Remodeling in Asthma and Chronic Obstructive Pulmonary Disease
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《美国胸部学报》
Departments of Pulmonology and Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
ABSTRACT
Airway and lung tissue remodeling and fibrosis play an important role in the development of symptoms associated with lung function loss in asthma and chronic obstructive pulmonary disease (COPD). In the past decades, much attention has been paid to the inflammatory cellular process involved in airway remodeling in these two diseases. However, it is increasingly clear that resident cells contribute to airway and lung tissue remodeling and to associated fibrosis as well. This article deals with some new aspects and discusses the role of vasculature and vascular endothelial growth factor in the development of airway obstruction and airway wall fibrosis in asthma and COPD. Moreover, it addresses the extracellular matrix (ECM) turnover as present in both asthma and COPD. All components of lung ECM (collagen, elastic fibers, proteoglycans) have been shown to be potentially altered in these two diseases. Finally, the interaction between transforming growth factor (TGF), Smad signaling, and TGF in the ECM turnover will be discussed. We propose that ECM damage and repair contribute to airway and lung tissue pathology and that the vasculature may enhance this process. The localization of this process is dependent on the etiology of the disease (i.e., allergen-driven in asthma and smoke-driven in COPD) and the local environment in which the pathologic process takes place.
Key Words: asthma;chronic obstructive pulmonary disease;fibrosis;remodeling
Remodeling is an important feature in the airways of patients with asthma and chronic obstructive pulmonary disease (COPD). It may contribute to a large extent to the progressive nature of airflow limitation that occurs in virtually all patients with COPD. Moreover, it may negatively influence the severity of symptoms and progression of asthma as well. It is now well accepted that pathologic processes leading to respiratory symptoms occur in the large airways in asthma. In the last decade research has elucidated that inflammation and remodeling in the small airways is equally important. Conversely, peripheral airway disease long has been acknowledged as the core feature of COPD, whereas the last decade has seen much progress toward understanding of the airway inflammation and remodeling in the larger airways in COPD. Studies have only recently compared both airway compartments and it has become somewhat clearer that the inflammatory and remodeling processes may not always be similar in these compartments.
One of the features that is important in this respect is the dissection of the role of inflammatory cells, resident cells (e.g., epithelial cells and fibroblasts), and remodeling with fibrosis of the airways. It is not clear how these cells and the extracellular matrix (ECM) proteins interact, at least not as far as the order of activation and deactivation. Furthermore, the role of the vasculature and of growth factors for vasculature in remodeling processes in the large and small airways is currently underexposed. This article discusses the current views on peripheral and central airway disease. We will put this in perspective of the contribution of the vasculature and vascular endothelial growth factor (VEGF), as well as the interaction between transforming growth factor (TGF), Smad signaling, and the ECM turnover in asthma and COPD.
THICKENING OF THE LAMINA RETICULARIS
The "true" basement membrane, comprising the lamina rara and lamina densa, separates the airway epithelium from the mesenchyme. Although the lamina rara and lamina densa in airways of subjects with asthma are not reported to differ from nonasthmatic subjects, the lamina reticularis is altered in patients with asthma. This region, which is composed of collagen I, collagen III, collagen V, fibronectin, and tenascin, and is situated just below the basement membrane, has an overall thickness of 3 to 4 μm in nonasthmatic subjects, whereas in asthma this is increased two- to threefold (1, 2). Functionally, thickening of the lamina reticularis has been linked to reduced airway distensibility and increased airflow limitation in asthma (3), suggesting that this altered structure has a negative impact on lung function. However, it has been suggested that thickening of the lamina reticularis may actually serve as a protective mechanism by increasing the stiffness of the airways to attenuate the sporadic bronchoconstriction (4).
Less is known about the basement membrane in COPD, with some reports mentioning increased airway wall thickness and others failing to report it. Whatever the reason behind this (e.g., patient selection, sample bias), it is clear that the constituents of the basement membrane are not similar to those of asthma (5).
INCREASED VASCULATURE AND VEGF CONTRIBUTING TO AIRWAY OBSTRUCTION AND FIBROSIS
Vasculature, VEGF, and Asthma
Angiogenesis is an important event both in the development of allergic inflammation and in the pathophysiology of tissue remodeling in atopic diseases (6–11). In the 1960s, a study by Dunnill (12) demonstrated for the first time that subjects with asthma who die of acute attacks have an enlarged capillary bed in the airway wall. Later, increased vascularity in the airways was recognized not only in patients with severe asthma but also in those with mild disease (6, 8). These characteristics can account for considerable swelling and stiffening of the airway wall. Recent studies in the airways of patients with asthma have revealed that the ratio between the level of VEGF and endostatin, proangiogenic and antiangiogenic mediators, respectively, is increased in the sputum of subjects with asthma in comparison with that of control subjects (10). Therefore, it seems that an imbalance in favor of proangiogenic factors leads to the abnormal growth of new blood vessels in asthma. This may then contribute to engorgement of the vasculature and either thickening or stiffening of the airway wall and hence affect airway obstruction.
