeled antibody method. Secretory component appeared first in the serous bronchial epithelium near the duct openings at the sixteenth gestational week, in goblet cells at the twentieth gestational week, and in bronchiolar epithelium at the twenty-second gestational week. The number of secretory component-positive cells (Y) in bronchial epithelium increased with age in weeks (X) according to the formula Y = 15.328 + 0.094 log X (p less than 0.001). Secretory component was almost absent in bronchiolar epithelium in atelectatic lungs with or without hyaline membrane. Secretory component-positive cells were never observed below the levels of respiratory bronchioles. Immunocompetent cells appeared in the bronchial walls after birth in normal lungs, but they appeared at the thirty-ninth gestational week in cases of pulmonary infection. The IgA- and IgM-containing cells were present around the bronchial glands in normal lungs, whereas IgG-containing cells were not associated with the glands. In normal lungs, IgA-containing cells were most prominent, followed by IgM-containing cells and IgG-containing cells. The apical portions of serous epithelial cells of bronchi and bronchial glands were positive for IgA and IgM. In bacterial and viral pulmonary infections, IgA-containing cells increased in number in the bronchial glands. The appearance of secretory component-positive cells long before immunoglobulin-containing cells in fetal lungs suggests that secretory component may play some role in the formation of the mucociliary blanket, instead of selective transport of IgA or IgM.

Bacterial Infections↗
PubMed1985

Laryngeal atresia, pleurodesis, and diaphragmatic hypertrophy in a newborn infant with findings relevant to fetal lung development.

A rare congenital malformation, cartilaginous subglottic laryngeal atresia, was found associated with developmental growth disturbances in the lungs (hypoplasia), diaphragm (hypertrophy), and pleural cavities (pleurodesis) in a newborn premature male infant who died immediately after birth. Because of coexistent esophageal atresia, tracheoesophageal fistula, and anal atresia, the lower respiratory tract and gastrointestinal canal together formed a closed system throughout fetal life. A mechanism whereby diaphragmatic hypertrophy and mesenchymal obliteration of the pleural cavities may have evolved during uterine development is suggested. Since pulmonary hypoplasia was also present, an explanation of this unique constellation of development abnormalities has a bearing on normal lung development.

Abnormalities, Multiple↗
PubMed1999

Significance of apoptosis in morphogenesis of human lung development: light microscopic observation using in situ DNA end-labeling and ultrastructural study.

To clarify the significance of apoptosis in lung morphogenesis, the occurrence and localization of apoptosis were investigated in developing human lungs, using TdT-mediated dUTP-biotin nick end labeling (TUNEL) and ultrastructural observation. Under light microscopic observation, apoptotic cells were demonstrated in the epithelial lining of the developing respiratory tubes and their growth ends (bronchial tips). Small numbers of apoptotic cells were also observed in the mesenchymal cells surrounding the immature respiratory trees. The apoptotic cells tended to aggregate at the bronchial tips and the bifurcation. The ultrastructural study disclosed the presence of apoptotic cells characterized by condensation of nuclear chromatin, fragmented nuclei (apoptotic bodies), and rather well-preserved cytoplasmic organelles, in the developing bronchial epithelium. In conclusion, the observations confirm that the occurrence of apoptosis plays an important role in lung morphogenesis.

Journal Article↗
PubMed1998

Salt and water transport across the alveolar epithelium in the developing lung: correlations between function and recent molecular biology advances (Review).

Significant progress have been made in understanding the mechanisms of alveolar fluid clearance at the time of birth and the transition from placental oxygenation to air breathing. During fetal life, the mammalian lung is a fluid filled secretory organ that fills no respiratory function. Its potential air spaces are filled with fluid that is actively secreted in response to an osmotic force generated by Cl(-)-secretion and the fluid-filled lung is necessary for a proper development of the air-breathing lung. As term approaches, net Cl(-)-secretion decreases, which is accompanied by a decreased secretion rate of the fluid into the air spaces. Concomitantly with the decreased Cl(-)-secretion, the alveolar epithelium begins to absorb Na+ to prepare for fluid absorption and the air breathing life. The causes for the decreased Cl(-)-secretion and the beginning of the Na+ absorption are not clear. Alterations in the hormonal milieu of the lung as well as changes in plasma stress hormone levels have been suggested to play roles. The switch from a placental oxygenation to pulmonary oxygenation requires that the fluid in the air spaces be rapidly removed from the lung lumen. Recent studies have demonstrated that removal of the alveolar fluid at birth is regulated via endogenous plasma epinephrine in the newborn. Molecular, cellular, and whole animal in vivo studies have demonstrated that fluid absorption at birth is related to expression and function of the epithelial sodium channel (ENaC). Several different in vivo and in vitro preparations have been used to investigate the mechanisms of alveolar fluid transport, primarily in adult lungs and have demonstrated that alveolar fluid absorption is driven by active Na+ transport. Both catecholamine-dependent and -independent regulatory mechanisms have been identified, probably acting on ENaC and other apical sodium channels and/or the basolaterally located Na+, K(+)-ATPase. Future studies are needed to integrate new insights to the molecular mechanisms behind fluid clearance with their function in both normal and pathological lungs.

