News Physiol Sci 14: 260-267, 1999;
1548-9213/99 $5.00
News in Physiological Sciences, Vol. 14, No. 6, 260-267,
December 1999
© 1999 Int. Union Physiol. Sci./Am. Physiol. Soc.
From Limbs to Lungs: A Newt Perspective on Compensatory Lung Growth
Kirk A. Gilbert and
D. Eugene Rannels
K. A. Gilbert is in the Department of Cellular and Molecular Physiology and D. E. Rannels is in the Department of Cellular and Molecular Physiology and the Department of Anesthesia at The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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Abstract
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Partial lung resection initiates compensatory growth of remaining lobes to restore pulmonary structure and function. Mechanisms underlying this response are not well defined. This article considers molecular pathways involved in control of amphibian limb regeneration and tissue pattern formation for novel insight into the understanding of compensatory lung growth.
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Introduction
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It has been known for many years that a variety of species exhibit a capacity for regenerative or compensatory growth of limbs or organs. Regenerative growth is particularly well-known in Amphibia of the order Urodela. Adult salamanders and newts can regenerate severed tails, digits, or even complete limbs, restoring structure and function over relatively short intervals. Although regenerative responses are not prevalent in other vertebrates, organs of numerous mammalian species are recognized to exhibit compensatory growth in response to appropriate stimuli. The latter processes involve accelerated growth of existing tissue rather than direct replacement of a resected organ. A familiar example of this response is hypertrophic growth of skeletal or cardiac muscle cells in response to imposition of an elevated workload. Similarly, both mass and function of partly resected liver or lung are restored through compensatory hyperplastic growth of the remaining tissue.
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Compensatory growth of the lung
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Research published more than 100 years ago established that partial pneumonectomy stimulates compensatory growth of the remaining lung lobes. Work in numerous laboratories, particularly during the last 30 years, has developed a basis for understanding both the sequence and consequences of the response, which replaces the resected lobe(s) with functional lung tissue of normal structure. Contemporary literature pertinent to the topic has been summarized and reviewed previously (7). Rather than covering similar ground in this article, we describe the response briefly before discussing its value as a model of normal lung growth as well as its utility for investigation of biological processes relevant to lung development and to repair of lung tissue. In this context, we take a fresh perspective on approaches to unravel the mechanisms that underlie its sequence and regulation.
In 1939, Cohn (6) published studies that provided a basis for much of the subsequent research pertaining to compensatory growth of the lung. In the introduction to his landmark paper, he stated that the increase in lung mass after partial pneumonectomy "is due solely to the mechanical stimulus of the change in pull exerted by the alteration in size of the thoracic cage which the lung must fill." Cohn demonstrated that compensatory growth rapidly restores normal lung mass through pathways regulated by age and initiated by mechanical stretch of the lung parenchyma, reflected postoperatively in increased inflation of the remaining lobes due to more negative intrapleural pressure. He thus recognized that biomechanical signals elicit a regulated growth response in lung tissue.
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Characteristics of postpneumonectomy lung growth
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Modern studies confirm that after surgical removal of the single lobe of the left lung in rats, the rate of growth of the remaining lobes increases two- to eightfold, depending on the age of the animal. Rapid growth is maintained until total lung mass is restored (Fig. 1
). The resulting tissue exhibits normal compliance and physiological properties. Morphometric analysis reveals restoration of tissue structure and cellular composition. Thickness and surface area of the diffusion barrier are comparable to lungs of sham-operated control animals (12), and alveolar number is increased (Fig. 2).
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FIGURE 1. Right lung growth after left pneumonectomy in rats. Male Sprague-Dawley rats (225–250 g body wt) were subjected to left pneumonectomy (PNX) on day 0, and subsequent change in right lung mass was followed postoperatively for 2 wk. After a short lag, lobes of right lung grew rapidly to restore normal total lung mass by day 14 (arrow). A second group of animals was adrenalectomized (ADX) 5 days before PNX (ADX-PNX). In this case, rate of compensatory lung growth was doubled, such that normal total lung mass was restored by day 7 (arrowhead). By day 14, right lung mass in ADX-PNX animals was 40% greater than that in adrenal-intact controls. Effect of ADX on response to PNX was prevented or reversed in ADX animals treated with hydrocortisone acetate (data not shown). Data are normalized to day 0 PNX value. See Ref. 7 for references.