VEGF and the Vasculature
Numerous inducers of angiogenesis have been identified, including members of the fibroblast growth factor (FGF) family, vascular permeability factor/VEGF, angiogenin, TGF- and TGF-?, platelet-derived growth factor, tumor necrosis factor (TNF-), hepatocyte growth factor, granulocyte-macrophage colony–stimulating factor (GM-CSF), interleukins, chemokines, and angiopoietin 1 and 2 (13). Among them, VEGF is the most potent directly acting regulator of angiogenesis (14, 15), and its expression is often excessive in chronic inflammation and fibrosis (Figure 1, Table 1). The submucosa of the airways of subjects with asthma has higher VEGF, FGF-2, and angiogenin immunoreactivity than that of healthy individuals (9). Importantly, expression of VEGF and its receptors VEGFR-1 and VEGFR-2 inversely correlates with the level of airway obstruction. Furthermore, higher numbers of VEGF-positive cells in the airway wall are associated with basement membrane thickening, involving VEGF in remodeling processes (15).
VEGF induces proliferation, migration, and tube formation of endothelial cells. It promotes secretion of interstitial collagenase (matrix metalloproteinase [MMP]-1) and the expression of chemokines, as well as leukocyte adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin (15).
VEGF and Immune Cells
Interestingly, VEGF also modulates immune cell functions. For example, it inhibits dendritic cell maturation and increases the production of B cells and immature myeloid cells. It can also inhibit the development of T cells from early hematopoietic progenitor cells. In addition, VEGF stimulates monocyte chemotaxis and contributes to hematopoietic stem cell survival and recruitment of bone marrow–derived endothelial cells in angiogenesis (13).
Regulation of VEGF and Angiogenesis
Many growth factors and cytokines can regulate VEGF expression. TGF-? was shown to induce VEGF gene expression and secretion in fibroblasts and epithelial cells. Interleukin (IL)-5 and GM-CSF have a similar effect on eosinophils (6). Many inflammatory mediators, such as prostaglandin E1 (PGE1), PGE2, TNF-, IL-1, IL-6, IL-8, nitric oxide, and platelet-activating factor, have been shown to induce expression of VEGF, angiogenesis, or both (13). Concerning negative regulation of angiogenesis and VEGF, at least 15 molecules are currently known to be endogenous inhibitors, including endostatin, thrombospondin 1, IFN-, angiostatin, and tissue inhibitors of metalloproteinases (TIMPs) (13).
Macrophages, neutrophils, epithelial cells, fibroblasts, and smooth muscle cells are all important sources of VEGF in inflamed tissue (13). Different conditions can induce these cells to release VEGF. Several cytokines and growth factors involved in allergic inflammation and in remodeling are responsible for increasing the basal level of VEGF in fibroblasts, smooth muscle cells, and keratinocytes. For example, bradykinin, IL-1?, IL-5, IL-13, and TGF-? are potent inducers of VEGF in airway smooth muscle cells, and TGF-?, together with IL-4 and IL-13, enhances the synthesis of VEGF in bronchial fibroblasts (16).
VEGF as Chemoattractant
VEGF is a potent chemoattractant for leukocytes in experimental asthma (17) and induces migration of mononuclear cells across an endothelial cell monolayer in vitro (Figure 1). Recent evidence indicates that eosinophil infiltration could be reduced by administration of anti–VEGF receptor antibodies in a murine model of toluene diisocyanate–induced asthma (17). This is possibly due to the fact that VEGF induces eosinophil migration and eosinophil cationic protein release, mainly through VEGF receptor 1 (VEGFR-1). Together with eosinophils, mast cells can also migrate in vivo and in vitro (13) in response to VEGF, suggesting their recruitment to sites of neovascularization during physiologic or pathologic angiogenesis. These results indicate that a positive feedback loop can take place in allergic inflammation, with Th2 mediators inducing VEGF release by eosinophils and mast cells and consequent angiogenesis and VEGF enhancing activation of mast cells and eosinophils.
Vasculature, VEGF, and COPD
Vascular abnormalities have been associated with development of COPD (18, 19). Wright and colleagues reported that there was an increase in wall area of small pulmonary vessels by intimal thickening in patients with mild to moderate COPD and medial thickening in severe cases as well. This thickening was correlated with a decline in FEV1 18, 20. Hashimoto and colleagues compared asthmatic and COPD small and large airways and found that the number of vessels in the medium and small airways in patients with asthma showed a greater increase than those in patients with COPD and control subjects, and the vascular area in the small airways was increased in patients with COPD versus control subjects, but not in asthma (21). Furthermore, it was shown recently that muscular pulmonary and bronchiolar arteries have increased adventitial infiltration of CD8 T lymphocytes (19, 22), cells that are also increased in airway walls in peripheral and central airways.
