PTHrP/PTHrP receptor signaling is upregulated by stretch- ing alveolar type II cells and intersitial lung fibroblasts, whereas overdistension downregulates PTHrP ...
(Evolutionary) Translational Review Deconvoluting Lung Evolution Using Functional/Comparative Genomics John S. Torday and Virender K. Rehan Department of Pediatrics, and Department of Obstetrics and Gynecology, Harbor-UCLA Research and Education Institute, Torrance, California
Parathyroid Hormone–related Protein (PTHrP) is a highly evolutionarily conserved, stretch-regulated gene that is necessary for the embryonic transition from branching morphogenesis to alveolization of the lung. It is expressed throughout vertebrate phylogeny, beginning with its expression in the fish swim bladder as an adaptation to gravity; microgravity downregulates the expression of PTHrP by alveolar type II cells, and by bones from rats exposed to 0 ⫻ g, suggesting that PTHrP signaling has been exploited for adaptation to 1 ⫻ g. PTHrP/PTHrP receptor signaling is upregulated by stretching alveolar type II cells and intersitial lung fibroblasts, whereas overdistension downregulates PTHrP and PTHrP receptor mRNA, further suggesting an evolutionary adaptation. Both surfactant homeostasis and alveolar capillary perfusion are under PTHrP control, indicating that alveolization and ventilation/perfusion matching may have evolved under the influence of PTHrP signaling. Phylogenetic analysis of lung evolution reflects the concomitant increases in alveolar surface area and surfactant production by “amplifying” the PTHrP pathway signal. This mechanism is discussed as a function of increased evolutionary respiratory demand to keep up with the increased metabolic demand for oxygen, and the role of the PTHrP signaling mechanism in leveraging this process.
Lung evolution is an excellent model for studying how genes signaling through cell–cell interactions have been integrated into this complex biological system through Darwinian selection (1). One gene in particular—Parathyroid Hormone–related Protein (PTHrP)—has been shown to be necessary for the formation of alveoli, or terminal air sacs, which are the structural and functional means of adaptation to the metabolic drive for oxygen (2). The evolutionary amplification of PTHrP signaling may well be the proximal cause of the developmental and phylogenetic modeling and remodeling of the alveolar wall. The following is a proposed cell/molecular mechanism for deciphering the hierarchical structure, function, and repair of the lung across vertebrate species.
Phylogeny as an Algorithm for Understanding How PTHrP Signaling “Molds” the Lung Phenotype Lung development and adaptation to air breathing were selected as a model process for molecular evolution largely because they
(Received in original form January 21, 2004) Address correspondence to: J. S. Torday, Harbor-UCLA Medical Center and Education Institute, 1124 W. Carson Street, RB-1, Torrance, CA, 90502. E-mail: jtorday@ gcrc.rei.edu Abbreviations: Adipose Differentiation Related Protein, ADRP; Parathyroid Hormone–related Protein, PTHrP. Am. J. Respir. Cell Mol. Biol. Vol. 31, pp. 8–12, 2004 DOI: 10.1165/rcmb.2004-0019TR Internet address: www.atsjournals.org
are well defined with regard to their phylogenetic origins (3), morphogenesis (4), structure (5), function (6), and repair (7) at the molecular (8), cellular (9), tissue (10), and organ levels (11). The intense, reductionist interest in lung biology is largely due to the focus of both biologists and clinicians on the surfactant system (12), which has been well characterized with respect to both health and disease, from the bench to the bedside over the last 50 years (13). Among mammals, embryonic lung development is subdivided into two major phases: branching morphogenesis and alveolization. Fortuitously, it has been observed that deleting the PTHrP gene results in failed alveolization (14), which is the primary vertebrate evolutionary strategy for the transition from water to air (15). This, and the fact that PTHrP and its receptor are highly conserved (PTHrP is expressed as far back in evolution as insects [16]), are stretch-regulated (17), and form a signaling pathway linking the endodermal and mesodermal germ layers of the embryo to the blood vessels (18), has compelled us to investigate its overall role in lung phylogeny and evolution. Figure 1 represents a broad view hypothesis, which predicts that for vertebrates with progressively increasing metabolic rates (be they elevated as a result of being warm-blooded and active, or cold-blooded species at high temperature) lung complexity (defined as increased surface area, decreased alveolar wall thickness, and increased activity of lung surfactant, as indicated on the y axis) will increase. Such a change might be constituted by an increase in PTHrP signaling strength, as reflected on the x axis. Here we explore this hypothesis in detail. The key functional feature of PTHrP signaling is that by simultaneously stimulating the activities of both PTHrP and its receptor (19), alveolar wall distension simultaneously increases surfactant production and alveolar capillary blood flow—the ˙) ˙ /Q physiologic process referred to as ventilation/perfusion (V ˙ matching is the net effect ˙ /Q matching. It is well recognized that V of the evolutionary