1 Department of Pediatrics, University of Alabama at Birmingham and Children's Hospital of Alabama, Birmingham, Alabama 35233; and 2 Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, Arkansas 72202
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Chronic lung disease due to
interstitial fibrosis can be a consequence of acute lung injury and
inflammation. The inflammatory response is mediated through the
migration of inflammatory cells, actions of proinflammatory cytokines,
and the secretion of matrix-degrading proteinases. After the initial
inflammatory insult, successful healing of the lung may occur, or
alternatively, dysregulated tissue repair can result in scarring and
fibrosis. On the basis of recent insights into the mechanisms
underlying acute lung injury and its long-term consequences, data
suggest that proteinases, such as the matrix metalloproteinases (MMPs),
may not only be involved in the breakdown and remodeling that occurs
during the injury but may also cause the release of growth factors and
cytokines known to influence growth and differentiation of target cells within the lung. Through the release of and activation of
fibrosis-promoting cytokines and growth factors such as transforming
growth factor-1, tumor necrosis factor-
, and
insulin-like growth factors by MMPs, we propose that these
metalloproteinases may be integral to the initiation and progression of
pulmonary fibrosis.
acute respiratory distress syndrome; bronchopulmonary dysplasia; lung fibrosis; cytokines; emphysema
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
PULMONARY FIBROSIS CAN BE an all too common consequence of an acute inflammatory response of the lung to a host of inciting events. Chronic lung injury due to fibrotic changes can result from an identifiable inflammatory event, or an insidious, unknown event (i.e., idiopathic pulmonary fibrosis) may precipitate the fibroproliferative reaction (5, 94, 113). Although inflammation may be evident in the early stages of disease, fibrosis and interstitial scarring are generally considered late and ominous events in lung injury. The inflammatory process can include infiltration of various inflammatory cell types, such as neutrophils and macrophages, the release of inflammatory cytokines and chemokines, and the secretion of matrix remodeling proteinases, principally the matrix metalloproteinases (MMPs). The progression from the initial inflammatory reaction to the subsequent fibroproliferative manifestations is poorly understood. However, a large body of literature now points to several growth factors and cytokines as key modulators in the initiation and progression of fibrotic events in the lung (61, 69). It is through multiple attempts to heal itself that the injured lung ultimately fails to reepithelialize denuded surfaces, demonstrates dysregulated and inadequate repair of alveoli, undergoes impaired extracellular matrix (ECM) remodeling, experiences excessive fibroblast migration and proliferation, and shows an exaggerated response to fibrogenic cytokines (61, 69, 94). It is now known that the seminal event in the initiation of fibrosis occurs at primary sites of ongoing injury and repair that have been identified as regions or nests of fibroblastic proliferation, so-called fibroblast foci (90). These sites represent focal points for the abundant deposition of many constituents of the ECM and expression of MMP activity. Furthermore, within these aggregates, myofibroblasts and fibroblasts actively proliferate, resulting in microscopic sites of ongoing alveolar epithelial injury associated with progressive fibrosis (90).
In many acute and chronic inflammatory events, followed by a period of
healing, MMPs have been shown to be upregulated, and their activities
have been shown to be important for alveolar repair. Several studies
demonstrate that type II pneumocytes are responsible for carrying out
alveolar reepithelialization. They are capable of producing MMP-1
(collagenase-1), and the addition of MMPs to wound models promotes
pneumocyte migration (77, 81). These same features are
similarly observed in the repair and reepithelialization of the skin
after injury (80). Therefore, MMPs likely are instrumental in the normal reepithelialization process of the alveolar surface that
occurs after an acute inflammatory event and during the regenerative process. Indeed, several animal models of pulmonary fibrosis have shown
that MMPs are important in the reepithelialization of the damaged lung
(12, 60). Histological examination of normal lungs and
lungs from patients with various degrees of interstitial disease also
points to MMPs and their inhibitors, tissue inhibitors of
metalloproteinases (TIMPs), as having a mechanistic role in the
development of fibrosis (32, 42). Interestingly, while MMPs appear to be involved in the initiation and progression of fibrosis, this would seem paradoxical since MMPs have classically been
described as proteases involved in the destruction of ECM, whereas the
process of fibrosis involves the building up and excess production of
ECM molecules by hyperproliferating mesenchymal cells. Thus it appears
that MMPs may also play ancillary roles in fibrosis that are not linked
to ECM degradation. Recent data suggest that beyond the effects of MMPs
to enhance ECM turnover and promote tissue remodeling, they may also
have profound effects on the release of growth factors and cytokines
known to affect fibrosis such as insulin-like growth factors (IGFs),
transforming growth factor- (TGF-
), and tumor necrosis factor-
(TNF-
) (14, 101, 112, 116). From an extensive survey of
the literature, it is now well established that a large part of
alveolar macrophage action is mediated by production of a large number
of growth factors (22). In the context of the lung, we
review direct and indirect evidence suggesting there is a potentially
important link between MMP activity and profibrotic growth factor
bioavailability, thus creating an environment of potentiating fibrosis
in the lung.