Animals↗
PubMed1998

Natural killer cell-derived large granular lymphocyte lymphoma of lung developed in a patient with hypersensitivity to mosquito bites and reactivated Epstein-Barr virus infection.

A 17-year-old female developed natural killer (NK) cell-derived large granular lymphocyte (LGL) lymphoma of the lung. She had a past history of hypersensitivity to mosquito bites (HMB). After an eight-year chronic, active Epstein-Barr virus (EBV) infection, she developed multiple lung lesions and pleural effusion. In the effusion, 60% of the cells were LGL. They were CD2+, 3-, 16+, 56+, 57+, 45RO+/RA + weak, and possessed strong NK activity. No rearrangement of T-cell-receptor genes was detected. From all these results, a diagnosis of NK-LGL lymphoma of the lung was made. EB virus DNA was detected in cells infiltrating the pleural effusion. The clonality of the LGLs was determined by Southern blot hybridization with the terminal repeat sequence of EB virus as a probe, and by chromosomal abnormalities. The patient died from respiratory failure. Necropsy of the lung revealed diffuse lymphoma composed of polymorphic cells with typical angiocentric lesions. Reportedly, lymphomas of NK lineage show predominantly extranodal involvement, and primary lung lesions are rare. In the pleural effusion of the present case, abnormally high levels of soluble Fas ligand, interleukin-10 and interferon gamma were detected. This hypercytokinemia, reflecting the microenvironment of lymphoma cells, may play a role in the progression of the lymphoma and organ injury in the lung.

Adolescent↗
PubMed1995

Effects of hypoxia and vascular tone on endothelium-dependent and -independent responses in developing lungs.

Both increases and decreases in endothelium-derived nitric oxide (EDNO) activity have been described in the developing pulmonary vasculature. We hypothesized that differences in baseline vasomotor tone and/or oxygen tension may contribute to this variability. Pulmonary arterial dose responses to endothelium-dependent and -independent vasodilators acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were measured in indomethacin-treated lungs of 1- to 2-day-old (2D) and 1-mo-old (1M) lambs. During 4% O2 ventilation, baseline pulmonary vascular resistance (PVR) and the dilator response to both ACh and SNP were greater in 2D lungs. However, when baseline PVR values were matched at both ages during either hypoxia or infusion of a thromboxane mimetic under normoxic conditions, developmental differences in ACh-induced vasodilation were minimal. Furthermore, hypoxia itself did not alter the responses to ACh in 2D lungs. In contrast, SNP caused greater vasodilation in 2D than in 1M lungs regardless of baseline PVR. These data and studies suggest that whereas high PVR enhances EDNO synthesis, responsiveness to ENDO decreases as synthesis of ENDO increases in developing lungs studied under basal conditions.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1975

Content and synthesis of glycosaminoglycans in the developing lung.

The function of lung is fundamentally linked to the connective tissue composition of the alveolar interstitium. The composition and synthesis of one class of interstitial connective tissue components, the glycosaminoglycans (GAG), was determined in lung parenchyma of rabbits at different stages of development. Parenchymal GAG content ranged between 0.2 and 0.4% (wt/wt) of dry weight, with highest concentration in adult lung. There were significant changes in types of GAG present at different ages. Fetal lungs contained a relatively high proportion of chondroitin 4-sulfate while the GAG in lung parenchyma of older animals was predominantly dermatan sulfate, heparan sulfate, and heparin. Methods were developed for the study of rates of synthesis of GAG by incorporation of [1-14C]glucosamine into lung explants. The rate of synthesis of total GAG per cell increased with development to a maximum in lung from weanling rabbits and fell to low rates of synthesis in mature rabbits. Fetal rabbit lung parenchyma synthesized mostly hyaluronic acid and heparan sulfate, while in weanling rabbit parenchyma hyaluronic acid and chondroitin 4/6-sulfate synthesis was greatest. In mature animals, the rates of synthesis of all types of GAG were relatively low but there was a relatively greater emphasis on synthesis of dermatan sulfate and heparin. These results may have significance in changes in lung function during development and in effects on other connective tissue components.