integration of cell/molecular interactions by which the lung and pulmonary vasculature have functionally adapted to the progressive increase in metabolic demand for oxygen (20). The structural adaptation for the increased efficiency of gas exchange is 3-fold: (i ) the progressive thinning of the alveolar wall (21), (ii) the concomitant decrease in alveolar diameter (22), and (iii) the maximal increase in total surface area (23). We suggest that these structural adaptations could have resulted from the phylogenetic amplification of the PTHrP signaling pathway between embryonic germ layers. PTHrP signaling through its receptor is coordinately stimulated by stretching the alveolar parenchyma (24). Binding of PTHrP to its receptor activates the cyclic AMP-dependent Protein Kinase A signaling pathway (25). Stimulation of this signaling pathway
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Figure 1. Major trends in lung evolution are plotted against epochs in vertebrate evolution. Briefly, metabolic drive for oxygen puts selection pressure on the evolution of lung structure, resulting in thinning of the alveolar septa, decreasing alveolar size, and increasing the production of surface active material.
results in the differentiation of the connective tissue cells of the alveolar wall, characterized by increased expression of specific nuclear transcription factors and their down-stream signaling targets Adipose Differentiation Related Protein (ADRP) and leptin. ADRP is necessary for the trafficking of substrate for surfactant production (26), and leptin stimulates the differentiation of the alveolar type II cell (27). PTHrP could affect the cellular composition of the alveoli in at least two ways: (i ) it inhibits lung fibroblast growth (14, 28; J. S. Torday, unpublished observation), which may account for the thinning of the alveolar wall, and (ii) the connective tissue stimulation of epithelial cell type II cell differentiation by leptin (29) could similarly inhibit epithelial growth (30). The combined effects would lead to natural selection for the progressive, concomitant decreases in both alveolar diameter and alveolar wall thickness through ontogeny (31) and phylogeny (32) that increase the surface areato-volume ratio of the lung. Mechanistically, PTHrP inhibits myofibroblast differentiation by inhibiting Gli (33), the first target in the constitutive mesodermal Wingless/int (Wnt) pathway (34). PTHrP induces the adipocyte-like mesodermal lipofibroblast, which facilitates surfactant production by alveolar type II cells (17, 24–27). The concommitant inhibitory effects of PTHrP on fibroblast and type II cell growth, in combination with PTHrP augmentation of surfactant production, would have the net effect of distending and “stenting” the thinning alveolar wall, synergizing the upregulation of PTHrP, and physiologically stabilizing what otherwise would result in an unstable structure that would collapse in “compliance” with the Law of Laplace (35). Evidence supporting the hypothesis that PTHrP regulates control of lung growth comes from the study of three dramatically different types of lung (36): the single-chambered lungs of fish, frogs, and lizards; the bronchoalveolar lung of mammals; and the cross-current saccular lung of birds. The frog and lizard terminal air sacs are called faveoli, which are up to 100 times larger in diameter (22) than the alveoli of a similarly sized mammal. Moreover, although the epithelial lining cells can be distinguished as type I and type II cells, the type II cells are not as well delineated as those of mammals (22). In addition, the alveolar wall is heavily populated with myofibroblasts (3), which are muscle-like connective tissue cells. Both the large size of the frog faveolus and its inherently high ability to expand and contract
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obviate the primary physiologic requirement for surfactant production among vertebrates for prevention of alveolar collapse. In addition, the faveolar interstitial muscle cells mediate its expansion and contraction for gas exchange. The prevalence of myofibroblasts may be due to decreased PTHrP signaling resulting from decreased stretching. In mammals, the conducting and terminal airways of the lung are convoluted, facilitating gas exchange in association with increasing metabolic demand for oxygen. The structural and functional changes seen during phylogeny may be explained by the increased amplification of PTHrP signaling through different levels of distension of the alveolar wall in different phyla, as depicted in Figure 2. PTHrP signaling inhibits myofibroblast differentiation by down-regulating the Wnt pathway, thus potentially explaining the trend toward decreasing numbers of myofibroblasts in the lungs with smaller alveoli and thinner alveolar walls, leading to a concomitant increase in the efficiency of gas exchange (37). Moreover, Daniels and Orgeig have demonstrated that the amount of pulmonary surfactant per surface area declines, but the level of saturation of the phospholipid increases between frogs and reptiles, on the one hand, and among mammals, on the other (38). It is likely that the increased saturation and also the greater turnover of surfactant in mammals would act to sustain the structural integrity of the smaller alveoli.