VEGF and Angiogenesis
Little is known, however, about the molecular mechanisms underlying the loss of alveolar tissue, including the vasculature, in emphysema. VEGF is one of the angiogenic factors that is also associated with COPD. Kranenburg and colleagues (23) found increased VEGF expression and their receptors (VEGFR-1, also called FLT-1, and VEGFR-2 also called KDR/Flk-1) in 14 ex-smoking patients with COPD in comparison with 14 ex-smoking healthy control subjects (23). Patients and control subjects had similar pack-years of smoking (on average, 42 and 44 pack-years, respectively). Patients with COPD had GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II, and four patients used inhaled steroids. They investigated both central and peripheral airways. VEGF expression was increased in bronchial and bronchiolar and alveolar epithelium, and in bronchiolar macrophages, as well as airway smooth muscle cells and vascular smooth muscle cells in both bronchiolar and alveolar regions. The VEGF receptors were increased in patients with COPD as well. Finally, they found an inverse correlation between VEGF and FEV1 in bronchial mucosal microvessels and airway smooth muscle cells, bronchiolar epithelium, and medial vascular smooth muscle cells of the larger pulmonary arteries associated with the bronchiolar airways. TGF-? staining in the bronchiolar epithelium also correlated with VEGF in the same patients. They postulated that VEGF and its receptor system may contribute to the maintenance of endothelial and epithelial cell viability in response to injury. In patients with pulmonary fibrosis, fibrotic regions are densely populated by mast cells and macrophages with increased KDR/Flk-1 expression (24). These cells are also increased in bronchiolar airway epithelium in COPD and have increased expression of TGF-?. Together, these data suggest that TGF-?–VEGF represents a molecular link between inflammatory cell infiltration at sites of smoking-induced injury contributing to airway remodeling in COPD.
FIBROSIS AND DESTRUCTION IN ASTHMA AND COPD: ROLE OF THE Smad PATHWAY
With respect to pathogenesis of COPD, there is a seeming contradiction in the destructive effect of cigarette smoke (CS) exposure in development of emphysema and, at the same time, a fibrotic effect of CS on inner and outer parts of the airway wall of in particular small airways. In asthma, the initial focus was on thickening of the reticular basement membrane (1, 2), which is an early event; more recently, more attention has been given to ECM changes in other parts of the airway wall, like the outer adventitial part (25). With respect to remodeling events in the pathogenesis of COPD, the main focus has been on the destructive effects (as a consequence of imbalance between oxidants and antioxidants and between proteases and antiproteases) (26–29). More recently, more attention has been given to an aberrant repair process, which also may contribute to development or progression of the disease (30).
Proteolysis and Fibrosis
The MMPs and their inhibitors are a main component in the destructive part of the remodeling events (31), whereas in the tissue repair/fibrotic changes, basic FGF (bFGF) and TGF-? play a main role. In particular, with respect to the seeming contradictory events in parenchyma and bronchial wall, interactions between MMPs and TGF-? have been suggested. The increased presence of MMP-9 (gelatinase/collagenase), which is associated with COPD (28, 29), could then coincide with increased presence of TGF-?, which has been found to be up-regulated in bronchial epithelial cells and alveolar type II cells (32, 33). This could, depending on relative contribution of each component in a specific compartment, result in either destructive or fibrotic events respectively. Similarly, increased TGF-? together with possible activation of MMP-12 (elastase) (34, 35) could, similar to the interaction between MMP-9 and TGF-?, have elastolytic together with fibrotic effects, depending on exact localization in either the airways or parenchyma.
Sources of Matrix Production
The main effector cells implied in tissue remodeling events are the fibroblasts, which themselves are a main component of the interstitium and are also main producers of ECM (30). Epithelial cells are resident cells, also capable of ECM production, and fibroblasts as well as epithelial cells are capable of producing TGF-?, MMPs, and proinflammatory mediators (5). With respect to the further intercellular interactions determining the outcome of remodeling events, mediators produced by local inflammatory cells play an important role by activation or inhibition of local production of MMPs and ECM.
Role of the Smad Pathway in Remodeling
With respect to tissue remodeling, apart from the intercellular interactions, aberrations in intracellular events may be of relevance in unravelling the aberrant response to CS as observed in patients with COPD. A very important intracellular pathway that may play a role in pathogenesis of COPD as well as asthma is the Smad pathway (Figure 2), activated through the TGF-? receptor (36–38).
In the Smad pathway, stimulatory as well as inhibitory pathways can be recognized (37). The main stimulatory pathway involves association of Smad-2 and Smad-3, which, together with Smad-4, leads to activation of nuclear transcription of some main ECM proteins such as collagens, versican, and biglycan. The inhibitory pathway is mainly mediated by Smad-7 (Figure 3), which inhibits the pathway described above and in this way also inhibits the transcription for collagen, versican, and biglycan. Together with this inhibitory activity, Smad-7 induces a pathway that leads to nuclear transcription of a limited number of other matrix proteins, of which decorin is most prominent. The fact that the balance in this intracellular Smad pathway itself is also important for actual production of matrix proteins implies that not only changes in TGF-? or TGF-? receptors as such determine whether this would lead to fibrosis or lack of adequate tissue repair. In a previous study on determinants relevant in airway fibrosis and emphysema, we found no differences in collagens in airway walls of small airways in a comparison between patients with mild or severe COPD and normal subjects (39). In lung tissue of patients with severe COPD as compared with mild COPD and control subjects, we found a significant prominent reduction of decorin, and less significantly, of biglycan, in particular in the outer parts (adventitia) of small airways, whereas in the adventitia from arterioles at the same location, no difference in decorin was present (39).
