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The Proceedings of the American Thoracic Society 6:607-613 (2009)
© 2009 The American Thoracic Society
doi: 10.1513/pats.200908-087RM
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Transforming Growth Factor-β Signaling across Ages

From Distorted Lung Development to Chronic Obstructive Pulmonary Disease

Rory E Morty1, Melanie Königshoff2 and Oliver Eickelberg2

1 Department of Medicine, University of Giessen Lung Center, University of Giessen, Giessen, Germany; and 2 Comprehensive Pneumology Center, Ludwig Maximilians University, Asklepios Hospital, and Helmholtz Zentrum München, Institute of Lung Biology and Disease, Neuherberg/Munich, Germany

Correspondence and requests for reprints should be addressed to Oliver Eickelberg, M.D., Comprehensive Pneumology Center, Ludwig Maximilians University Munich and Helmholtz Zentrum München, Institute of Lung Biology and Disease (iLBD), Ingolstädter Landstraße 1, 85764 Neuherberg/Munich, Germany. E-mail: oliver.eickelberg{at}helmholtz-muenchen.de

ABSTRACT

The transforming growth factor (TGF)-β superfamily of secreted growth factors consists of more than 40 members, including the TGF-β isoforms themselves, bone morphogenetic proteins, and activins. Most of these factors have been shown to be essential for proper organ development, a process often recapitulated in chronic diseases. Importantly, TGF-β superfamily members are key regulators of extracellular matrix composition and alveolar epithelial cell and fibroblast function in the lung. Both during lung development and disease, TGF-βs therefore control lung homeostasis by providing the structural requirements and functional micromilieu needed for physiological epithelial cell function and proper gas exchange. Prolonged alterations of TGF-β signaling have been shown to result in structural changes in the lung that compromise gas exchange and lung function, as seen in arrested lung development, a feature of bronchopulmonary dysplasia, lung fibrosis, and chronic obstructive pulmonary disease. All these syndromes share a loss of functional alveolar structures, which ultimately leads to a decreased life expectancy. In this review, we cover our current understanding of the impact of TGF-β signaling on chronic lung disease. We focus on distorted TGF-β signaling in bronchopulmonary dysplasia and chronic obstructive pulmonary disease as prototype diseases of the premature and matured lung, respectively, which are both characterized by functional and structural loss of alveolar units.

Key Words: bronchopulmonary dysplasia • chronic obstructive pulmonary disease • emphysema • small airway disease • transforming growth factor-β

The lung is the key organ of respiration in air-breathing animals, and its principal function is to transport oxygen from the atmosphere into the bloodstream, and to release carbon dioxide from the bloodstream into the atmosphere. In mammals, this exchange of gases takes place in the alveoli, which are hollow spherical outcroppings of the respiratory bronchioles with an average diameter of 200 to 300 µm. These alveoli, which consist of an epithelial layer supported by extracellular matrix, are surrounded by capillaries. It is across this alveolocapillary barrier that gas exchange takes place, and it is clearly advantageous that this barrier should (1) be as narrow as possible (to facilitate optimal exchange of gas molecules across the barrier) and (2) cover as large a surface area as possible to maximize the area over which gas exchange might take place.

Disturbances to the alveolar architecture have serious consequences for gas exchange by mammals. In humans, these disturbances are exemplified by diseases such as bronchopulmonary dysplasia (BPD), which limits late lung development and the formation of alveoli, and emphysema, a feature of chronic obstructive pulmonary disease (COPD) that is characterized by progressive destruction of alveoli. Both diseases are characterized by a reduction in total alveolar number and increased airspace size, which leads directly to a reduction in the ratio of gas exchange surface area to lung volume, and respiratory insufficiency.

OVERVIEW OF POSTNATAL LUNG DEVELOPMENT

The process of lung development strives to maximize the surface area available for gas exchange, while minimizing the thickness of the alveolocapillary barrier (the distance between the alveolar epithelium and the capillary endothelium) (1, 2). The branched lung structure is achieved by successive division of the developing airways during early lung development, and then by progressive formation of the developing airspaces—ultimately forming alveoli—during late lung development, by the process of alveolarization (2).