![]() |
MMPS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
MMPs currently comprise a family of zinc-dependent,
matrix-degrading proteinases that are highly homologous and number over 20 family members (for a recent review, see Ref. 74).
Their activities are highly regulated by TIMPs, of which four members have been described (TIMPs 1-4) (15). Classically,
MMPs have been subclassified into functional groups based on their
substrate specificity (Table 1):
collagenases that are active against fibrillar forms of
collagen; gelatinases that have high activity against denatured
collagens (type IV collagen); stromelysins that exhibit activity
against a wide array of noncollagen components of the ECM; and the
recently described membrane type MMPs (MT-MMPs) that are transmembrane
MMPs that have activity against some ECM molecules as well as
activating other MMP family members (74, 101). With the
exception of MT-MMPs, MMPs are secreted as inactive proenzymes, requiring the cleavage of a propeptide for activation
(74). Once activated, their proteolytic activity within
tissues is primarily regulated through a balance between the production
and secretion of TIMPs and MMPs. TIMPs 1-4 can form stable
complexes with MMPs, usually in a 1:1 molar fashion (3,
13); thus a highly coordinated and intricate balance among
production, activation, and inhibition is necessary to prevent untoward
effects of these proteinases on tissue morphology and homeostasis.
|
![]() |
MMPS AND THE LUNG |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Under normal circumstances, MMPs are likely involved in the normal development of the lung. They have been implicated in promoting branching morphogenesis and the development of airway glands (55, 79). For instance, during the pseudoglandular stage of lung development, epithelial cells must invade the submucosa, which requires remodeling of the basal lamina. Animal studies suggest that expression of MMP-2 is important in this process (55). Review of the literature also suggests a role for MMPs in the regulation of lung matrix turnover, promoting angiogenesis, and also in the immunoprotection of the lung through allowing migration of inflammatory cells into infected or damaged lung tissues (79).
Although several groups of proteinases have been implicated in the lung damage observed in both acute and chronic lung injury, including proteinases such as neutrophil elastase, cathepsin G, and proteinase 3 (103), it is the MMPs that have recently received attention because of their capacity to cause severe damage to the lung when overexpressed in the lung parenchyma. Attempts to identify the source of these proteinases within the human lung show that several types of cells, including neutrophils, alveolar macrophages, and even airway epithelial cells, produce several different MMPs and TIMPs (96, 99). MMPs are produced by lung epithelial cells in sheets of airway lining cells, lung epithelial cell cultures from human lung explants, and in normal and neoplastic human lung tissue (17, 51, 117). Because inflammatory cell types such as neutrophils and macrophages produce several different forms of MMPs and their induction can be markedly enhanced under the influence of proinflammatory cytokines, these cells have been viewed as likely sources of MMPs in lung inflammation and injury (96, 99).
MMP-1, when transgenically overexpressed, results in emphysematous lung disease, whereas deletion of the MMP-12 gene in mice results in protection against cigarette smoke-induced emphysema (29, 31, 47). Similarly, lungs from mice made null for TIMP-3 show increased alveolar septation and histological evidence of emphysema, suggesting that unchecked proteinase activity can result in degradation of basement membranes within the lung (62). Thus on the basis of transgenic modeling, MMPs appear to be critical in the development and maintenance of lung architecture and function, with dysregulation in their activities resulting in lung damage. Furthermore, studies on humans now support a role for MMPs and an imbalance of MMP and TIMP homeostasis in the pathogenesis of several well-recognized pulmonary disorders associated with increased risk of hyperproliferative and/or fibrotic lung changes, including acute respiratory distress syndrome (ARDS), neonatal respiratory distress syndrome (RDS), chronic reactive airway disease, and idiopathic interstitial pneumonias (51, 52, 58, 93, 97, 104, 109, 114).
