SPECIAL TOPIC
Editorial
Introduction: pre- and postnatal lung development, maturation, and plasticity


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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-beta 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-1alpha and IL-1beta 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, beta -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.


    ACKNOWLEDGEMENTS

I thank Dr. S. A. Gebb for helpful suggestions in preparing this editorial.


    FOOTNOTES

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)


Am J Physiol Lung Cell Mol Physiol 282(3):L341-L344
1040-0605/02 $5.00 Copyright © 2002 the American Physiological Society




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