1 Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas 77030; 2 Division of Neonatology, Department of Pediatrics, Women's and Children's Hospital, University of Southern California School of Medicine, Los Angeles, California 90033; 3 Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, California 95616; 4 Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201; 5 Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, Ohio 45229; and 6 Department of Pediatrics and Obstetrics and Gynecology, Harbor-University of California Los Angeles Research and Education Institute, Torrance, California 90502
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ABSTRACT |
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We propose that lung morphogenesis and repair are characterized by complex cell-cell interactions of endodermal and mesodermal origin, leading to (or returning back to) an alveolar structure that can effectively exchange gases between the circulation and the alveolar space. We provide the developmental basis for cell/molecular control of lung development and disease, what is known about growth and transcription factors in normal and abnormal lung development, and how endodermal and mesodermal cell origins interact during lung development and disease. The global mechanisms that mediate mesenchymal-epithelial interactions and the plasticity of mesenchymal cells in normal lung development and remodeling provide a functional genomic model that may bring these concepts closer together. We present a synopsis followed by a vertical integration of the developmental and injury/repair mechanisms.
bronchopulmonary dyplasia; smooth muscle; terminal sac
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INTRODUCTION |
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THE PREMISE OF THIS SYMPOSIUM was that lung morphogenesis and repair are characterized by complex cell-cell interactions of endodermal and mesodermal origin, leading to (or returning back to) an alveolar structure that can effectively exchange gases between the circulation and the alveolar space. The presenters provided the developmental basis for cellular/molecular control of lung development and disease, what is known about growth and transcription factors in normal and abnormal lung development, and how endodermal and mesodermal cell origin interacts during lung development and disease. The global mechanisms that mediate mesenchymal-epithelial interactions and the plasticity of mesenchymal cells in normal lung development and remodeling provide a functional genomic model that may bring these concepts closer together. The following is a synopsis of each presentation, followed by an integration of the developmental and injury/repair mechanisms.
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MOLECULAR MECHANISMS OF LUNG DEVELOPMENT1 |
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In general, neonatal lung disease overlaps ongoing lung
development. Thus bronchopulmonary dysplasia (BPD) may be viewed as the
consequence of arrested normal development (alveologenesis) combined
with abnormal repair of immature, injured lungs. This is an important
concept because mechanisms of repair recapitulate fundamental
strategies of normal development. Thus the etiology of BPD may be
related to interactions between untimely or spatially inappropriate
signaling that arises from injury [e.g., inflammatory mediators,
transforming growth factor (TGF)-, etc.] with morphogenetic signaling and transcriptional pathways that control normal development and repair [e.g., fibroblast growth factor (FGF), Nkx2.1].
Lung development. The focus on lung developmental biology is relatively recent and, as in other organs, owes much to the analysis of Drosophila developmental genes. To be pertinent to BPD, the focus of the current discussion will be on the "terminal sac" phase of lung development.
Two forces drive lung development. Intrinsic forces consist of the integrated functional activities of a complex set of morphoregulatory molecules that fall into three classes: transcription factors [e.g., Nkx2.1, GATA, hepatocyte nuclear factor (HNF)-3]; signaling molecules [FGF, bone morphogenetic protein (BMP)-4, platelet-derived growth factor (PDGF), Sonic hedgehog (Shh), TGF-Inflammation.
BPD is a highly complex, chronic lung disease of multifactorial
etiology. We have proposed that the main pathway through which the effects of various insults, such as antenatal infection, surfactant insufficiency (volutrauma), or oxygen toxicity are translated into lung
injury, is "inflammation." The close association between preterm
labor and maternal infection is well established (15). Also, antenatal inflammation, as assessed by elevated tumor necrosis factor (TNF)-, interleukin (IL)-1
, IL-8, or IL-6, correlates with
adverse neonatal outcome (53). In preterm neonates, we and
others (18) have found that mediators of inflammation are present in the lungs as early as the first hour of life. Alveolar macrophages from preterm neonates at risk for BPD exhibit a robust "termlike" capacity to produce TNF-
and IL-1
(M. J. Blahnik, R. Ramanathan, C. R. Riley, C. A. Jones, and P. Minoo, unpublished observation). Notably, neonatal alveolar macrophages show
reduced potential for expression of IL-10, an anti-inflammatory
mediator that is key in controlling self-injury caused by dysregulated, smoldering inflammation (18). Although incapable of
producing IL-10, neonatal macrophages retain normal capacity for
responding to exogenous IL-10, raising the possibility for effective
IL-10 recombinant peptide or gene therapy as a plausible and rational therapeutic strategy (21).
