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THIS ISSUE of the American Journal of Physiology-Lung Cellular and Molecular Physiology presents a special call for papers, a review and 18 original studies on "Pre- and Postnatal Lung Development, Maturation, and Plasticity." Because of the very enthusiastic response to this call (a case of an experiment done too well), this issue is largely devoted to papers dealing with various aspects of this special topic.
The study of lung development and maturation is important because it advances our understanding of lung biology from both basic and clinical science perspectives. First, there is the challenge of deciphering the series of coordinately regulated molecular, biochemical, and biophysical events that turn primitive foregut endoderm into the lung, a gas-exchange organ of parallel airway and blood vessel branches and associated parenchyma that comprise more than 40 different cell types. Second, a better understanding of the mechanisms of lung morphogenesis, and of lung plasticity, will hopefully improve our ability to treat and/or prevent a variety of neonatal and adult lung diseases. The process of lung development and maturation begins in the embryo with the emergence of lung buds from the ventral foregut (or even before there is a definitive sign of a lung bud) and culminates, depending on the species, in late gestation and/or shortly after birth with formation of gas-exchanging alveoli and an integrated capillary network (for recent reviews, see Refs. 2-4, 6, 12, 13, 19, 20, 26, 27, 29). Although lung morphogenesis is obviously a continuous process, developmental biologists have subdivided it, on the basis of histological features, into the successive pseudoglandular, canalicular, saccular, and alveolar stages to help systematically identify the multitude of molecular signals that guide the highly ordered and extraordinarily complex processes of branching morphogenesis, alveolarization, and vascularization.
This special topic begins with the end of lung morphogenesis, i.e., with a thought-provoking review by Massaro and Massaro (18) that addresses the mechanisms of alveoli formation (by septation and "other") and of postseptation remodeling (plasticity) of the lung's gas-exchange region. The authors propose the intriguing hypothesis that there is a complex and poorly understood signaling mechanism by which O2 uptake regulates the onset, rate, and cessation of alveolar formation as well as the destruction and regeneration of alveoli in the adult lung. The 18 original studies that accompany this review address a range of topics of lung development and maturation, and their highlights are summarized below.
Shortly after primary lung budding, the highly ordered sequence of events referred to as branching morphogenesis begins to generate the bronchial tree of the lung. Three of the reports in this special topic address mechanisms that influence this process. Although thyroid hormone triiodothyronine (T3) clearly affects late fetal lung development, little is known about its effects on early branching morphogenesis. Thus Archavachotikul et al. (1) studied T3 in early fetal mouse lung explants and observed that it accelerated epithelial and mesenchymal cell differentiation and reduced branching and lung growth. These morphological effects were associated with increased epithelial cell expression of the thyroid transcription factor Nkx2.1 and surfactant protein (SP) C and with reduced mesenchymal cell expression of the transcription factor Hoxb-5. Because many of the hormones, growth factors, and extracellular matrix interactions involved in regulation of branching morphogenesis lead to activation of mitogen-activated protein (MAP) kinases, Kling and colleagues (16) tested whether the MAP kinases extracellular regulated kinase (ERK)1 and -2 played a role in fetal lung growth. They found in fetal rat lung explants that inhibition of the upstream kinase MEK led to specific inhibition of ERK1/2 signaling and to increased mesenchymal cell apoptosis, decreased epithelial cell proliferation, and reduced branching morphogenesis. Although cells of the developing lung express the nitric oxide synthases NOS I and NOS II, it is unknown whether NO plays a role in lung development. To address this question, Young et al. (30) exposed fetal rat lung explants to NO donors and NOS inhibitors and observed that donors increased and inhibitors decreased airway branching. The stimulation of branching by NO was apparently not mediated by cGMP. Whether branching morphogenesis is significantly altered in any of the various NOS knockout mice has not been reported.