How Can PTHrP Signal Amplification Explain Lung Evolution? Up to this point the explanation of how PTHrP has promoted the structural and functional phylogeny of the lung is based upon mechanisms relevant to lung physiology. However, the Baldwin Effect—the ability of organisms to genetically inherit traits through embryonic development—would account for the evolutionary retention and amplification of PTHrP signaling, because the capacity to increase the efficiency of gas exchange would be expected to confer a selective advantage. We have hypothesized that PTHrP signaling is amplified phylogenetically from colder, relatively inactive animals such as frogs, to high-activity, high body temperature, warm-blooded organisms such as mammals (see schematic in Figure 2) due to the selection pressure for metabolic efficiency, which in turn selects for increased structural and functional efficiency of oxygenation. The complementary effects of PTHrP on alveolar structure and function are hypothesized to facilitate this process. It could be argued that the interrelationship between PTHrP signaling and the evolution of the lung are circular reasoning, i.e., that the increased surface area would naturally distend the parenchyma, leading to increased PTHrP signaling. Several aspects of this mechanism, however, suggest that the effect of PTHrP on the evolution of the gas exchange unit is causal: (i ) PTHrP is necessary for alveolization (14); (ii) PTHrP is a gravisensor (19), suggesting that it facilitates adaptation to gravity; (iii) PTHrP is nonlinearly affected by stretch (19, 39), potentially explaining the so-called overengineering of the bird lung (37); (iv) signaling pathway determines the myogenic and adipogenic fibroblast phenotypes of the alveolar interstitium (14, 17, 24–27, 39), providing a mechanism for the phylogenetic transition from a muscle cell–dominated interstitium in amphibians and reptiles to the fat cell–dominated interstitium of mammals (40, 41); and (v ) inhibition of fibroblast proliferation may account for the thinning of the interstitium (42).
Avian Lung Structure–Function Relationship: The Exception that Proves the Rule As is often the case, the exception to the hypothesized amplification of PTHrP signaling through ontogeny and phylogeny may
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Figure 2. Structural evolution of the organ of gas exchange. During phylogeny from fish to mammals, the organ of gas exchange becomes more and more complex, increasing in surface area to accommodate the metabolic demand for oxygen. This is particularly true of the arboreal conducting airways and clustering of alveoli in the mammalian lung. Cellular changes in the interstitium of the lung from amphibians to reptiles and mammals are characterized by a decrease in myofibroblasts and an increase in lipofibroblasts. There is a concomitant decrease in the diameter of the alveoli. We hypothesize that the structural changes are due to the progressive increase in the PTHrP/PTHrP receptor amplification signaling (x axis), which enhances surfactant produc˙ matching (y axes). ˙ /Q tion and V
prove the rule. Birds are exceptional in vertebrate phylogeny because their lungs lack alveoli; indeed, the lung is stiff and is fixed to the dorsal thorax, preventing the expansion and contraction of the lung seen in amphibians, reptiles, and mammals. Yet the bird lung possesses type II cells that express PTHrP (43) and surfactant (44); in birds the surfactant system is not necessary for the prevention of alveolar collapse, and may, as in amphibians, only take on such roles as preventing exudation of lymph from the vasculature (45), or as a local immune system (46). Birds may have evolved “overengineered” lungs (32) in response to the selective advantage of efficiently oxygenating in flight. Bird lungs are up to four times more efficient in exchanging oxygen and carbon dioxide with the atmosphere as mammals. Because PTHrP is necessary for bone morphogenesis (47), and the hollow bones of many birds are linked to the respiratory system (because they contain part of the air sac system), control of development of the lung and skeletal phenotypes may be tightly linked. It is noteworthy that the chick PTHrP signaling mechanism is relatively “weak” compared with that of mammals, suggesting a convergent molecular adaptation to dampen PTHrP signaling in both the lung and bone of avians possibly as an evolutionary strategy for flight. To paraphrase the old chestnut about which came first, a systematic study of PTHrP signaling in the lung and bone of flightless versus flying birds might provide the solution.