![]() |
MMPS IN LUNG DISEASES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Acute lung injury and acute respiratory distress syndrome. Acute lung injury (ALI) can be a devastating disease, which not uncommonly can progress to ARDS. Although in recent years progress has been made in the definition and understanding of the natural history of ALI and ARDS, our understanding of the pathophysiology underlying these disorders remains incomplete. Although the mainstay of therapy in these patients remains primarily supportive in nature, even with the use of aggressive supportive care the current overall mortality rate in all age groups continues to be >40% (11, 49, 50, 114). Although the lungs from some individuals with ALI may heal normally, in others, progression to fibrosing alveolitis with persistent hypoxemia, increased alveolar dead space, and a persistent decrease in pulmonary compliance is seen (7, 83). Histologically, lungs from these individuals may show fibrosis associated with inflammatory cell infiltrates, while the alveolar space may be filled with mesenchymal cells and profibrotic factors (43). The initiation of fibrosing alveolitis likely begins early in the course of ARDS, during the time that the lung may be exposed to other inflammatory mediators, such as MMPs (114). The events leading to fibrosis in this disorder are critical to preventing mortality, because fibrosing alveolitis on histological analysis correlates with an increased risk of death (67).
In ARDS, MMPs and TIMPs can be easily detected by sampling fluids obtained from bronchoalveolar lavage (BAL). In adult patients with active ARDS, an increase in MMP-2 (72-kDa gelatinase or gelatinase A) and MMP-9 (92-kDa gelatinase or gelatinase B) as well as in TIMP-1 has been shown in BAL fluid (25). In addition, inflammatory cells, which are increased in the respiratory tract of patients with ARDS, appear to be involved in releasing MMPs into the alveolar and pericellular space (51). In vitro studies have shown that stimulation of human alveolar macrophages with lipopolysaccharides (LPS), to simulate ARDS, results in an increase in the release of MMPs, primarily MMP-9, as well as TIMPs (98). Neutrophils have also been shown to make and store MMPs, and in the presence of inflammatory mediators, to secrete preformed MMPs from storage vesicles (20). Furthermore, LPS increases the release of MMP-9 and MMP-2 by human bronchial epithelial cells obtained from biopsies but does not modify TIMP-1 release, suggesting an imbalance in favor of MMPs leading to degradation of ECM components. In vivo models of acute lung injury have shown an important role for increased MMP activity in mediating pulmonary damage induced by immune complexes, hyperoxia, cardiopulmonary bypass, ozone, or LPS. LPS exposure leads to an increase of MMP-2 and MMP-9 in BAL fluid from several different animal models (27, 33, 34, 111), and a synthetic MMP inhibitor prevents the pathological changes typical of acute lung injury after cardiopulmonary bypass in an animal model of lung injury (18). This is corroborated in an endotoxin-induced lung injury model showing that a modified tetracycline (COL-3), a potent inhibitor of MMPs, prevents the development of ARDS. MMP-2 and MMP-9 levels were significantly increased in this ARDS model, but pretreatment with COL-3 ameliorated the rise in MMP-2 and MMP-9 levels (19). Recently, Gibbs and colleagues (45) have confirmed a specific role for MMPs in vivo in alveolar macrophage-mediated acute lung injury associated with both immune complexes and LPS by showing that TIMP-2 can diminish the lung damage seen in both models. Mechanical ventilation has also been associated with acute lung injury and has been thought to possibly contribute to and/or worsen the clinical course of individuals suffering from ARDS. In a rat model examining high-volume ventilation, upregulation of MMP-2, MMP-9, and MMP-14 was demonstrated, and pretreatment with the MMP inhibitor Prinomastat lessened the lung injury (36). To directly examine the role of MMPs in acute lung injury, studies have now been performed in genetically modified animals made null for different MMPs. In mice made null for MMP-3 and MMP-9, acute lung injury from exposure to immunoglobulin G immune complexes results in less severe lung damage than in their genetically normal littermates, confirming a role for these proteinases in the destruction of lung tissue after an acute lung injury (115). Together, these data support that MMPs are elevated in adult humans with ARDS as well as in animal modeling of ARDS, suggesting that their inhibition may be a useful means to control the acute effects of these proteinases on the dissolution of lung tissue. However, the data does not address the issue of how enhanced MMP activity may in the long run contribute to the fibrotic and scarred lung seen in this disorder.Neonatal RDS. RDS in infants is characterized by surfactant depletion and often leads to chronic lung disease, known as bronchopulmonary dysplasia (BPD). After the acute phase of the disease, lung regeneration begins to occur by reepithelialization of damaged alveoli. In the late and chronic stages of the disease, alveoli are lined primarily with type II pneumocytes, and within areas of fibrosis, increased numbers of fibroblasts are observed (4). Recent evidence suggests that the inflammation in RDS may contribute to lung damage by increasing the release of proteolytic enzymes. A recent study demonstrated that in preterm infants, an imbalance between MMP-8 and TIMP-2 exists (21). Tracheal aspirate samples were collected from preterm neonates during their first five postnatal days, and MMP-8 levels were found to be higher in tracheal fluid from the babies who subsequently developed BPD compared with children who did not go on to develop chronic lung disease. In addition, TIMP-2 levels were lower in the infants who required prolonged mechanical ventilation (21). Another recent study supported that MMP-8 can be found in BAL fluid from preterm babies, with higher levels being seen in the children who later develop BPD (106). Finally, immunohistochemistry localization of MMP-1, TIMP-1, and TIMP-2 has been investigated in postmortem lung tissue from infants who died during different phases of BPD development (32). These studies show that type II pneumocytes produce immunoreactive MMP-1 and both TIMPs. Furthermore, fibroblasts located within fibrotic foci express MMP-1, TIMP-1, and TIMP-2, supporting the hypothesis that MMPs contribute to the development of RDS, and that in the case of MMP-8, the degree of expression correlates with the long-term fibrotic picture seen in the lungs of these children.