Early lung development starts during the embryonic stage (at 4–7 wk postconception in humans, and Embryonic Day [E] 9.5–E12 in mice) and continues through the pseudoglandular stage (at 5–17 wk in humans, and E12–E16.5 in mice) and canalicular stage (at 16–26 wk in humans, and E16.5–E17.5 in mice) (1). The alveolarization process begins at the end of the canalicular stage. Sections of mouse lungs in the pseudoglandular stage (E15) are illustrated in Figures 1A and 1B, whereas lungs in the canalicular stage (E17) are illustrated in Figures 1C and 1D. The thinning of the interstitial tissue, evident from the open airspaces (compare Figures 1B and 1D), marks the beginning of alveolarization. As late lung development proceeds, distal airways form saccular units in the saccular stage (at 24–38 wk in humans, and E17.5–Postnatal Day [P] 4 in mice), and secondary septae then divide these units (a process called septation) during the alveolar stage (at 36 wk preterm to 36 mo postnatal, or later, in humans, and P4–P28 in mice) (1). A progressive decrease in the size of the alveolar airspaces, together with a concomitant increase in the total number of alveoli, is clearly evident on comparing sections of mouse lungs in the saccular stage (P3; Figures 1E and 1F) and alveolar stage (P28; Figures 1G and 1H) (compare the number of alveoli in the region of fixed area encompassed by the dotted lines). Alveolarization was quantified as the mean linear intercept (MLI), a parameter that relates lung surface area to volume, and is used as a rough indicator of alveolar number, being inversely proportional to the number of alveoli. As illustrated in Figures 1F and 1H, the MLI decreased from 58 ± 8 µm in the saccular stage to 22 ± 5 µm in the alveolar stage, confirming an increase in the number of alveoli. From these images, a dramatic increase in the number of alveoli (and, hence, surface area available for gas exchange), during late lung development is clearly evident.


Figure 1
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  		Figure 1. Development of the lung architecture. Paraffin sections (3 µm) of pressure-fixed (20 cm H2O) lungs at various developmental stages were stained for smooth muscle actin and counterstained with hematoxylin, as described previously (26). Representative sections are illustrated for the (A and B) pseudoglandular, (C and D) canalicular, (E and F) saccular, and (G and H) late alveolar (mature) stages. Where high-magnification images (right-hand column) are derived from low-magnification images (left-hand column), the magnified area is demarcated by solid lines. Dotted lines encompass an area of interstitium. The mean linear intercept (MLI) is specified in (F) and (H). aw = airways; v = vessels.

 
This process of late lung development is carefully controlled by the coordinated action of many different transcription factors, mechanical forces (such as breathing movements), and growth factors (3–5). The diverse and important regulatory roles played by the transforming growth factor (TGF)-β superfamily of growth factors, which control the proliferation, transformation, and apoptosis of several cell types, as well as extracellular matrix (ECM) deposition and remodeling, have led to TGF-β and related superfamily members being accredited with key roles in late lung development (3, 5–7).

TGF-β SIGNALING

The TGF-β superfamily of growth factors encompasses more than 30 members, including the archetypical TGF-β family members, as well as the bone morphogenetic proteins, growth and differentiation factors, activins, and nodal (8, 9). In the case of TGF-β, signaling is initiated by binding of TGF-β ligands to the type II TGF-β receptor (Tgfbr2, also called TβRII), which then forms a complex with a type I TGF-β receptor, which can be either Tgfbr1 (also called activin-like kinase [ALK]-5) or Acvrl1 (also called ALK-1), depending on the cell type (10). The type I receptor then transmits signals within the cell via second-messenger Smad proteins, namely Smad2, Smad3, and Smad4, or by Smad-independent pathways (Figure 2). TGF-β signaling is potentiated by two accessory type III TGF-β receptors, Tgfbr3 (also called betaglycan) and endoglin (CD105, the eng gene product) (10). TGF-β signaling is also regulated by Smad6 and Smad7, inhibitory Smads that antagonize TGF-β signaling. Activated (phosphorylated) Smads are translocated into the nucleus, where they regulate gene transcription, and hence cell function (8, 9).