Do Stretch Effects on PTHrP Expression Reflect its Role in Adapting to Unit Gravity? Both lung and bone must be kept under tension to maintain functionality (19, 48). Since PTHrP is an interactive paracrine factor that is necessary for the homeostatic control of both bone and lung, and stretch affects PTHrP expression in both (19), it was hypothesized that loss of tension on bone or lung cells, both of which express PTHrP, would cause a decrease in PTHrP expression. Fetal rat lung alveolar type II cells were suspended in “free-fall” using a Rotating Wall Vessel to mimick 0 ⫻ g (49). Cells were harvested periodically and analyzed for PTHrP mRNA expression. PTHrP expression decreased significantly over an 8- to 12-h period. The decreased expression of PTHrP remained stable for at least 72 h, at the end of which time the cells were put in culture at unit gravity. PTHrP expression upon
return to 1 ⫻ g suggests that the effect of 0 versus 1 ⫻ g is specifically due to the effect of gravity. The apparent effect of gravity on PTHrP expression was subsequently evaluated in vivo. Bones from rats flown in low earth orbit for 14 d were obtained from NASA mission STS-14, as were bones from ground-based controls. The bones were analyzed for PTHrP mRNA amount. There were significant differences in PTHrP expression in the tibia and femur of spaceversus ground-based rats. However, there was no difference in PTHrP mRNA expression by the skull bones from the spaceversus ground-based rats. These findings are consistent with the hypothesized effect of gravity/tension on PTHrP expression. It is generally thought that such unweighting effects are due to tension transmitted to weight-bearing bones by the muscle, ligaments, and tendons—an effect not seen on the skull. Knowledge of the effects of gravity on humans derives from the physiologic study of astronauts. It has been shown that there is a linear loss of bone among astronauts as a function of the length of time in space (50), suggesting that microgravity somehow affects bone calcium flux, consistent with our experimental evidence for a microgravitational effect on PTHrP expression by osteoblasts. J. B. West has shown that microgravity also affects lung function, disrupting the normal regional differences in alveolar gas exchange (51). We speculate that this may have resulted from altered PTHrP expression, resulting in loss of PTHrP regu˙ matching (see above). ˙ /Q lation of V From an evolutionary perspective, these observations are consistent with PTHrP mediating the adaptational response to unit gravity: the lung has structurally derived from the lower pharynx, and functions to adapt to gravity by moving gases (O2, out of the blood into the bladder to correct for buoyancy—i.e., it is an “anti-gravity” device).