Asthma. Asthma is a chronic inflammatory condition of the airways and lung parenchyma. Bronchial biopsies from patients with asthma demonstrate increased numbers of T helper lymphocytes and eosinophils, with inconsistently observed increases in mast cell numbers (56). New data support the concept that asthma may represent an aberrant repair response of the respiratory epithelium to injury (85). This results in a persistent proinflammatory milieu of epithelium-derived cytokines and growth factors that drive the chronic inflammatory response and remodeling activities seen in the subepithelial compartments, which include subepithelial fibrosis, activation of adjacent fibroblasts/myofibroblasts, increased smooth muscle cell mass, goblet cell hyperplasia, and submucosal gland hypertrophy (reviewed in Ref. 56).
Because airways in asthma display chronic inflammation, it is probable that MMPs may be oversecreted in this condition. Indeed, studies in asthmatics show that compared with normal subjects, MMP-9 is increased in BAL fluid and sputum of asthmatic subjects (58, 109, 119). Other studies reveal that MMP-9 immunoreactivity is increased in bronchial biopsies of asthmatics (54). In asthmatic patients with increased levels of MMP-9, MMP-1 (collagenase-1), MMP-2, and MMP-3 (stromelysin-1) levels were generally 8-30 times less than MMP-9 levels. However, other forms of MMPs were not measured (119). Thus it appears that an increase in MMP-9 production and/or secretion by cells lining the bronchiolar and alveolar surfaces, such as alveolar macrophages, may contribute to the pathogenesis of asthma and possibly other reactive airway disease, such as chronic obstructive pulmonary disease (COPD).Emphysema/COPD. COPD is characterized by loss of lung parenchyma and enlargement of the air spaces with loss of functioning alveoli. In COPD, bronchoscopic evaluation reveals inflammation of bronchiolar epithelium and increased release of proinflammatory cytokines (108). There is infiltration of the wall of small airways by T suppressor/cytotoxic cells, and there is an increase in the number of macrophages in the airways and alveolar spaces (91). This inflammatory pattern appears to be associated with chronic changes referred to as "respiratory bronchiolitis-associated interstitial lung disease," which includes septal thickening of alveolar walls and patchy alveolar wall fibrosis with a peribronchiolar distribution (56, 72).