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FIGURE 2. Effect of adrenalectomy on pneumonectomy-induced increases in alveolar number and volume. Effects of left pneumonectomy (PNX) on alveolar number and volume were quantified morphometrically in right lungs of adrenal intact rats and of animals subjected to bilateral adrenalectomy (ADX) 5 days before sham thoracotomy (Sham) or PNX (12). Fourteen days after PNX, alveolar number increased significantly (*P < 0.05) in right lungs of both PNX and ADX-PNX animals (top), in parallel with increasing right lung mass (see Fig. 1 ). Although alveolar volume increased modestly after PNX (bottom left), no effect was evident in ADX-PNX animals (bottom right). Taken with additional data (not shown; see Ref. 12), these observations suggest that adrenal corticosteroids regulate rate and extent of lung growth along with alveolar formation after PNX.
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Lung growth after pneumonectomy is modulated by the hormonal status of the animal, most dramatically by adrenal hormones (7). In rats adrenalectomized before left pneumonectomy, both the rate and extent of gain in right lung mass are enhanced by mechanisms that can be prevented or reversed by administration of adrenal corticosteroids at noncatabolic doses. Although adrenal-intact animals restore total lung mass in 14 days, only 7 days are required in their adrenalectomized counterparts (Fig. 1). In the latter case, accelerated growth continues such that by day 14, right lung mass is 40% greater than that in adrenal-intact or in corticosteroid-treated adrenalectomized controls. Compensatory lung growth thus proceeds more rapidly and to a greater extent in adrenalectomized animals. This accelerated gain in mass is accompanied by dissociation of the time courses of tissue growth and remodeling. Consequently, significant but transient thickening is evident in the alveolar wall of adrenalectomized-pneumonectomized animals; these changes are reflected in reduced tissue compliance as well as in the ultrastructure of the diffusion barrier. These observations suggest that adrenal hormones are essential to maintain coordinate accumulation of both cellular and noncellular components of the growing lung (12).
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Mechanisms of the response to pneumonectomy
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Regulation of lung growth after pneumonectomy is not well understood. Historically, four related hypotheses have been advanced to address the basis of the response (Fig. 3). These have focused on putative regulatory roles for 1) hypoxia, 2) increased blood flow to the remaining lobes, 3) increased alveolar inflation, and 4) production and release of soluble growth factors during the early postoperative interval. Each of these possibilities has been studied and discussed at length, but none has been clearly implicated at the mechanistic level to account for, or to regulate, the growth response. Recent investigations argue against a major role for hypoxia or elevated blood flow. In contrast, other data support probable roles for mechanochemical signaling pathways and/or soluble mediators of growth and differentiation.
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FIGURE 3. Schematic of compensatory lung growth after left pneumonectomy (PNX) in rat. Immediately after removal of left lobe, several regulatory factors are proposed to contribute to initiation of compensatory growth. These, in turn, can provide either a mechanical or a chemical stimulus to remaining lung tissue to initiate a multifactorial cascade of events leading to coordinated tissue growth. Within this cascade, it is likely that several classes of genes are involved, including those regulating pattern formation and branching morphogenesis. Local growth factor- and receptor-mediated events within the remaining tissue are also likely to be involved in this process. Coordination of these as yet undefined events results in rapid compensatory lung growth and preservation of lung tissue structure and gas exchange function. RA, retinoic acid; RAR, RA receptor; FGF, fibroblast growth factor; FGFR, FGF receptor.
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Significance of the response to pneumonectomy
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Observations that fully functional lungs can be stimulated to grow in vivo in a rapid and coordinated manner are of both physiological and pathophysiological interest, particularly given that the resulting tissue ultimately exhibits structural and functional characteristics of the intact lung. Successful strategies to enhance similar growth of the human lung would thus clearly be clinically significant. An approach to accelerate or initiate lung growth would benefit cases of developmental pulmonary hypoplasia as well as those involving destruction or surgical resection of lung tissue. Practical application of the observations outlined above is limited by a lack of understanding of the molecular and cellular regulatory mechanisms that underlie the response. These issues are best addressed by dissection of the process at the most basic level, in a manner similar to that applied to regulation of other complex phenomena of development and growth.