Role of the Smad Pathway in Abnormal Composition of Matrix
Proteoglycans such as decorin and biglycan have important functions, not only as a component of integral construction of the ECM but also as a main regulatory molecule by their ability to bind several cytokines and growth factors (30, 40). With respect to the architecture of ECM, decorin has a main function as a cross-linking molecule between collagen fibrils; in this way, the amount of decorin that is present determines how tight or loose collagen fibrils are attached together. Consequently, a strong increase in decorin would imply stiffening of local collagens, whereas loss of decorin would lead to a loosening and perhaps destruction of collagen structure. This implies that even when an aberrant increase or sustained presence of collagens as seen in small airways would suggest rigidness and fibrosis, this still could be a very loose structure if insufficient decorin were present. Consequently, considering the decrease in decorin we found in the adventitia of small airways in patients with severe COPD with sustained collagen (39) (Figure 4), this implies that although there may still be a thickening of the airway wall, this would be accompanied by loosening of the adventitial collagen and, in due time, loss of elastic recoil. Together with the smoking-related net proteolytic and oxidative effects in COPD, this vulnerability would lead to easy destruction of the peribronchial attachments of the parenchyma to the adventitia of small airways. Moreover, using polymerase chain reaction on tissue derived from small airways in patients with COPD, Springer and colleagues (41) demonstrated that there was a significant decrease of Smad-6 and Smad-7 when compared with normal individuals. This could fit well with our findings that a reduced Smad-7 would be in concordance with a lack of inhibition of fibrotic events in the small airways together with a reduction of presence of decorin production at the same spot. In asthma, similar events are observed in the airways, with reduced decorin in the bronchial mucosa (42), but in fatal asthma less decorin is also found in the external area of small airways (25). Similar to the findings in airways in COPD (41), a reduction of Smad-7 was found in epithelial cells in patients with asthma, with an inverse correlation with basement membrane thickness (38).
Modulating Factors in the Smad Pathway
Although TGF-? is the main inductor of the Smad pathway, the inhibition of the Smad pathway as mediated by Smad-7 can be induced by extracellular influences of TNF-, as produced by the CS-exposed epithelium, and also by CS itself. This would mean that, in a study of the role of tissue repair in development of COPD, not only a locally increased presence of TGF-? (32, 33) is the main determinant of actual production or lack of production of matrix proteins, but also whether and to what extent mediators like TNF-, IFN-, and CS are present in the same pulmonary compartment. This would mean that the actual state of inflammation in airways and also whether a patient with COPD actually smokes are main components in determining the outcome of the local capabilities of matrix production. Although smoking is generally associated with COPD, it should be recognized that the percentage of patients with asthma who smoke is about the same as in the general population (43). This implicates the relevance of the above also for (smoking) patients with asthma.
When considering the reduced presence of Smad-7, it is not yet clear whether this is really a structural difference between tissue from the bronchial wall of patients with COPD and normal subjects or whether this is due to long-term exposure to TNF-, IFN-, CS, or other inhibiting factors. However, because an increase in TGF-? is mainly found in bronchial epithelial cells, and in type 2 alveolar epithelial cells, mainly present around the peribronchial adventitia, this would mean that effects from TGF-? might be expected primarily in the small airway wall and not as much in the parenchyma.
Speculatively, if Smad-7 were structurally reduced in patients with COPD or asthma (38, 41), this could lead to profibrotic events mediated by the regular Smad pathway, with lack of inhibition by Smad-7, but with loosening of the collagenic tissue by lack of decorin. Both in asthma and in COPD, this could lead to fibrotic changes in the airway wall with loss elastic recoil of peribronchial attachments, which would contribute to airway obstruction.
As can be concluded from the above, understanding of the pathogenesis of COPD and asthma includes knowledge of the development of remodeling changes in small and large airways. In COPD, the latter should be studied in conjunction with destructive events in the parenchyma. Pathogenetic studies should therefore include abnormal regulation of remodeling events affecting the local ECM, the connective tissue cells, and vascular changes contributing to the final remodeling effect.
As discussed in this overview, the contribution of vascular changes to remodeling in asthma and COPD is not limited to simple increase in number of small vessels or changes in blood flow. Such vascular changes are phenomena that are the result of the complex regulatory abnormalities in which VEGF and its receptors can be considered as key factors. As described above, VEGF is not only involved in angiogenesis but also plays an important role in regulation of local inflammation and, by its interaction with TGF-?, in regulation of matrix production.
The other important issue in this overview is that the scope of studies of ECM remodeling goes beyond MMPs and TGF-?. In particular, changes in regulation and balance of components of the Smad pathway in epithelial cels and (myo-) fibroblasts deserve attention. Further studies involving this Smad pathway will shed light on complex changes in amount of ECM in general as well as in the composition of this matrix. The latter, particularly where proteoglycans are concerned, can be expected to have profound functional effects on structural integrity as well as on regulation of inflammation.
As the authors have illustrated above for some important parameters in remodeling, results of studies regarding pathogenesis of asthma and COPD should be placed in a perspective of the intercellular as well as intracellular main events in the respective specific pulmonary compartments such as large airways, small airways, alveoli, or lung parenchyma. Such an approach would allow one to find clues for pathogenetic events in these particular tissue compartments and to determine the contribution of the changes in these compartments to the development and progression of disease. An important implication of realizing differences in the microenvironment of the different lung compartments is that this will have consequences for future targets for therapy and thus for the way future therapeutic interventions have to be targeted to the selective pulmonary compartments.