Figure 2
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  		Figure 2. The transforming growth factor (TGF)-β signaling pathway. Ligands of the TGF-β superfamily bind to their respective receptors, initiating the recruitment and phosphorylation (P) of Smad proteins. TGF-β ligands bind to the type II TGF-β receptor (TβRII), which initiates the formation of a heteromeric complex with type I TGF-β receptors (TβRI). Receptor-regulated Smads 2 and 3 are phosphorylated and, in combination with co-Smad 4, translocate to the nucleus, where they regulate gene transcription. The bone morphogenetic protein (BMP) family of the TGF-β superfamily exhibits similar characteristics; BMPs bind to a heteromeric receptor complex of BMP receptors (BMPRII, BMPRIa/b), initiating intracellular signaling. BMPR activation leads to the phosphorylation and activation of Smads 1, 5, and 8.

 
TGF-β SIGNALING IN POSTNATAL LUNG DEVELOPMENT

TGF-β signaling has been widely implicated in early lung development. All three TGF-β ligand isoforms, TGF-β1, TGF-β2, and TGF-β3 (11), as well as the type I and type II TGF-β receptors (6, 12, 13), are expressed in the embryonic rodent lung. The addition of exogenous TGF-β ligands inhibited airway branching in vitro (14), and abrogation of TGF-β signaling, either by genetic down-regulation either of Tgfbr2 (15), or of Smad2, Smad3, or Smad4 (16), promoted lung branching in vitro. Consistent with these observations, overexpression of the inhibitory Smad, Smad7, which antagonizes TGF-β signaling, promoted lung branching in vitro (17).

Fewer studies, however, have examined the role of TGF-β signaling in late lung development. Overexpression of TGF-β1 ligand in the lung, either by adenovirus-mediated transfer of the tgfb1 gene to the neonatal rat lung (18) or by conditional overexpression of the tgfb1 gene in the developing mouse lung between P7 and P14 (19), disrupted late lung development, in particular alveolarization. These studies thus provided strong evidence that TGF-β was a negative regulator of alveolarization. Of interest, and perhaps paradoxically, the blockade of TGF-β signaling by genetic ablation of Smad3 between P7 and P28 generated a similar phenotype in mice, which indicates that TGF-β can also act as a positive regulator of alveolarization (20). Data supporting this idea have also been generated by genetic recombination, in which Smad3 deficiency in mice resulted in progressive airspace enlargement with age, implicating TGF-β in the maintenance of alveolar integrity in the developing, as well as developed, lung (21). Taken together, these data indicate that TGF-β plays a key role in the alveolarization process, as well as in the maintenance of alveolar structure. These studies provided a clear rationale for the hypothesis that the structural changes induced by altered TGF-β signaling in the premature and mature lung may underlie the complex pathophysiology of BPD as well as COPD.

This idea is further supported by subsequent studies, which have demonstrated that the expression and localization of components of the TGF-β signaling machinery are dynamically regulated during late lung development in both mouse and human lungs (6). Similar changes in the temporal and spatial regulation of the related bone morphogenetic protein family (members of the TGF-β superfamily of growth factors) during late lung development have also been described (7).

Active TGF-β signaling has been reported in the interstitium of the developing lung (6). Alveolar epithelial type II (ATII) cells are proposed to serve as progenitor cells of the alveolar epithelium, in particular alveolar epithelial type I (ATI) cells, and are an important component of the alveolar unit (22). TGF-β/Smad signaling has been shown to contribute to ATII to ATI transdifferentiation (23) and to epithelial–mesenchymal transition (EMT) (24), an important feature of the alveolarization process (1) and disease development. Thus, it has been proposed that TGF-β signaling in the interstitium during the alveolar phase of late lung development may promote ATII to ATI transdifferentiation. Several studies have indicated that TGF-β signaling plays important regulatory roles in the process of late lung development, in several cell types, including the developing epithelial layer of the immature alveoli, as well as in the maturation of the epithelial and smooth muscle layers of the developing airways.