At the interface of inflammation and development.
Ultimately, the etiology of BPD must be explained in the context of
alveolar hypoplasia. If inflammation is the main culprit, what are the
potential linkages connecting inflammation and morphogenesis? Recent
data regarding the regulation of Nkx2.1 by various mediators are
tantalizing. First, decreased expression of Nkx2.1 has been documented
in the lungs of neonates who died with BPD (40). Second,
TNF-, which is abundantly expressed in the lungs of preterm neonates
at risk for BPD, negatively regulates Nkx2.1 gene expression (30). These data provide examples of potential
interactions between mediators of injury and those of normal
morphogenetic pathways. Disruption of key factors such as Nkx2.1
potentially derails both ongoing morphogenesis and repair.
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EPITHELIAL-MESENCHYMAL INTERACTIONS IN LUNG2 |
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The importance of epithelial-mesenchymal interactions in normal lung development was first demonstrated 70 years ago by Dr. Dorothy Rudnick, who showed that removal of mesenchyme from chick lungs grafted onto chorioallantoic membranes in ovo resulted in arrested lung development. Subsequent studies in mammals extended these observations to mammals and demonstrated the inductive potency of lung mesenchyme (LgM). One example of this was the experiments of Alescio and Cassini, who showed that grafting a piece of distal LgM onto trachea denuded of its own mesenchyme resulted in the induction of a supernumerary bud that subsequently branched in a lunglike pattern. These studies, however, did not examine whether the tracheal epithelium (TrE) had been induced to express markers of lung differentiation. When we grafted distal LgM onto TrE we also observed that the induced epithelium would invade the grafted tissue and branch within it. We further observed that the TrE exhibited all of the ultrastructural characteristics of alveolar type II cells, including numerous osmiophilic lamellar bodies. Expression of surfactant protein C (SP-C), a specific marker of the distal lung, was also induced in the grafted TrE and was apparent by 24 h postgrafting. We next analyzed the epithelial phenotype of reciprocal recombinants of embyronic lung epithelium (LgE) and tracheal mesenchyme (TrM). In this case, the TrM reprogrammed the distal LgE to assume a tracheal phenotype, including the induction of ciliated and mucous cells; all distal lung epithelial markers were suppressed. From these experiments, we concluded that mesenchyme specifies both epithelial morphogenesis and differentiation and that the entire respiratory epithelium, from the larynx to the distal tips, exhibits a significant plasticity in its eventual phenotype that is dependent on the inductive cues it receives from the mesenchyme.
The inductive factors responsible for specification of distal lung epithelial phenotype are diffusible and active over a short distance. To determine whether the reprogramming of TrE to a lung phenotype required direct epithelial-mesenchymal contact, we constructed recombinations of LgE, LgM, TrE, and TrM in which a 40-µm-thick meshtype Teflon filter with a nominal pore size of 0.45 µm was interposed between the two tissues. Under the influence of LgM, both LgE and TrE grew and branched within a Matrigel substratum. Under the influence of TrM, both LgE and TrE grew but did not branch, instead forming an epithelial cyst. TrE-cultured transfilter to LgM was induced to express SP-C mRNA in the cells in the most distal aspects of the epithelium. The inductive influence of LgM, however, showed spatial constraints because TrE that was positioned to the side of the LgM did not respond. We have demonstrated the spatial influence of LgM in experiments in which LgE and LgM were both enrobed in Matrigel but separated by a distance of ~200 µm. In these cultures, the LgE was drawn to the LgM by chemoattraction and would then invade and branch within the LgM. Studies in other laboratories have shown that FGF-10 is a potent chemoattractant found in LgM. Increasing the distance between the two tissues to >300 µm abolished the chemoattractive effect.
Control of lung epithelial growth and differentiation are multifactorial. We designed a culture system in which embyronic LgE will traverse the full developmental pathway from undifferentiated columnar epithelial cells to fully differentiated alveolar type II cells in the absence of LgM. We further refined this system to demonstrate the TrE could be reprogrammed to an alveolar type II cell phenotype in the absence of mesenchyme and that members of the FGF family, notably FGF-7 and FGF-1, were critical to this process. Somewhat surprisingly, FGF-10 was not able to induce reprogramming of TrE.