The response to pneumonectomy is regulated by mechanical and hormonal signals, each of which is relevant not only to growth and development of lung but also to a spectrum of other tissues. These signals initiate coordinated hyperplastic growth of multiple lung cell populations, causing cells to enter the cell cycle and progress to form complex and highly organized tissue. Compensatory lung growth and remodeling thus involves regulated pathways of cell cycle activity, cellular differentiation, synthesis and organization of connective tissue components, vascular growth, and tissue remodeling.
These observations not withstanding, little attention has been given to the potential of the pneumonectomy model for investigations of regulation of these processes. This, in part, reflects the complexity of the integrated growth response, which involves multiple cell types and is tightly coordinated. Even in adrenalectomized animals, in which tissue remodeling is slowed relative to growth, it has been difficult to resolve the sequence of cellular events that underlie the response to pneumonectomy (12). For example, it is not known whether growth of the pulmonary capillary bed is a proximal event or whether it is necessary to lay down an extracellular matrix framework before cell division and tissue growth are accelerated. Resolution of these possibilities is complicated by the heterogeneous structure and composition of lung tissue.
A more complete understanding of the response to pneumonectomy might be developed more readily if the process were viewed in the context of more clearly defined precedents. Such precedents include pattern formation during development both of Drosophila and of the mammalian lung as well as the processes of vertebrate limb development and regeneration. The observation that homologous gene products are involved in patterning and tissue growth in these diverse systems suggests that these genes may play a role in compensatory growth of the lung.
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Can we learn from lower vertebrates?
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The compensatory growth response that occurs after partial lung resection in mammals has been recognized for over a century. Likewise, the ability of some animals, namely, those of the order Urodela (consisting of salamanders and newts), to regenerate entire body parts was first described over two centuries ago. There are striking parallels between events that occur during limb regeneration in lower vertebrates and the regulatory pathways involved in lung development, particularly those involving specific growth factors and patterns of gene expression. Although there are obvious differences between the two growth models, such parallels provide an intriguing opportunity to examine similarities between salamander limb regeneration and mammalian compensatory lung growth in the context of pattern formation and branching morphogenesis. Recent insights concerning amphibian limb regeneration may provide a unique framework for devising new strategies to further define the process of compensatory lung growth.
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Amphibian limb regeneration
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The urodele amphibians are the only adult vertebrates known to be capable of complete limb regeneration. Although limb regrowth is the most characterized regenerative process in urodeles, they can also regenerate other body parts including tail, jaws, and ocular tissues such as the retina and lens. After amputation, limb regeneration commences at the zone of polarizing activity (ZPA) formed by rapid migration of epithelial cells to the site of limb transection (2). The formation of this wound epidermis is required for distal outgrowth of the regenerating limb. Skeletal, myogenic, and connective tissues located beneath the wound epidermis morphologically dedifferentiate and then reenter the cell cycle, forming a blastema of undifferentiated mesenchymal cells at the limb stump. These cells proliferate rapidly and then progressively exit the cell cycle, redifferentiating into cartilage, connective tissue, and muscle of the regenerate. Limb regeneration is rapid, the response being both functionally and morphologically complete within 6–10 wk.
The amphibian limb blastema is morphogenetically autonomous, that is, stimuli from adjacent differentiated tissue are not required for blastemal tissue redifferentiation to occur, such that if a blastema is transplanted to a different location, it will retain the regenerative capacity appropriate for the tissue at its level of origin. Various properties that govern normal limb regeneration are thought to be inherited by parent cells at the wound epidermis during dedifferentiation; cell determination takes place very early in the response. Interestingly, the blastema only forms structures distal to the level of amputation such that amputation at the shoulder gives rise to an entire limb, whereas amputation at the wrist gives rise only to the hand and digits. These observations argue against the earlier hypothesis that a pluripotent mass of regenerative cells receives continuous guidance from the local tissue environment.
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Molecular regulation of limb regeneration
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Undefined intrinsic properties in amphibian mesenchymal cells that permit dedifferentiation in response to limb resection distinguish these cells from their mammalian counterparts. Recently, attention has focused on several families of gene products and growth factors that play a role in vertebrate limb regeneration and in the related processes of limb development and injury-induced tissue repair. Indeed, several recently characterized products of diverse gene families are essential to pattern formation and branching morphogenesis throughout the body axis of the developing vertebrate. Although many of these genes are conserved from Drosophila to humans, their mechanisms of action are only in the early stages of characterization. Products of these genes include growth factors and morphogens, cell surface and nuclear receptors, components of signal transduction pathways, and transcription factors.