TGF-β SIGNALING IN DEFECTS OF POSTNATAL LUNG DEVELOPMENT

Although TGF-β signaling is clearly required for normal lung development, this requirement is finely tuned, as described in the preceding section. Clearly, either too much or too little TGF-β signaling leads to impaired alveolar development. Dramatic reductions in TGF-β signaling are rarely encountered naturally, as functional impairment of key components of the TGF-β signaling machinery (such as knockout [KO] animals) are generally lethal. Conditional deletion of Smad3, a key component of the TGF-β signaling cascade, does impact late lung development in mice, causing alveolar enlargement reminiscent of that observed in patients with BPD or emphysema, leading to the proposal that TGF-β is a positive regulator of late lung development (20, 21). When Smad3 KO mice are allowed to age, they spontaneously develop increased airspace enlargement, along with increased matrix metalloproteinase-9 (MMP9) and MMP12 levels in the bronchoalveolar lavage fluid (21). Furthermore, a different Smad3 KO mouse line exhibited altered lung alveolarization, which resulted from reduced peripheral lung cell proliferation during lung development (20). Interestingly, however, artificial up-regulation of TGF-β signaling also severely disrupted late lung development, leading to alveolar enlargement reminiscent of that observed in patients with BPD (18, 19). So dramatic was the effect of TGF-β that conditional overexpression of TGF-β in the developing mouse lung has been proposed as a model for BPD (19).

Interestingly, neonatal rodents chronically exposed to normobaric hypoxia (25) or hyperoxia (26) exhibit arrested alveolarization and develop BPD-like features. Most importantly, both of these animal models of BPD exhibit increased TGF-β signaling (25, 26). In the case of chronic hypoxic exposures, levels of bioactive TGF-β are increased in bronchoalveolar lavage fluids of hypoxia-treated neonatal rodents, and increased expression of at least two TGF-β receptors is observed (25). Similarly, in the case of hyperoxia, a BPD-like alveolar structure developed concomitantly with up-regulated Tgfbr2 and Smad4 expression, and increased TGF-β/Smad2,3 signaling in the developing lung (26). Thus, increased TGF-β signaling is associated with retarded alveolar growth in both models of BPD, underscoring a potentially important role for dysregulated TGF-β activity in BPD.

This idea is strengthened by the observation that dampening of TGF-β signaling in the hyperoxia model of BPD, using neutralizing anti–TGF-β antibodies, largely restored normal alveolar architecture (27), validating a pathological role for TGF-β in hyperoxia-induced arrest of alveolar development. The observation that levels of TGF-β ligands are elevated in lavage fluids from human neonates with BPD undergoing oxygen therapy further indicates that elevated TGF-β levels are indeed associated with the development of BPD in humans (28).

The precise role played by TGF-β in the development of BPD has not been clarified; however, the pivotal effects of TGF-β in cell growth, proliferation, ECM production, and remodeling suggest a multitude of possibilities (Figure 3). For example, TGF-β exhibits potent antiproliferative properties on epithelial cells and some types of smooth muscle cells. Indeed, TGF-β can arrest proliferation of ATII cells (29, 30) and prevent keratinocyte growth factor–stimulated ATII cell proliferation (31). It has also been demonstrated that ATII cells exposed to hyperoxia are significantly more sensitive to the proapoptotic effects of TGF-β than are ATII cells exposed to normoxia (26). These observations suggest that improper TGF-β signaling in BPD might contribute to the alveolar hypoplasia associated with BPD by preventing, at least in part, alveolar epithelial cell proliferation and differentiation.


Figure 3
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  		Figure 3. The role of transforming growth factor (TGF)-β signaling in the immature lung. A proposed model depicting the effects of increased TGF-β signaling during the development of bronchopulmonary dysplasia is shown. ATII = alveolar epithelial type II cells; ECM = extracellular matrix.