After the period of branching morphogenesis, the developing lung enters
the saccular stage characterized by mesenchymal thinning, epithelial
differentiation, and SP expression. Four papers address mechanisms of
regulation of SP expression. Klein et al. (15) investigated the role of SP-A in the regulation of SP-B expression and
the formation of tubular myelin in midtrimester human fetal lung
explants. Specific elimination of SP-A mRNA and protein
expression with an antisense oligonucleotide did not affect SP-B
mRNA levels but did reduce tubular myelin formation. Strayer et
al. (23) generated transgenic mice containing an
SP-B reporter gene and investigated the developmental expression of
SP-B. The SP-B promoter directed tissue- and lung cell-specific
transgene expression and was regulated during fetal development and in
adult lung by transforming growth factor- and in response to
bleomycin-induced lung injury. Torday et al. (24) used
cultured cells and fetal rat lung explants to test the hypothesis that
leptin mediates the paracrine effect of parathyroid hormone-related
protein (PTHrP) on alveolar type II cell SP synthesis. A thorough
series of experiments demonstrated a paracrine loop in which
lipofibroblast-derived leptin and epithelial cell-derived PTHrP
cooperatively interacted to stimulate SP-B expression and type II cell
maturation. Willet et al. (28) investigated whether the
maturational effects of endotoxin on fetal sheep lung were mediated by
interleukin (IL)-1. They observed that intra-amniotic administration of
IL-1
and IL-1
at 118 days of gestation mimicked the effects of
endotoxin by causing lung inflammation and accelerating lung
maturation, as reflected in improved lung function and increased alveolar SP mRNA expression in lamb fetuses delivered at 125 days. Beyond SP expression, another feature of lung maturation is
ciliogenesis in the large airway epithelium, and Carson et al.
(5) studied the developmental expression of a ciliary
axonemal dynein gene in human fetal lungs. Axonemal dynein was
expressed during airway epithelial maturation and well before there was
ultrastructural evidence of ciliogenesis.
An important regulator of lung growth during the period of lung maturation is distension of the lung, and three papers address this issue. Kitterman and colleagues (14) created oligohydramnios in rats at 16 days of gestation to reduce fetal lung distension. They observed in 21- to 22-day-old fetuses that the oligohydramnios reduced lung growth and impeded the formation of alveolar type I cells relative to type II cells but did not affect SP production. Gillett et al. (10) used selective left bronchus obstruction in fetal lambs to study effects of lung distension. Calmodulin-2 mRNA expression was increased after 2 days of distension and had returned to control levels at 4 and 10 days. The changes in calmodulin-2 expression closely paralleled previously reported changes in lung DNA synthesis, and it was speculated that increased intracellular calmodulin-2 may partly mediate distension-induced cell proliferation in fetal lungs. Sanchez-Esteban et al. (21) tested the hypothesis that mechanical forces play a role in inducing thinning of the periacinar mesenchyme during late fetal lung development by examining effects of intermittent stretch on cultured fibroblasts isolated from fetal rat lungs at 18 (pseudoglandular stage), 19 (early canalicular stage), and 20 (saccular stage) days of gestation. Whereas cyclic stretch inhibited cell cycle progression and increased apoptosis in fibroblasts isolated from 19-day-old fetal lungs, it had no effects on either proliferation or apoptosis in 18- and 20-day-old fibroblasts.