Examples of specific molecules involved in the process of limb development and regeneration include the vitamin A derivatives, or retinoids, and their receptors; fibroblast growth factors (FGFs) and their receptors; homeobox (hox) genes; and segment polarity genes such as the wnt and hedgehog (hh) gene families. A significant number of these genes were first characterized on the basis of specific mutations in Drosophila; homologs have more recently been cloned in several vertebrate species, including urodeles. Many of the genes thought to be involved in regulation of vertebrate limb development are either constitutively expressed or induced in the adult urodele limb, although in some cases temporal and spatial patterns of expression are altered. Thus the possibility exists that many of the cellular and molecular mechanisms that regulate limb morphogenesis and development are recapitulated during limb regeneration. Understanding these processes as they relate to limb growth may further our understanding of the adult growth potential in other vertebrate tissues, including the lung.
The following text introduces several gene families that play a role in limb development and regeneration as well as in lung development. Although this treatment is not all-inclusive, discussion of these gene families provides a framework for understanding molecular mechanisms that may underlie both general tissue growth and compensatory growth of the lung.
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Retinoids and retinoic acid receptors
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Vitamin A and its derivatives are collectively referred to as retinoids. Retinoids are signaling molecules that play an important role in cellular differentiation and maturation in the mammalian lung, as well as in growth, patterning, and repatterning of nonpulmonary vertebrate tissues. One of the best characterized derivatives, retinoic acid (RA), acts by direct interaction with a group of nuclear protein retinoic acid receptors, or RARs. RARs are members of the steroid/thyroid hormone superfamily of receptors and are capable of binding to specific retinoic acid response elements (RAREs) of target genes to activate their transcription. RA has a profound effect in regulating expression of diverse gene products involved in cellular differentiation and tissue morphogenesis. Exogenous RA treatment during development can alter normal patterning of various tissues. For example, exogenously administered retinoids affect patterning of both developing and regenerating vertebrate limbs. During chick development, placement of RA-soaked beads into the developing limb bud induces an ectopic ZPA, resulting in limb duplication. Likewise, in the regenerating urodele limb bud, RA exposure acts in a concentration-dependent fashion to alter the positional identity of the regenerate.
In developing mammalian lung, exogenous RA has been shown by in situ hybridization to alter expression of genes involved in pattern formation and branching morphogenesis (4). RA treatment in early postnatal rats increases alveolar formation by as much as 50%; additionally, RA reverses the dexamethasone-induced inhibition of alveolar formation (9). Qualitatively similar observations have been reported in embryonic rat lung explants (10). RA treatment in fetal mouse lung explants alters expression of pattern-related genes such as sonic hedgehog (shh) and fibroblast growth factor 10 (fgf10) (1). Thus retinoids exhibit a strong influence on pattern formation and branching morphogenesis, such as occur in development of both limb and lung.
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Homeobox genes
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Expression patterns of homeobox, or hox, genes are also altered by RA exposure. Vertebrate hox genes are related to the Drosophila antennapedia (Antp) and bithorax (BX-C) complexes, which comprise the Drosophila homeotic complex HOM-C. In flies, mutations in these genes cause homeotic transformations in which one body segment is transformed into structures normally found in other body segments. The vertebrate hox complex consists of four clusters, hoxa, hoxb, hoxc, and hoxd, and totals at least 38 different genes. Hox genes are expressed in overlapping regions of the embryo; they regulate pattern formation and positional signaling along the developing anterior-posterior axis.
Hox genes respond to RA through an RA-responsive locus control region and/or RAREs located within the hox clusters. Hox proteins, in turn, bind to DNA as monomers to activate transcription of downstream target genes, the products of which are involved in a spectrum of complex cellular processes and in both cell-cell and cell-matrix interactions. Several hox genes are important in both limb and lung development, with nearly one-half of the known vertebrate hox genes being expressed at some point during development of the mouse lung. The fact that hox gene expression is restricted to the mesenchyme underscores the importance of mesenchymal-epithelial interactions in cellular differentiation.