BMP-4 is a secreted protein found in the distal LgE. Disruption of BMP-4 signaling in the distal lung disrupts lung morphogenesis and correct spatial epithelial differentiation. Because BMP-4 has been shown to be induced by FGF-10, it has been hypothesized that BMP-4 is involved in specification of distal epithelial phenotype. We first tested this hypothesis by examining the effects of the different FGF family members found in the lung (FGF-1, -2, -7, -9, -10, and -18) on the expression of both BMP-4 and SP-C in cultured TrE. We found that although all of the FGFs induced BMP-4, only FGF-1, -2, -7, and -9 induced SP-C. Second, we antagonized the effects of BMP-4 in tracheal epithelial cultures with the protein Noggin, which acts by binding directly to BMP-4. We observed that a concentration of Noggin sufficient to block the effects of exogenously added BMP-4 had no effect on tracheal epithelial growth or the induction of SP-C. Third, direct addition of BMP-4 to cultures of TrE did not induce SP-C expression and actually inhibited rudiment growth and SP-C expression. From these three lines of investigation, we conclude that the role of BMP-4 in lung development is not to specify distal lung phenotype.
Proteoglycans (PGs) are multifunctional macromolecules found in the extracellular matrix as well as on cell surfaces. We have investigated the role of PGs in lung development by treating cultured lung explants with sodium chlorate, which prevents sulfation of the glycosaminoglycan side chains that are attached to PG core proteins. We found that sulfated PGs are required for growth and branching morphogenesis in intact lung tips as well as in recombinants consisting of LgM plus LgE or LgM plus TrE. Quantitative real time PCR showed that expression of SP-C was significantly diminished in the intact tips and LgM plus LgE recombinants and essentially abolished in LgM plus TrE recombinants. We next analyzed the effects of specifically inhibiting chondroitin sulfate PGs by treating cultured tissues with chondroitinase ABC lyase (EC 4.2.2.4). We found that chondroitinase treatment inhibited growth and branching morphogenesis in a manner identical to that seen in chlorate-treated tissues. When we examined SP-C expression, however, we found that chondroitinase treatment did not affect the induction or maintenance of SP-C mRNA. These data suggest that chondroitin sulfate PGs play a critical role in lung growth and patterning but seem not to be involved in specification of lung epithelial differentiation.
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ROLE OF DEVELOPMENTALLY IMPORTANT TRANSCRIPTION AND GROWTH FACTORS IN ADULT LUNG PHYSIOLOGY AND PATHOBIOLOGY3 |
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The revolution in molecular biology that occurred over the
last two decades saw new and exciting approaches in defining factors that regulate lung development and differentiation. In vitro and in
vivo analyses have identified the transcription and growth factors that
regulate lung development from the early stages of branching
morphogenesis through alveolarization (47). Many of these
factors have also been found to regulate the function of the adult
lung. Of the transcription factors found to regulate lung function are
such factors as Nkx2.1 (6), HNF-3 (1, 6,
33), and CCAAT enhancer binding protein-
(C/EBP-
)
(8). Of the growth factors known to be critical for the
regulation of lung development, the FGF signaling pathway has been
shown to be important for regulating adult pulmonary physiology.
Transcription factor analysis of the promoters for the regulation of
cell specific gene expression in the lung have identified several
transcription factors as being important for the regulation of lung
gene expression. The promoter for the Clara cell secretory protein
(CCSP) has been used as a model to identify the elements regulating the expression of pulmonary epithelial genes. CCSP is
expressed preferentially in the nonciliated secretory cells (Clara
cells of the airways reviewed in Ref. 9). Promoter
analysis of CCSP gene expression has identified Nkx2.1
(33), HNF-3 (9), and C/EBP-
(8) as being important in regulating the expression of
CCSP. Ablation of these genes results in neonatal lethality. Ablation
of Nkx2.1 (26) and C/EBP-
results in pulmonary defects. Ablation of HNF-3
results in embryo lethality at a stage before lung
development (1). However, analysis of the physiological and pathophysiological regulation of CCSP expression demonstrates these
genes are important for the regulation of CCSP.
CCSP is involved in protecting the lung from hyperoxic, bacterial, and
viral insults (14, 16, 17, 25). Analysis of the regulation
of CCSP has demonstrated roles for cytokines such as IFN- and
hyperoxia (9). There are two candidate regions in the CCSP
promoter that may mediate IFN-
stimulation. The promoter contains a
-activation sequence that may mediate IFN-
activation of CCSP.