 
In addition to the effects of TGF-β on the cellular compartment of the lung, TGF-β also controls the composition of the ECM. The deposition and remodeling of the ECM constitute a key step in the alveolarization process (32), and TGF-β is an important regulator of the synthesis and secretion of collagens, elastin, and other components of the ECM. When primary fibroblasts are cultured in hyperoxia, they are more sensitive to TGF-β signaling, and produce excessive amounts of collagen I{alpha}1, tropoelastin, and tenascin C mRNAs in response to TGF-β stimulation, in comparison with fibroblasts cultured in normoxia (26). TGF-β also regulates the secretion of MMPs and their cognate inhibitors, tissue inhibitors of MMP (TIMPs). Several of these molecules, MMP-1, MMP-2, MMP-9, and TIMP-2, are strongly expressed in the lungs of humans (33) and mice (34) throughout the canalicular, saccular, and alveolar phases of normal lung development. Fibroblasts exposed to hyperoxia also produce more TIMP and less MMP-1 and MMP-2 in response to TGF-β stimulation than do fibroblasts exposed to normoxia (26). Thus, dysregulated TGF-β activity may well impact proper ECM production and remodeling in BPD, and promote excessive ECM production and impair ECM remodeling, leading to the perturbed alveolar structures observed in the lungs of animal models and patients affected with BPD.

TGF-β IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Although BPD is a prototypical disease with a functional loss of alveolar structures in the newborn, these features are recapitulated in the lungs of patients with COPD, in particular emphysema. COPD is the fourth leading cause of death in the developed world, with continuously rising prevalence and mortality (35–37). COPD is characterized by irreversible expiratory airflow limitation due to two main intrapulmonary features: small airway disease and emphysema. Small airway disease includes airway inflammation with increased mucus production, airway wall remodeling, and peribronchiolar fibrosis, whereas emphysema is defined as destruction of the alveolar architecture due to distal airspace enlargement (38–41). Emerging interest in the role of TGF-β in the pathogenesis of COPD has evolved, particularly because genetic studies have identified TGF-β as a promising candidate gene related to COPD (42, 43). Studies of various COPD populations identified several single-nucleotide polymorphisms (SNPs) in patients with COPD. These polymorphisms have also been linked to functional measurements, such as airflow obstruction, dyspnea, as well as computerized tomography–based emphysema status. Some of these SNPs, however, have not been confirmed in various populations or cohorts. Given the complex etiology, as well as the heterogeneity and individual severity of COPD features, this is not entirely surprising, and underlines the need for further studies deciphering the relevance of TGF-β gene polymorphisms in COPD.

Evidence of impaired functional TGF-β1 signaling has emerged from studies investigating tissue from patients with COPD. Several studies reported increased expression of TGF-β1 in the airway epithelium of smokers, as well as in patients with chronic bronchitis or COPD (44–48). Furthermore, decreased expression of the inhibitory Smads 6 and 7 in bronchial biopsies of patients with COPD has been reported, further suggesting increased TGF-β signaling in COPD (49). Increased TGF-β1 signaling has been associated with enhanced fibrotic airway remodeling, as well as with clinical features, such as lung function (50). The intratracheal administration of recombinant TGF-β1 to mice resulted in increased collagen in the distal airways without noticeable inflammatory processes in vivo, further underlining that TGF-β1 signaling leads to airway wall remodeling and peribronchiolar fibrosis (51). Notably, decreased TGF-β1 and TGF-β receptor expression has also been reported for various cell types, such as macrophages and bronchial glands, highlighting once more the finely tuned TGF-β signaling system, with the various susceptibilities of distinct cell types (52, 53) (Figure 4).


Figure 4
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  		Figure 4. The role of transforming growth factor (TGF)-β signaling in the mature lung. A proposed model depicting the effects of altered TGF-β signaling during the development of chronic obstructive pulmonary disease is shown. ATII = alveolar epithelial type II cells; COPD = chronic obstructive pulmonary disease; ECM = extracellular matrix.