The final stage of lung morphogenesis is the formation of thin-walled alveoli and an integrated capillary network. In rats and mice, these are largely postnatal events. Three papers report studies of postnatal alveolarization. Because a decrease in interstitial fibroblasts contributes to the postnatal alveolar thinning that facilitates effective gas exchange, Srinivasan et al. (22) examined the regulation of apoptosis in interstitial fibroblasts isolated from postnatal rat lung. After alveoli formation, apoptosis occurred only in a lipid-filled population of fibroblasts and only in a subset of this population that contained higher levels of lipid droplets. The apoptosis was correlated with decreased expression of insulin-like growth factor I (IGF-I) receptor and could be induced by antibody blockade of the IGF-I receptor and by inhibitors of the downstream phosphatidylinositol 3-kinase and ras-raf MAP kinase pathways. Because retinoid signaling also plays an important role in alveolarization, Hind et al. (11) mapped the temporal and spatial expression of retinoid binding proteins and retinoic acid receptor isoforms in postnatal and adult mouse lungs. Both binding proteins and receptors were expressed in alveolar septal regions and temporally regulated, supporting a role for dynamic retinoid signaling in alveoli formation. The administration of glucocorticoids to rats during the first 2 wk of life impairs alveolarization, an effect that persists into adulthood. To determine whether a shorter course of dexamethasone treatment would have similar effects, Luyet et al. (17) treated neonatal rats only on postnatal days 1-4 and analyzed lung morphology and number of proliferating and dying lung cells at various times from 1 to 36 days later. The short period of dexamethasone treatment caused a similar degree of premature thinning of alveolar walls and impairment of alveolarization as does longer-term treatment, but the effects were transient as reflected in an apparent recovery of the normal process of alveoli maturation by day 10.
The remaining four reports of this special topic also address issues of
postnatal lung maturation. Because components of extracellular matrix
influence cell growth and differentiation, Wang et al. (25) compared expression of chondroitin sulfate,
chondroitin sulfate proteoglycan, and decorin in fetal, neonatal, and
adult rat lungs. Fetal and 1- to 10-day-old neonatal lungs showed
strong staining for chondroitin sulfate and chondroitin sulfate
proteoglycan in alveolar and airway extracellular matrix, whereas
decorin staining was confined to developing airways and blood vessels.
The expression of these matrix components was reduced and more focal in
alveolar regions in older lungs. To investigate mechanisms and effects of matrix turnover on postnatal lung growth, Franco et al.
(9) measured the metalloproteinase 92-kDa gelatinase
activity and lung growth after lipopolysaccharide (LPS)-induced lung
injury in 6-day-old neonatal and adult rats. LPS-induced injury led to recruitment of intra-alveolar inflammatory cells and increased gelatinase activity in both neonatal and adult lungs. These responses were accompanied with decreases in lung volume, alveolar surface, and
air space volume in the neonates. The metalloproteinase inhibitor doxycycline reduced the increase in gelatinase activity but not the
impairment of alveolar growth. Because molecular defects in, and
knockout of, the cystic fibrosis transmembrane conductance regulator
(CFTR) chloride channel do not impair lung morphogenesis, Edmonds et
al. (7) reasoned that non-CFTR chloride channels are
important in regulating airway epithelial ion and fluid transport in
fetal and neonatal lungs and examined the ontogeny of expression of the
Ca2+-regulated chloride channel-5 (ClC-5). ClC-5 mRNA and
protein were most strongly expressed along the luminal surface of
airway epithelium in the fetal lung. Expression of ClC-5 was maintained but downregulated postnatally. Conversion of distal airway epithelium from secretion to adsorption is critical for the neonatal switch from
placental to pulmonary gas exchange, and Folkesson et al. (8) measured airspace fluid clearance in 21- to 22-day-old fetal and 40-h neonatal rats. While there was no distal airspace fluid
clearance in lungs of 21-day-old fetuses, there was rapid, -adrenergic receptor-mediated clearance in 22-day-old fetuses that
coincided with elevated plasma epinephrine levels. This high rate of
fluid clearance declined to adult levels within the first 40 h
after birth.
Each of the above studies contributes a significant piece of new information to our overall understanding of the mechanisms governing lung morphogenesis and maturation. The editors and contributors hope that the new information and insights presented in this special topic will stimulate further study of the fascinating and important science of pre- and postnatal lung development, maturation, and plasticity.
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ACKNOWLEDGEMENTS |
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I thank Dr. S. A. Gebb for helpful suggestions in preparing this editorial.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajplung.00445.2001
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Ivan F. McMurtry, Associate Editor American Journal of Physiology- Lung Cellular and Molecular Physiology March 2002, Volume 282 (26) |
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