Developmentally expressed hox genes are again expressed in the urodele model of limb regeneration. This observation opens the possibility that some hox genes required for normal lung development may also be involved in regulatory mechanisms that underlie compensatory lung growth. For example, Hoxb-5 protein expression peaks at embryonic day 14.5—15.5 in mouse lung and then decreases through postnatal day 2 (14). This interval spans from the pseudoglandular to the terminal saccule phase of development, suggesting a role for Hoxb-5 expression in lung branching morphogenesis. The fact that new alveoli are formed after pneumonectomy suggests that terminal branching occurs during this process. Thus Hoxb-5 may be reexpressed during formation of new alveoli after pneumonectomy. Prospects such as this remain unexplored.
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Wnt genes
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The wnt family of genes is also important in pattern formation and development. Wnt genes are related to the Drosophila segment polarity gene wingless (wg) and to the mouse homolog int-1 (hence the term "wnt"). They comprise at least 16 mammalian family members that encode multipotent secretory glycoproteins involved in patterning of the body axis. Receptors for Wnt proteins, identified only recently, comprise a group of at least eight mammalian members of the Frizzled (Fz) receptor family (named for the Drosophila tissue polarity gene frizzled). Fz receptors are part of the seven-transmembrane-spanning receptor superfamily; they incorporate an extracellular NH2-terminal Wnt binding domain and an intracellular COOH-terminal tail. Binding of Wnt to the Fz receptor likely activates a unique signal-transduction cascade, although the pathway for receptor-mediated Wnt signaling is not well understood.
Little is known about the function of Wnt proteins during lung development. A recently identified member of the mouse wnt gene family, wnt13, is expressed in the lung bud tip during embryogenesis (15). Several other mammalian wnt genes are developmentally expressed in an anterior-to-posterior and dorso-ventral gradient throughout the body axis, but the exact role that these genes play in development is not known.
Graded expression of at least four amphibian wnt genes has been observed along the anterior-posterior axis in the regenerating tail of adult urodele amphibians (5), although wnt expression has received little attention in this context. During chick and mouse limb development, however, some wnt genes are expressed in the limb bud tips, and altering the level of expression of specific wnt gene products can result in abnormal limb development. Thus the wnt genes encode an important class of signaling molecules that appear to be necessary for normal embryonic patterning and development, the mechanistic details of which are currently being deciphered. Further characterization of wnt gene expression will provide information regarding the mechanisms of action of Wnt proteins and may provide clues as to their role in lung branching morphogenesis and/or compensatory lung growth.
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Fibroblast growth factors and receptors
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The family of FGFs comprises powerful functional regulators of development, cell proliferation and differentiation, and the response to injury. The FGF family includes at least 18 unique members. Four types of high-affinity FGF receptors (FGFRs) have been identified (FGFR-1, -2, -3, and -4); they contain an NH2-terminal extracellular FGF-binding region, a single membrane-spanning region, and an intracellular COOH-terminal tyrosine kinase region. Because of alternate mRNA splicing, there are 48 known isoforms each for FGFR-1, -2, and -3, yielding a total of at least 145 different FGFR proteins. FGF-FGFR interaction activates intracellular tyrosine kinase, which can ultimately lead to induced expression of specific genes regulating patterning and branching.
FGF family members and their receptors are important in both lung and limb development. FGFR-1, -2, -3, and -4 subtypes are expressed in embryonic lung along with many FGFs. During development of mouse lung, Fgf10 is expressed in mesenchyme at the distal tips of developing lobes (1). The branchless gene in Drosophila is the homolog to mammalian Fgf10; its expression in the surrounding mesenchyme is required for normal branching to occur in the insect tracheal system (13). Addition of recombinant human FGF-10 to cultured E11.5 mouse lungs induces significant budding of the endoderm within 48–60 h, both in the presence and absence of mesoderm (1).
In addition to FGF-10, FGF-1 and FGF-7 are also expressed in embryonic lung; exogenous treatment with these growth factors promotes lung bud formation and epithelial proliferation, respectively (3). These findings support the view that localized production of FGF in the mesenchyme allows direct action on the endoderm to promote branching morphogenesis. This conclusion is supported by the observation in transgenic animals that a dominant negative FGFR-2 gene targeted to developing lung tissue using the SP-C promoter completely blocks lung bud branching and epithelial cell differentiation (11). Although development of other tissues in the same animals appeared normal, lung bud outgrowth occurred only as two simple, unbranched epithelial tubes (11). Thus mesenchymal-epithelial interactions as well as FGF-FGFR interactions appear to be required for normal branching morphogenesis in the mammalian lung. The potential role of FGF-FGFR interactions in compensatory lung growth has not been explored.