FOOTNOTES
Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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ABSTRACT
Airway and lung tissue remodeling and fibrosis play an important role in the development of symptoms associated with lung function loss in asthma and chronic obstructive pulmonary disease (COPD). In the past decades, much attention has been paid to the inflammatory cellular process involved in airway remodeling in these two diseases. However, it is increasingly clear that resident cells contribute to airway and lung tissue remodeling and to associated fibrosis as well. This article deals with some new aspects and discusses the role of vasculature and vascular endothelial growth factor in the development of airway obstruction and airway wall fibrosis in asthma and COPD. Moreover, it addresses the extracellular matrix (ECM) turnover as present in both asthma and COPD. All components of lung ECM (collagen, elastic fibers, proteoglycans) have been shown to be potentially altered in these two diseases. Finally, the interaction between transforming growth factor (TGF), Smad signaling, and TGF in the ECM turnover will be discussed. We propose that ECM damage and repair contribute to airway and lung tissue pathology and that the vasculature may enhance this process. The localization of this process is dependent on the etiology of the disease (i.e., allergen-driven in asthma and smoke-driven in COPD) and the local environment in which the pathologic process takes place.
Key Words: asthma;chronic obstructive pulmonary disease;fibrosis;remodeling
Remodeling is an important feature in the airways of patients with asthma and chronic obstructive pulmonary disease (COPD). It may contribute to a large extent to the progressive nature of airflow limitation that occurs in virtually all patients with COPD. Moreover, it may negatively influence the severity of symptoms and progression of asthma as well. It is now well accepted that pathologic processes leading to respiratory symptoms occur in the large airways in asthma. In the last decade research has elucidated that inflammation and remodeling in the small airways is equally important. Conversely, peripheral airway disease long has been acknowledged as the core feature of COPD, whereas the last decade has seen much progress toward understanding of the airway inflammation and remodeling in the larger airways in COPD. Studies have only recently compared both airway compartments and it has become somewhat clearer that the inflammatory and remodeling processes may not always be similar in these compartments.
One of the features that is important in this respect is the dissection of the role of inflammatory cells, resident cells (e.g., epithelial cells and fibroblasts), and remodeling with fibrosis of the airways. It is not clear how these cells and the extracellular matrix (ECM) proteins interact, at least not as far as the order of activation and deactivation. Furthermore, the role of the vasculature and of growth factors for vasculature in remodeling processes in the large and small airways is currently underexposed. This article discusses the current views on peripheral and central airway disease. We will put this in perspective of the contribution of the vasculature and vascular endothelial growth factor (VEGF), as well as the interaction between transforming growth factor (TGF), Smad signaling, and the ECM turnover in asthma and COPD.
THICKENING OF THE LAMINA RETICULARIS
The "true" basement membrane, comprising the lamina rara and lamina densa, separates the airway epithelium from the mesenchyme. Although the lamina rara and lamina densa in airways of subjects with asthma are not reported to differ from nonasthmatic subjects, the lamina reticularis is altered in patients with asthma. This region, which is composed of collagen I, collagen III, collagen V, fibronectin, and tenascin, and is situated just below the basement membrane, has an overall thickness of 3 to 4 μm in nonasthmatic subjects, whereas in asthma this is increased two- to threefold (1, 2). Functionally, thickening of the lamina reticularis has been linked to reduced airway distensibility and increased airflow limitation in asthma (3), suggesting that this altered structure has a negative impact on lung function. However, it has been suggested that thickening of the lamina reticularis may actually serve as a protective mechanism by increasing the stiffness of the airways to attenuate the sporadic bronchoconstriction (4).
Less is known about the basement membrane in COPD, with some reports mentioning increased airway wall thickness and others failing to report it. Whatever the reason behind this (e.g., patient selection, sample bias), it is clear that the constituents of the basement membrane are not similar to those of asthma (5).
INCREASED VASCULATURE AND VEGF CONTRIBUTING TO AIRWAY OBSTRUCTION AND FIBROSIS
Vasculature, VEGF, and Asthma
Angiogenesis is an important event both in the development of allergic inflammation and in the pathophysiology of tissue remodeling in atopic diseases (6–11). In the 1960s, a study by Dunnill (12) demonstrated for the first time that subjects with asthma who die of acute attacks have an enlarged capillary bed in the airway wall. Later, increased vascularity in the airways was recognized not only in patients with severe asthma but also in those with mild disease (6, 8). These characteristics can account for considerable swelling and stiffening of the airway wall. Recent studies in the airways of patients with asthma have revealed that the ratio between the level of VEGF and endostatin, proangiogenic and antiangiogenic mediators, respectively, is increased in the sputum of subjects with asthma in comparison with that of control subjects (10). Therefore, it seems that an imbalance in favor of proangiogenic factors leads to the abnormal growth of new blood vessels in asthma. This may then contribute to engorgement of the vasculature and either thickening or stiffening of the airway wall and hence affect airway obstruction.