Does Ontogeny Recapitulate Phylogeny? The Role of PTHrP in Lung Development PTHrP is necessary for mammalian lung development—deletion of the PTHrP gene results in failed alveolization, which is also phylogenetically relevant because generation of alveoli is the strategy by which the lung has evolved in vertebrates (2–6). This deletion results in death due to pulmonary insufficiency within minutes to hours after birth. Structurally, the lung develops up
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to the canalicular stage, coincident with the point in lung development when PTHrP is produced in the mouse (52), rat (53), and human (54). Functionally, the lung does not produce surfactant, consistent with failed alveolization due to immaturity of the embryonic lung tissue layers. Phylogenetically, PTHrP is expressed in the swim bladder of fish, as is surfactant. Both PTHrP and surfactant are expressed in every lunged vertebrate so far examined. In frogs, the PTHrP receptor has been profiled during metamorphosis (55). It is upregulated in the tadpole before air breathing in association with the appearance of lungs. Bird lungs also express PTHrP (43), and the profile of PTHrP expression parallels that of surfactant content (56), increasing in mRNA expression for PTHrP one day before the accelerated increase in surfactant phospholipids in Gallus domesticus, suggesting a causal relationship between amplification of PTHrP signaling and lung development. However, the chick lung does not form alveoli. Because overdistension of the alveolar type II cell causes downregulation of PTHrP expression in rodents (39), we speculate that birds do not alveolize because of their stiff, flow-through lungs that are four times more efficient in exchanging gases than the most efficient mammalian lung, taking maximal advantage of the “jet engine” design for optimal gas exchange during flight. In addition, consistent with the ontogeny/phylogeny interrelationship, PTHrP inhibits myofibroblast differentiation, inducing the lipofibroblast phenotype seen in mammals. Lipofibroblasts facilitate surfactant phospholipids production, compensating for the lack of structural support by the elastic myofibroblasts. This pattern provides an “on-demand” mechanism for accommodating cyclic inspiration/expiration of oxygen and CO2 in a lung with progressively thinner alveolar walls and decreasing alveolar diameter. Hence the mammal lung is structurally increasingly prone to alveolar collapse if it were not for the tandem increase in surfactant production and “quality” (i.e., greater surface activity) (22, 23). On the one hand, it is hard to conceive of the dynamic structural and functional changes that have occurred through phylogeny being a serendipitous concatenation of events. This is particularly true considering that the physical and biochemical changes have to have complemented one another or the system would literally implode! On the other hand, the scenario that PTHrP signaling coordinates the structural and functional changes evolved because it conferred a selective advantage that orchestrated genes linked to cellular structure and function provides a unifying mechanism.
Interrelationship between PTHrP, Development, Homeostasis, and Repair: Is Repair a Recapitulation of Ontogeny and Phylogeny? The processes that occur during development prepare the fetus for birth and physiologic homeostasis (58). The development and maturation of the lung is key to the transition to postnatal survival, because surfactant production is crucial for effective gas exchange (13, 58). Based on this functional linkage between lung development and homeostasis, we have generated data demonstrating that the underlying mechanisms of repair may recapitulate ontogeny. If lung connective tissue cells are experimentally deprived of PTHrP, mimicking lung epithelial injury, their structure changes (39) as follows: the first function that is lost is the PTHrP receptor on the cell surface, which is progressively lost, as are its down-stream targets, such as ADRP and leptin; the decline in the PTHrP-dependent structure is mirrored by the gain of the muscle-like structure, characteristic of fibrosis. This structural change can be exacerbated by Transforming Growth Factor 1, or reversed by treatment with PTHrP. The readaptation of the fibroblast in response to the loss of the PTHrP/leptin cross-talk is indicative of the interrelationship
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between homeostasis and repair, particularly the early loss of the cell-surface functional marker. We speculate that repair recapitulates ontogeny because it is programmed to express the crosstalk through evolution. In the model that has been developed to test this hypothesis, there are three key principles: (i ) the cross-talk between epithelium and mesoderm is necessary for the maintenance of homeostasis; (ii) damage or injury to the epithelium impedes the cross-talk, leading to loss of homeostasis/ re-adaptation to the newly established “set-point,” i.e., myofibroblast proliferation (59); and (iii) depending upon the nature and severity of the injury (mild, moderate, severe; proximal/ distal to the regulatory mechanisms for homeostasis, etc.), and the condition of the host (healthy, compromised, polymorphism for key genes necessary for re-establishing homeostasis, infected, premature, etc.), normal physiology will either be re-established, or cell/tissue remodeling/altered lung function may occur, and/ or fibrosis will persist, leading to chronic lung disease. Based on this model, we speculate that cell-molecular injury affecting epithelial–mesenchymal cross-talk recapitulates ontogeny (in reverse), providing diagnostic and therapeutic targets in the process. Furthermore, based on the larger concept that phylogeny provides stable phenotypes for evolution/ontogeny, we speculate that cell signaling in parenchyma of fish, frog, reptile, rodent, and bird reflects the amplification of the PTHrP/ surfactant mechanism. Conflict of Interest Statement: J.S.T. has no declared conflicts of interest; V.K.R. has no declared conflicts of interest.
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