Animals↗
PubMedDate not supplied

Thyroid hormone affects distal airway formation during the late pseudoglandular period of mouse lung development.

We recently showed that T3 treatment of cultured gestational day 11.5 early pseudoglandular period mouse lungs, accelerated terminal airway development at the expense of decreased branching morphogenesis. As the ability of T3 to influence epithelial cell differentiation increases with advancing development, we hypothesized that in the late pseudoglandular period, T3 would cause further premature changes in the morphology of the distal airways leading to abnormal saccular development. Gestational day 13.5 embryonic mouse lungs were cultured for 3 and 7 days without or with added T3. Increasing T3 dose and time in culture resulted in progressive development of thin walled, abnormal saccules, an increase in cuboidal and flattened epithelia and airway space with a concomitant decrease in mesenchymal cell volume. Consistent with increased cuboidal and flattened epithelial cell volume identified by morphometry, immunostaining suggested increased cell proliferation detected by localization of proliferating cell nuclear antigen (PCNA) in epithelial cells of T3 treated lungs. T3 decreased mesenchymal expression of Hoxb-5 protein and caused progressive localization of Nkx2.1 and SP-C proteins to distal cuboidal epithelia of early abnormal saccules, evidence that T3 prematurely and abnormally advanced mesenchymal and epithelial cell differentiation. Western blot showed a T3-dependent decrease in Hoxb-5 and a trend towards decreased Nkx2.1 and SP-C, after 3 and 7 days of culture, respectively. We conclude that exogenous T3 treatment during the late pseudoglandular period prematurely and abnormally accelerates terminal saccular development. This may lead to abnormal mesenchymal and epithelial cell fate.

Animals↗
PubMed2002

Temporal regulation of CFTR expression during ovine lung development: implications for CF gene therapy.

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a small conductance chloride ion channel that may interact directly with other channels including the epithelial sodium channel (ENaC). CFTR is known to be more abundant in the airway epithelium during the second trimester of human development than after birth. This could be a consequence of the change in function of the respiratory epithelium from chloride secretion to sodium absorption near term. Alternatively it might reflect an additional role for CFTR in the developing airway epithelium. Though the lung epithelia of CF fetuses and infants rarely show gross histological abnormalities, there is often evidence of inflammation. Our aim was to establish whether CFTR expression levels correlated with specific developmental stages or differentiated functions in the ovine fetal lung. We evaluated CFTR expression using a quantitative assay of mRNA at 14 time points through gestation and showed highest levels at the start of the second trimester followed by a gradual decline through to term. In contrast, ENaC expression increased from the start of the third trimester. These results support a role for CFTR in differentiation of the respiratory epithelium and suggest that its expression levels are not merely reflecting major changes in the sodium/chloride bulk flow close to term. These observations may have significant implications for the likely success of CF gene therapy in the postnatal lung.

Animals↗
PubMed2003

Role of neuregulin-1 beta in the developing lung.

Neuregulins play a critical role in the developing heart, nervous, and mammary systems. Neuregulin-1-induced cardiac, neuronal, and mammary differentiation is based on a cell-cell communication model, where the ligand neuregulin-1 is produced and secreted by one cell type, which does not express its receptors erbB3 and erbB4 and acts on neighboring cell types that do express these receptors. We proposed that neuregulin-1 affects fetal lung maturation through a similar mechanism. Immunostaining showed neuregulin-1 in fetal lung that increased in fibroblasts at the onset of surfactant synthesis. Neuregulin-1 beta was found to be secreted by the fetal lung fibroblast and stimulated type II cell surfactant synthesis. Both fetal lung fibroblast-conditioned media and neuregulin-1 stimulated erbB2 receptor phosphorylation in type II cells. The effects of neuregulin-1 and of fibroblast-conditioned media on both surfactant synthesis and type II cell erbB2 phosphorylation were specifically blocked by antibody to neuregulin-1. Thus, neuregulin-1 beta may control fetal lung maturation through mesenchymal-epithelial interactions in a paracrine mechanism similar to that described for the developing heart, brain, and mammary systems.