Mediation of IFN-
stimulation may also be mediated by HNF-3
(24).
CCSP is important for the protection of the lung from hyperoxic
injury (25). Hyperoxia represses the expression of CCSP. Transcriptional analysis of CCSP expression reveals that the repression of CCSP by hyperoxia may occur by several mechanisms. First, activator protein-1 binding may repress CCSP expression. Second,
hyperoxia may alter the binding of Nkx2.1 to the CCPS promoter.
Finally, there may be altered binding of C/EBP- to the CCSP
promoter. This analysis demonstrates that developmentally important
transcription factors are pivotal in regulating lung physiology. The
same can also be said for developmental growth factors.
FGF signaling is important for pulmonary development. Ablation of FGF-10 (3) as well as its receptor FGFR-2 (32) signaling disrupts lung branching morphogenesis. The development of gene switch technology has allowed the investigation of the disruption of FGF signaling in the adult mouse in vivo (10, 44, 47). Altered expression of FGF-3 in the adult mouse lung causes two phenotypes, depending on the level of induction of FGF-3. Low levels of FGF-3 induction cause increased macrophage invasion of the lung, presumably due to increased activity of the alveolar type II cells. High levels of FGF-3 expression cause a significant increase in alveolar type II cells. Therefore, this developmentally important signaling pathway regulates the influx of inflammatory cells into the lung as well as the differentiation of alveolar type II cells. This discussion demonstrates that understanding the function of processes important for lung development will also lead to the identification of factors important in lung pathobiology and physiology.
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ROLE OF THE MYOFIBROBLAST IN LUNG BIOLOGY AND PATHOLOGY4 |
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Bronchial myogenesis begins in the trachea (around day
10 of gestation in the mouse) and extends in a proximal to distal
fashion along the developing bronchial tree. Smooth muscle (SM)
differentiation is preceded by a change in peribronchial cell shape
from round to elongated that also follows a proximal-distal path. We
found that this change in shape is crucial for bronchial myogenesis. Regardless of the organ of origin, embryonic mesenchymal cells remain
undifferentiated in culture if forced to stay round and become SM cells
if allowed to elongate, even if the cells come from an organ that would
not normally develop significant SM, such as the kidney
(52). In the embryonic lung, the process of cell
elongation is promoted, at least in part, by the developing bronchial
basement membrane (35, 37, 51). New epithelial-mesenchymal contacts produced during branching morphogenesis stimulate the synthesis of laminin-1 chain by both cell types
(37). Laminin-1, the main basement membrane constituent,
is then produced and polymerizes at the epithelial-mesenchymal
interface. Apposed mesenchymal cells use this polymer to spread and
elongate, a process that triggers SM differentiation (35,
50). Concomitantly, mesenchymal cell elongation induces
laminin-2 synthesis and deposition, which further stimulates myogenesis
(35).
In more recent studies, we tried to understand why a change in cell
shape could induce SM differentiation. Because spreading/elongation might be sensed by the cytoskeleton as mechanical tension and because
SM develops at sites that sustain mechanical tension, we determined
whether stretch may induce an undifferentiated mesenchymal cell to
differentiate into a SM cell. By stretching round embryonic mesenchymal
cells, we found that stretching was sufficient to initiate SM
myogenesis, but only if it caused cell elongation (35). A
similar effect was seen in embryonic lung explants by controlling the
intrabronchial hydrostatic pressure. Both cell stretching and spreading
induced SM myogenesis by a mechanism involving serum response factor
(SRF) and its dominant negative isoform SRF5, produced by
alternative splicing of exon 5 (2). We found that
undifferentiated mesenchymal cells synthesize SRF and SRF
5, but
during bronchial myogenesis, or on spreading/stretching, SRF
5
synthesis is suppressed in favor of increased SRF production. Furthermore, human hypoplastic lungs related to conditions that hinder
cell stretching continue to synthesize SRF
5 and show a marked
decrease in bronchial and interstitial SM cells and tropoelastin (50).
In more recent studies, we searched for genes that were differentially
expressed during SM differentiation. One of these genes was
rhoA, a member of the GTPase family involved in the
control of the cytoskeleton (5). RhoA levels were high in
round, undifferentiated mesenchymal cells in vivo and in vitro and
drastically decreased on SM differentiation (4).