VEGF and the Vasculature
Numerous inducers of angiogenesis have been identified, including members of the fibroblast growth factor (FGF) family, vascular permeability factor/VEGF, angiogenin, TGF- and TGF-?, platelet-derived growth factor, tumor necrosis factor (TNF-), hepatocyte growth factor, granulocyte-macrophage colony–stimulating factor (GM-CSF), interleukins, chemokines, and angiopoietin 1 and 2 (13). Among them, VEGF is the most potent directly acting regulator of angiogenesis (14, 15), and its expression is often excessive in chronic inflammation and fibrosis (Figure 1, Table 1). The submucosa of the airways of subjects with asthma has higher VEGF, FGF-2, and angiogenin immunoreactivity than that of healthy individuals (9). Importantly, expression of VEGF and its receptors VEGFR-1 and VEGFR-2 inversely correlates with the level of airway obstruction. Furthermore, higher numbers of VEGF-positive cells in the airway wall are associated with basement membrane thickening, involving VEGF in remodeling processes (15).
VEGF induces proliferation, migration, and tube formation of endothelial cells. It promotes secretion of interstitial collagenase (matrix metalloproteinase [MMP]-1) and the expression of chemokines, as well as leukocyte adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin (15).
VEGF and Immune Cells
Interestingly, VEGF also modulates immune cell functions. For example, it inhibits dendritic cell maturation and increases the production of B cells and immature myeloid cells. It can also inhibit the development of T cells from early hematopoietic progenitor cells. In addition, VEGF stimulates monocyte chemotaxis and contributes to hematopoietic stem cell survival and recruitment of bone marrow–derived endothelial cells in angiogenesis (13).
Regulation of VEGF and Angiogenesis
Many growth factors and cytokines can regulate VEGF expression. TGF-? was shown to induce VEGF gene expression and secretion in fibroblasts and epithelial cells. Interleukin (IL)-5 and GM-CSF have a similar effect on eosinophils (6). Many inflammatory mediators, such as prostaglandin E1 (PGE1), PGE2, TNF-, IL-1, IL-6, IL-8, nitric oxide, and platelet-activating factor, have been shown to induce expression of VEGF, angiogenesis, or both (13). Concerning negative regulation of angiogenesis and VEGF, at least 15 molecules are currently known to be endogenous inhibitors, including endostatin, thrombospondin 1, IFN-, angiostatin, and tissue inhibitors of metalloproteinases (TIMPs) (13).
Macrophages, neutrophils, epithelial cells, fibroblasts, and smooth muscle cells are all important sources of VEGF in inflamed tissue (13). Different conditions can induce these cells to release VEGF. Several cytokines and growth factors involved in allergic inflammation and in remodeling are responsible for increasing the basal level of VEGF in fibroblasts, smooth muscle cells, and keratinocytes. For example, bradykinin, IL-1?, IL-5, IL-13, and TGF-? are potent inducers of VEGF in airway smooth muscle cells, and TGF-?, together with IL-4 and IL-13, enhances the synthesis of VEGF in bronchial fibroblasts (16).
VEGF as Chemoattractant
VEGF is a potent chemoattractant for leukocytes in experimental asthma (17) and induces migration of mononuclear cells across an endothelial cell monolayer in vitro (Figure 1). Recent evidence indicates that eosinophil infiltration could be reduced by administration of anti–VEGF receptor antibodies in a murine model of toluene diisocyanate–induced asthma (17). This is possibly due to the fact that VEGF induces eosinophil migration and eosinophil cationic protein release, mainly through VEGF receptor 1 (VEGFR-1). Together with eosinophils, mast cells can also migrate in vivo and in vitro (13) in response to VEGF, suggesting their recruitment to sites of neovascularization during physiologic or pathologic angiogenesis. These results indicate that a positive feedback loop can take place in allergic inflammation, with Th2 mediators inducing VEGF release by eosinophils and mast cells and consequent angiogenesis and VEGF enhancing activation of mast cells and eosinophils.
Vasculature, VEGF, and COPD
Vascular abnormalities have been associated with development of COPD (18, 19). Wright and colleagues reported that there was an increase in wall area of small pulmonary vessels by intimal thickening in patients with mild to moderate COPD and medial thickening in severe cases as well. This thickening was correlated with a decline in FEV1 18, 20. Hashimoto and colleagues compared asthmatic and COPD small and large airways and found that the number of vessels in the medium and small airways in patients with asthma showed a greater increase than those in patients with COPD and control subjects, and the vascular area in the small airways was increased in patients with COPD versus control subjects, but not in asthma (21). Furthermore, it was shown recently that muscular pulmonary and bronchiolar arteries have increased adventitial infiltration of CD8 T lymphocytes (19, 22), cells that are also increased in airway walls in peripheral and central airways.