Animals↗
PubMed2001

Fetal alveolar epithelial cells contain [D-Ala(2)]-deltorphin I-like immunoreactivity: delta- and mu-opiate receptors mediate opposite effects in developing lung.

Opiate-like peptides can regulate many cellular functions. We now map [D-Ala(2)]deltorphin I (DADTI)-like immunoreactivity (DADTI-LI) in developing mouse lung and analyze potential functional roles. Most DADTI-LI-positive cells were alveolar cells negative for prosurfactant protein (proSP)-C immunoreactivity. Peak numbers of DADTI-LI-positive cells occurred on embryonic Day 18, decreasing postnatally. To analyze developmental effects of DADTI, e17-18 lung explants were treated with [D-Ala(2)]deltorphin II (DADTII, soluble DADTI analogue, delta-receptor-specific) versus dermorphin (mu-receptor-specific). Type II pneumocyte differentiation, assessed by [(3)H]choline incorporation into saturated phosphatidylcholine and proSP-C immunostaining, was inhibited by DADTII but stimulated by dermorphin. Cell proliferation, measured as [(3)H]-thymidine incorporation and proliferating cell nuclear antigen immunostaining, was stimulated by DADTII and inhibited by dermorphin. All effects were dose-dependent. DADTII-inhibited choline incorporation was reversed by the delta-blocker, naltrindole. Unexpectedly, DADTII-stimulated thymidine incorporation was augmented by naltrindole and reversed by naloxone (mu-blocker). Although dermorphin-stimulated choline incorporation was appropriately blocked by binaltorphimine, dermorphin-inhibited thymidine incorporation was reversed by delta, kappa-, or mu-blockers. The delta- and mu-receptor messenger RNAs occurred pre- and postnatally, whereas kappa-receptor transcripts occurred mainly prenatally. All three receptor proteins were present in epithelial and mesenchymal cells in e18 lung. Thus, DADTI-LI from proSP-C-immunonegative alveolar cells could regulate development via both direct and indirect effects involving multiple opiate receptors.

Animals↗
PubMedDate not supplied

Structure and function of the adventitial and mucosal nerve plexuses of the bronchial tree in the developing lung.

1. The aim of the present study was first to determine when airway smooth muscle first appears in the airways of the developing foetal lung and when its contractility is mature and, second, when the airway smooth muscle becomes innervated, both structurally and functionally. 2. Narrowing and relaxation of the airways of the intact bronchial tree from the lungs of foetal pigs at varying stages of gestation was recorded by real time video microscopy. Nerves and smooth muscle were stained immunohistochemically and their spatial relationships were visualized by confocal microscopy. 3. From early in gestation (pseudoglandular stage/branching morphogenesis), airways were covered with a single layer of smooth muscle cells orientated cylindrically around the airway wall. Thick nerve trunks containing loosely packed nerves, with ganglia forming at their junctions ensheathed the airways to the growing tips, with a network of fine varicosed nerves lying on the smooth muscle cells. Some of these nerves were functional and cholinergic, as electrical field stimulation caused substantial narrowing that was blocked by atropine and by tetrodotoxin. By mid-term, an extensive plexus of nerves, well-defined ganglia and varicosed nerves to the smooth muscle had developed. Some nerves extended through the airway smooth muscle to form the elements of a mucosal nerve plexus in conjunction with developing vascular tissue forming a bronchial circulation. In 3 week postnatal pigs the distal and terminal airways were densely supplied with varicosed nerves to the smooth muscle. The ganglia were more centrally located. 4. An abundant network of calcitonin gene-related peptide (CGRP) nerves with prominent nerve endings lay just below the surface of the epithelium. The nerve bundles to the terminal arterioles in the mucosa also contained CGRP-positive fibres as well as sympathetic nerves (neuropeptide Y- and tyrosine hydroxylase-positive). It is hypothesized that these epithelial and arteriolar CGRP nerves form the local axon reflex purported to cause neurogenic inflammation. 5. The spontaneously active tone exerted by the airway smooth muscle from early in gestation is hypothesized to provide the force across the airway wall and adjacent parenchyma that is the stimulus for lung growth in foetal life.

Animals↗