 
The most important risk factor for COPD is cigarette smoke. Increased TGF-β1 expression in airway epithelial cells from patients with COPD and smokers correlated with the burden of cigarette smoking (48). It is therefore reasonable to investigate TGF-β signaling in response to cigarette smoke exposures. Several studies have focused on the direct effect of cigarette smoke exposure on TGF-β signaling. Surprisingly, whole genome expression studies in human bronchial epithelial cells exposed to cigarette smoke in vitro have revealed a down-regulation of the TGF-β pathway (54–56), whereas tracheal explants that were exposed to cigarette smoke in vitro exhibited enhanced active TGF-β signaling (57). Importantly, mice exposed to cigarette smoke in vivo exhibited enhanced profibrotic TGF-β signaling in the small airways (58). In addition, it has been shown that cigarette smoke activates TGF-β1 in lung fibroblast cultures (59), altogether suggesting that TGF-β effects in airway remodeling and fibrosis may be provoked by cigarette smoke.

The role of TGF-β signaling in emphysema is less defined and investigated. Emphysema is characterized by the rarefaction of alveolar walls with loss of parenchymal tissue (60). MMP and TIMP, which regulate ECM homeostasis, have been implicated in cigarette smoke–induced pulmonary emphysema, much like their suggested involvement in BPD and animal models thereof (61). Several studies identified TGF-β is an important regulator of MMP expression. Most of these studies indeed suggested that too little or inhibited TGF-β signaling may lead to increased MMP expression and subsequent ECM degradation, which may contribute to emphysema development (62, 63). In detail, it has been shown that TGF-β inhibits MMP9 and MMP12 expression in alveolar macrophages and monocytes (64, 65), and that mice lacking the β6 subunit of the {alpha}vβ6 integrin exhibited decreased TGF-β signaling along with increased expression of MMP12 in alveolar macrophages (63). These mice spontaneously developed progressive alveolar enlargement over time, which was similar to the course of human emphysema. Evidence of decreased TGF-β signaling in emphysema was further provided by in vitro studies investigating rat tracheal explants exposed to cigarette smoke. Here, ongoing TGF-β expression has been observed in small airways, but not in the surrounded parenchyma (66).

Importantly, too much TGF-β signaling may also contribute to emphysema development. It has been shown that cigarette smoke–induced TGF-β signaling further potentiated the growth-inhibitory effects in alveolar epithelial cells, thereby providing another potential pathomechanism responsible for parenchymal tissue destruction in COPD (67, 68). Furthermore, it has been demonstrated that interstitial fibroblasts from patients with COPD with emphysema exhibited reduced baseline expression of active intracellular TGF-β mediators, such as phosphorylated Smad3, whereas inhibitory Smads were increased (69). Most interestingly, the response of COPD fibroblasts to TGF-β1, although releasing increasing amounts of TGF- β1, was reduced (69).

CONCLUSIONS

BPD is a significant complication of premature birth, affecting up to 10,000 newborns annually in the United States alone, and has long-term respiratory consequences that reach beyond childhood (70, 71). The severity and socioeconomic impact of BPD is superseded by COPD, a disease with similar characteristics in terms of functional alveolar loss. The data reviewed herein provide compelling evidence of the involvement of the TGF-β signaling pathway in the pathogenesis of BPD and COPD, and highlight similar mechanisms between these diseases.

ACKNOWLEDGMENTS

The authors thank Dr. Miguel A. Alejandre-Alcázar (Department of Pediatrics, University Hospital Erlangen) for preparation of the samples in Figure 1.

FOOTNOTES

Supported by the Helmholtz Association, the German Research Foundation (DFG; KliFo 118), the International Graduate Program "Signaling Mechanisms of Lung Physiology and Disease" (GRK1062), and a career development award from the University of Giessen School of Medicine.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form August 10, 2009; accepted in final form September 4, 2009)

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