VEGF and Angiogenesis
Little is known, however, about the molecular mechanisms underlying the loss of alveolar tissue, including the vasculature, in emphysema. VEGF is one of the angiogenic factors that is also associated with COPD. Kranenburg and colleagues (23) found increased VEGF expression and their receptors (VEGFR-1, also called FLT-1, and VEGFR-2 also called KDR/Flk-1) in 14 ex-smoking patients with COPD in comparison with 14 ex-smoking healthy control subjects (23). Patients and control subjects had similar pack-years of smoking (on average, 42 and 44 pack-years, respectively). Patients with COPD had GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II, and four patients used inhaled steroids. They investigated both central and peripheral airways. VEGF expression was increased in bronchial and bronchiolar and alveolar epithelium, and in bronchiolar macrophages, as well as airway smooth muscle cells and vascular smooth muscle cells in both bronchiolar and alveolar regions. The VEGF receptors were increased in patients with COPD as well. Finally, they found an inverse correlation between VEGF and FEV1 in bronchial mucosal microvessels and airway smooth muscle cells, bronchiolar epithelium, and medial vascular smooth muscle cells of the larger pulmonary arteries associated with the bronchiolar airways. TGF-? staining in the bronchiolar epithelium also correlated with VEGF in the same patients. They postulated that VEGF and its receptor system may contribute to the maintenance of endothelial and epithelial cell viability in response to injury. In patients with pulmonary fibrosis, fibrotic regions are densely populated by mast cells and macrophages with increased KDR/Flk-1 expression (24). These cells are also increased in bronchiolar airway epithelium in COPD and have increased expression of TGF-?. Together, these data suggest that TGF-?–VEGF represents a molecular link between inflammatory cell infiltration at sites of smoking-induced injury contributing to airway remodeling in COPD.
FIBROSIS AND DESTRUCTION IN ASTHMA AND COPD: ROLE OF THE Smad PATHWAY
With respect to pathogenesis of COPD, there is a seeming contradiction in the destructive effect of cigarette smoke (CS) exposure in development of emphysema and, at the same time, a fibrotic effect of CS on inner and outer parts of the airway wall of in particular small airways. In asthma, the initial focus was on thickening of the reticular basement membrane (1, 2), which is an early event; more recently, more attention has been given to ECM changes in other parts of the airway wall, like the outer adventitial part (25). With respect to remodeling events in the pathogenesis of COPD, the main focus has been on the destructive effects (as a consequence of imbalance between oxidants and antioxidants and between proteases and antiproteases) (26–29). More recently, more attention has been given to an aberrant repair process, which also may contribute to development or progression of the disease (30).
Proteolysis and Fibrosis
The MMPs and their inhibitors are a main component in the destructive part of the remodeling events (31), whereas in the tissue repair/fibrotic changes, basic FGF (bFGF) and TGF-? play a main role. In particular, with respect to the seeming contradictory events in parenchyma and bronchial wall, interactions between MMPs and TGF-? have been suggested. The increased presence of MMP-9 (gelatinase/collagenase), which is associated with COPD (28, 29), could then coincide with increased presence of TGF-?, which has been found to be up-regulated in bronchial epithelial cells and alveolar type II cells (32, 33). This could, depending on relative contribution of each component in a specific compartment, result in either destructive or fibrotic events respectively. Similarly, increased TGF-? together with possible activation of MMP-12 (elastase) (34, 35) could, similar to the interaction between MMP-9 and TGF-?, have elastolytic together with fibrotic effects, depending on exact localization in either the airways or parenchyma.
Sources of Matrix Production
The main effector cells implied in tissue remodeling events are the fibroblasts, which themselves are a main component of the interstitium and are also main producers of ECM (30). Epithelial cells are resident cells, also capable of ECM production, and fibroblasts as well as epithelial cells are capable of producing TGF-?, MMPs, and proinflammatory mediators (5). With respect to the further intercellular interactions determining the outcome of remodeling events, mediators produced by local inflammatory cells play an important role by activation or inhibition of local production of MMPs and ECM.
Role of the Smad Pathway in Remodeling
With respect to tissue remodeling, apart from the intercellular interactions, aberrations in intracellular events may be of relevance in unravelling the aberrant response to CS as observed in patients with COPD. A very important intracellular pathway that may play a role in pathogenesis of COPD as well as asthma is the Smad pathway (Figure 2), activated through the TGF-? receptor (36–38).
In the Smad pathway, stimulatory as well as inhibitory pathways can be recognized (37). The main stimulatory pathway involves association of Smad-2 and Smad-3, which, together with Smad-4, leads to activation of nuclear transcription of some main ECM proteins such as collagens, versican, and biglycan. The inhibitory pathway is mainly mediated by Smad-7 (Figure 3), which inhibits the pathway described above and in this way also inhibits the transcription for collagen, versican, and biglycan. Together with this inhibitory activity, Smad-7 induces a pathway that leads to nuclear transcription of a limited number of other matrix proteins, of which decorin is most prominent. The fact that the balance in this intracellular Smad pathway itself is also important for actual production of matrix proteins implies that not only changes in TGF-? or TGF-? receptors as such determine whether this would lead to fibrosis or lack of adequate tissue repair. In a previous study on determinants relevant in airway fibrosis and emphysema, we found no differences in collagens in airway walls of small airways in a comparison between patients with mild or severe COPD and normal subjects (39). In lung tissue of patients with severe COPD as compared with mild COPD and control subjects, we found a significant prominent reduction of decorin, and less significantly, of biglycan, in particular in the outer parts (adventitia) of small airways, whereas in the adventitia from arterioles at the same location, no difference in decorin was present (39).