FGF signaling is also important in both limb development and regeneration. Application of FGF-1, FGF-2, or FGF-4 to developing limb buds can cause limb duplication in the chick embryo, similar to the repatterning effects of exogenous RA treatment. The same phenomenon occurs in response to either exogenous FGF-8 or FGF-10. Indeed, the release of growth factors at or near the wound surface of the amputated amphibian limb, as well as in the developing vertebrate limb bud, coincides with the expression of several genes involved in pattern formation and branching morphogenesis, such as those genes described above.
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Hedgehog genes
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Another group of genes important to the process of normal pattern formation is the hedgehog family, with sonic hedgehog being the most characterized in vertebrates. Other members include indian hedgehog and desert hedgehog. Hedgehog (hh) genes are segment polarity genes that were first described in Drosophila. These genes encode secreted signaling proteins that play a key role in regulating branching morphogenesis. The Sonic hedgehog (Shh) signaling pathway involves a unique mechanism of signal transduction comprising at least two additional membrane-bound proteins, the hedgehog receptor protein Patched (Ptc) and a companion signaling protein, Smoothened (Smo). In the absence of Shh, Ptc represses the constitutive signaling activity of Smo by forming a Ptc-Smo complex; binding of Shh to Ptc releases Smo, which then acts downstream of Shh.
During mouse lung development, shh mRNA expression is highest in epithelium at the tips of the distal lung buds, with Ptc expression highest in surrounding mesenchymal cells. The opposite is true for the developing chick limb bud, in which shh expression is limited to the mesenchyme and colocalizes with the ZPA. Shh is also expressed in cells surrounding the embryonic newt limb bud and is reexpressed in the wound epidermis of the regenerating newt limb blastema. Cells expressing shh can cause limb duplication when implanted into developing chick limb buds in a manner similar to that induced by placement of RA-soaked beads. Indeed, exogenous RA treatment at the anterior portion of the limb bud induces shh expression, as does RA treatment of embryonic mouse lung explants.
Shh expression coincides with changes in expression patterns of specific hox, wnt, and FGF family members, thus revealing that many of these signaling pathways (RA, FGF, Wnt, Hox) are linked to coordinate normal pattern formation in specific tissues. Additional molecular pathways not addressed in this review likely contribute to the overall regulation of tissue patterning and growth. Similar to shh, the Notch signaling pathway is thought to contribute to complex events during both normal and cancerous growth. This pathway includes the Notch family of receptors, the Jagged/Serrate/Delta family of ligands, and Fringe-related proteins, which regulate ligand signaling through the Notch receptor. Although evidence exists that Notch signaling contributes to coordinated growth and patterning in the developing Drosophila wing and vertebrate limb (8), its role in lung development remains to be explored.
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Summary and conclusions
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Development of both limb and lung involves three-dimensional pattern formation and branching morphogenesis along the anterior-posterior, dorsal-ventral, and proximal-distal axes. Many of the genes responsible for normal patterning are expressed in both of these very different tissues, where their abnormal expression causes abnormal development. Only some of these genes are discussed above; the list is by no means complete. The unique ability of several adult amphibian species to regenerate identical copies of complete body parts after amputation remains one of the most intriguing phenomena in modern biology. Similarly, the capacity of adult mammalian tissues to compensate both structurally and functionally for tissue loss due to injury or to partial resection begs the question, "How does this occur?"
Our primary goal in this article is to stimulate a reexamination of the process of compensatory lung growth in the context of amphibian limb regeneration. The hypothesis is that molecular events essential to limb regeneration may represent common pathways of repair and compensatory growth in other species and in other tissues. Although it has been recognized for over a century that the lung is capable of compensatory growth, we know surprisingly little about the mechanisms that underlie this process. Recent observations in diverse model systems now provide a template for a fresh approach to dissect the regulation of a biologically and medically significant response.
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Acknowledgments
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Work from the laboratory of the authors was supported by grant HL-20344 from the National Heart, Lung, and Blood Institute.
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Introduction
Compensatory growth of the...