Functional studies using agonists and antagonists of RhoA
activation and dominant positive and negative plasmid constructs
demonstrated that high RhoA activity was required to maintain the
round, undifferentiated mesenchymal cell phenotype. This was, in
part, achieved by restricting the localization of SRF and SRF5
mostly to the cytoplasm. Upon spreading on laminin-2, but not
on other main components of the extracellular matrix, the activity and
level of RhoA rapidly decreased, accompanied by disappearance of
SRF
5 and translocation of SRF to the nucleus. All this was prevented
by overexpression of dominant positive RhoA (4). Our
studies, therefore, suggest that a change in SRF alternative splicing,
together with its enrichment in the nucleus, is an important stimulus
of SM myogenesis.
Another gene differentially expressed during SM myogenesis was
p311. P311 is an 8-kDa protein with several
PEST-like motifs found in neurons and muscle (42,
43). P311 transfection into two fibroblast cell lines, NIH/3T3
and C3H/10T1/2, induced phenotypic changes consistent with
myofibroblast transformation, including upregulation of SM- actin
and SM22, induction of FGF-2, vascular endothelial growth factor, and
PDGF and PDGF receptors, stimulation of integrins
3 and
5, and increased proliferation and migration rate. The
P311-induced changes differed, however, from the well-characterized fibrogenic myofibroblast in that P311 inhibited TGF-
1, TGF receptor II, and TGF-
1-activating matrix metalloproteinase (MMP)-2
and MMP-9, with the resultant decrease in collagen 1 and 3 expression. Supporting a role for P311 in vivo, immunohistochemical examination of
human wounds showed P311 only in myofibroblasts and their activated precursors (D. Pan, X. Zhe, S. Jakkaraju, G. A. Taylor, and L. Schuger,
unpublished observations). These studies are the first to
implicate P311 in myofibroblast transformation, to demonstrate that
transformation can occur independently of TGF-
1, and to suggest that
myofibroblasts, long considered the main source of fibrosis, may also
have the potential to prevent it. Our current goal is to better
understand the role of laminins, SRF, and P311 in lung myogenesis and
lung diseases characterized by abnormal SM-like cells.
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A FUNCTIONAL GENOMIC APPROACH TO UNDERSTANDING HOW OVERDISTENSION MAY CAUSE BPD5 |
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Each of the presenters has addressed a key aspect of lung development, alluding to the use of this basic knowledge in understanding lung pathology. The laboratory in which I conduct research has taken a functional genomic approach to understanding the role of paracrine factors in cell cross talk as a means of identifying up- and downstream signaling pathways involved in lung development and pathophysiology. The stretch-sensitive parathyroid hormone-related protein (PTHrP) gene (45) is an excellent candidate for such a study because it is necessary for normal lung development (36), is expressed during the terminal sac phase of lung development (36), and has been linked to neonatal lung disease (39). We are interested in paracrine factors like PTHrP that are mediated by ligands of endodermal origin with cognate receptors on mesoderm (or visa versa) as a way of getting at functionally relevant up- and downstream signaling elements.
Alveolar distension is an important mechanism of lung morphogenesis and
dysmorphogenesis alike (Fig. 1).
The paracrine paradigm in Fig. 1 incorporates many of the
molecular regulatory motiffs enumerated by the previous presenters. Dr.
Minoo highlighted the importance of Shh in normal lung
development. Shh determines the expression of PTHrP in type
II epithelial cells. Dr. DeMayo underscored the importance of
C/EBP-, which regulates adipocyte differentiation-related protein
and leptin expression in fibroblasts. As earlier indicated, when PTHrP
signaling is interrupted, the mesodermal lipofibroblasts default to the
myofibroblasts, which Dr. Schuger has elucidated for us. Dr. Shannon
has elegantly shown us how epithelial-mesenchymal interactions
determine lung morphogenesis. Thus we have forged a link between normal
and abnormal lung development through common pathways of homeostasis
and repair.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. S. Torday, Dept. of Pediatrics and Obstetrics and Gynecology, Harbor-Univ. of California Los Angeles Research and Education Institute, Torrance, CA (E-mail: jtorday{at}gcrc.rei.edu).
1 Presented by P. Minoo.
2 Presented by J. Shannon.
3 Presented by F. DeMayo.
4 Presented by L. Schuger.
5 Presented by J. S. Torday.
10.1152/ajplung.00144.2002
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