Role of the Smad Pathway in Abnormal Composition of Matrix
Proteoglycans such as decorin and biglycan have important functions, not only as a component of integral construction of the ECM but also as a main regulatory molecule by their ability to bind several cytokines and growth factors (30, 40). With respect to the architecture of ECM, decorin has a main function as a cross-linking molecule between collagen fibrils; in this way, the amount of decorin that is present determines how tight or loose collagen fibrils are attached together. Consequently, a strong increase in decorin would imply stiffening of local collagens, whereas loss of decorin would lead to a loosening and perhaps destruction of collagen structure. This implies that even when an aberrant increase or sustained presence of collagens as seen in small airways would suggest rigidness and fibrosis, this still could be a very loose structure if insufficient decorin were present. Consequently, considering the decrease in decorin we found in the adventitia of small airways in patients with severe COPD with sustained collagen (39) (Figure 4), this implies that although there may still be a thickening of the airway wall, this would be accompanied by loosening of the adventitial collagen and, in due time, loss of elastic recoil. Together with the smoking-related net proteolytic and oxidative effects in COPD, this vulnerability would lead to easy destruction of the peribronchial attachments of the parenchyma to the adventitia of small airways. Moreover, using polymerase chain reaction on tissue derived from small airways in patients with COPD, Springer and colleagues (41) demonstrated that there was a significant decrease of Smad-6 and Smad-7 when compared with normal individuals. This could fit well with our findings that a reduced Smad-7 would be in concordance with a lack of inhibition of fibrotic events in the small airways together with a reduction of presence of decorin production at the same spot. In asthma, similar events are observed in the airways, with reduced decorin in the bronchial mucosa (42), but in fatal asthma less decorin is also found in the external area of small airways (25). Similar to the findings in airways in COPD (41), a reduction of Smad-7 was found in epithelial cells in patients with asthma, with an inverse correlation with basement membrane thickness (38).
Modulating Factors in the Smad Pathway
Although TGF-? is the main inductor of the Smad pathway, the inhibition of the Smad pathway as mediated by Smad-7 can be induced by extracellular influences of TNF-, as produced by the CS-exposed epithelium, and also by CS itself. This would mean that, in a study of the role of tissue repair in development of COPD, not only a locally increased presence of TGF-? (32, 33) is the main determinant of actual production or lack of production of matrix proteins, but also whether and to what extent mediators like TNF-, IFN-, and CS are present in the same pulmonary compartment. This would mean that the actual state of inflammation in airways and also whether a patient with COPD actually smokes are main components in determining the outcome of the local capabilities of matrix production. Although smoking is generally associated with COPD, it should be recognized that the percentage of patients with asthma who smoke is about the same as in the general population (43). This implicates the relevance of the above also for (smoking) patients with asthma.
When considering the reduced presence of Smad-7, it is not yet clear whether this is really a structural difference between tissue from the bronchial wall of patients with COPD and normal subjects or whether this is due to long-term exposure to TNF-, IFN-, CS, or other inhibiting factors. However, because an increase in TGF-? is mainly found in bronchial epithelial cells, and in type 2 alveolar epithelial cells, mainly present around the peribronchial adventitia, this would mean that effects from TGF-? might be expected primarily in the small airway wall and not as much in the parenchyma.
Speculatively, if Smad-7 were structurally reduced in patients with COPD or asthma (38, 41), this could lead to profibrotic events mediated by the regular Smad pathway, with lack of inhibition by Smad-7, but with loosening of the collagenic tissue by lack of decorin. Both in asthma and in COPD, this could lead to fibrotic changes in the airway wall with loss elastic recoil of peribronchial attachments, which would contribute to airway obstruction.
As can be concluded from the above, understanding of the pathogenesis of COPD and asthma includes knowledge of the development of remodeling changes in small and large airways. In COPD, the latter should be studied in conjunction with destructive events in the parenchyma. Pathogenetic studies should therefore include abnormal regulation of remodeling events affecting the local ECM, the connective tissue cells, and vascular changes contributing to the final remodeling effect.
As discussed in this overview, the contribution of vascular changes to remodeling in asthma and COPD is not limited to simple increase in number of small vessels or changes in blood flow. Such vascular changes are phenomena that are the result of the complex regulatory abnormalities in which VEGF and its receptors can be considered as key factors. As described above, VEGF is not only involved in angiogenesis but also plays an important role in regulation of local inflammation and, by its interaction with TGF-?, in regulation of matrix production.
The other important issue in this overview is that the scope of studies of ECM remodeling goes beyond MMPs and TGF-?. In particular, changes in regulation and balance of components of the Smad pathway in epithelial cels and (myo-) fibroblasts deserve attention. Further studies involving this Smad pathway will shed light on complex changes in amount of ECM in general as well as in the composition of this matrix. The latter, particularly where proteoglycans are concerned, can be expected to have profound functional effects on structural integrity as well as on regulation of inflammation.
As the authors have illustrated above for some important parameters in remodeling, results of studies regarding pathogenesis of asthma and COPD should be placed in a perspective of the intercellular as well as intracellular main events in the respective specific pulmonary compartments such as large airways, small airways, alveoli, or lung parenchyma. Such an approach would allow one to find clues for pathogenetic events in these particular tissue compartments and to determine the contribution of the changes in these compartments to the development and progression of disease. An important implication of realizing differences in the microenvironment of the different lung compartments is that this will have consequences for future targets for therapy and thus for the way future therapeutic interventions have to be targeted to the selective pulmonary compartments.
FOOTNOTES
Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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