There is significant evidence that an excess of proteolytic activity over the inhibitory capacity of the lung is associated with parenchymal destruction in COPD and emphysema. Recently, there has been considerable speculation on the potential involvement of MMPs in the matrix degradation in emphysematous lung disease. Finlay et al. (35) in 1997 were the first to report that MMPs were involved in the development of emphysema. In patients with emphysema, both MMP-1 and MMP-9 levels are increased in BAL fluid compared with control smoking patients without emphysema. In addition, increased activity of MMP-9 and MMP-2 in the lung parenchyma of patients with emphysema has been reported (9). Animal models also support the role of MMPs in the development of emphysema. Mice made null for MMP-12 are significantly protected from smoke-induced emphysema compared with wild-type animals (48, 96). Clearly, MMPs appear to play a role in the ECM destruction seen in COPD and possibly in the concomitant fibrosis. They may also be potentially critical to the continued distortion of the lung parenchyma seen with emphysematous changes. Although their role in the development of fibrosis and hyperplasia in these disorders is not as clear, cytokines and chemokines are elevated in the sputum of patients with COPD (57).Interstitial pulmonary fibrosis. Interstitial pulmonary fibrosis (IPF) is a chronic fibrotic lung disorder of unknown origin characterized by a progressive interstitial fibrosis, which ultimately leads to respiratory failure. IPF is characterized by progressive dyspnea, dry cough, crackles, decreased lung volumes, and diffuse reticulonodular opacities on chest X-ray. Fibroblast proliferation and abnormal accumulation of ECM occurs in the damaged alveoli, leading to subsequent abnormal lung remodeling within fibroblast foci (90). The abnormal ECM remodeling observed in the lungs of patients with IPF is due, at least in part, to an imbalance between some MMPs and TIMPS (42, 48, 95). Normal lung fibroblasts do not make MMP-9 in vitro, whereas fibroblasts from IPF lungs strongly express MMP-9. In addition, fibroblasts from patients with IPF express increased levels of all TIMPs (90). In this setting, TIMPs may play a role in apoptosis in some cell populations or increased proliferation of other cell populations. Interestingly, TIMP-2 is almost exclusively expressed in the fibroblast foci, which is considered the site where most ongoing lung injury and fibrosis occur (90). In vitro studies of alveolar macrophages obtained from untreated patients with idiopathic pulmonary fibrosis showed marked increases in MMP-9 secretion compared with macrophages collected from normal individuals (64). In animal models of bleomycin-induced pulmonary fibrosis, MMPs have been shown to be elevated in BAL fluid. Indeed, a synthetic inhibitor of MMP, Batimastat, has been shown to significantly reduce bleomycin-induced lung fibrosis, again pointing to the importance of MMPs in the development of this fibrotic disease of the lung (26).
![]() |
GROWTH FACTOR-MMP INTERACTIONS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Data clearly support a prominent role for MMPs in the pathogenesis
of several well-recognized disorders of the lung as summarized above.
However, it is unclear what molecules, beyond ECM, might be targets for
these proteinases. Indeed, because MMP production precedes or parallels
the development of fibroproliferative events in the lung, it seems
plausible that MMPs may play an expanded role in profibrotic events
that occur in lung pathology. Several mechanisms have been invoked to
explain how cellular activities may be linked to MMP action (reviewed
in Ref. 102). First, cell-matrix and cell-cell
interactions may be modified. For example, MMP-mediated cleavage of
laminin-5 generates a fragment (2-chain fragment) that
can enhance cell motility (40). In addition, MMPs have been shown to cleave cell surface molecules involved in cell-cell interactions such as E-cadherin (75). Second, MMPs, such
as MMP-7, have been shown to modify cell surface shedding of proteins such as Fas ligand. Therefore, MMP actions may be important in regulating Fas-mediated apoptosis (84). Third,
MMPs may function to modulate the migration of cells into a given
location, as has been shown for MMP-mediated cleavage of
1-proteinase inhibitor, which results in the release of
a bioactive chemoattractant for neutrophils (8). Finally,
a number of studies have shown that the actions of MMPs can result in
the release of growth factors and cytokines, which may have a myriad of
effects on cellular growth and proliferation (41, 112,
116). It is this final pathway of how MMPs may interface with
growth factor release and activation in the lung that we will explore.
The roles of several well-described growth factors and cytokines have
been implicated in the pathogenesis of lung fibrosis (2, 61,
69). However, a number of profibrotic growth factors require
proteolytic processing for their activation or release from ECM or
carrier proteins before they can exert their mitogenic and metabolic
effects (reviewed in Ref. 107). Few studies have examined
how sequestered or inactivated profibrotic growth factors are released
during the pathogenesis of pulmonary fibrosis. Recent studies show that
the proteolytic processing of several key growth factors involved in
fibrosis occurs through the actions of MMPs, thereby activating or
releasing them from inhibitory protein-protein interactions. Included
among this group are several growth factors that have been shown to be
involved in the fibrotic process, including IGFs, TGF-, and TNF-
.
We next review recent data suggesting that MMPs are critical
proteinases in the release and/or activation of these three profibrotic
growth factors and highlight how this interplay may be involved in the
fibroproliferative process within the lung.
IGFs. Recent reports suggest a role for IGFs in the process of lung repair after acute lung injury (70). However, while IGFs may play important roles in the normal growth and restoration of lung tissue, they also have been implicated in fibrotic events taking place within several tissues, including the lung. Indeed, in IPF, studies have revealed that epithelial cells can express several cytokines and growth factors that can both promote fibroblast migration and proliferation as well as enhance the formation and accumulation of ECM (61). Among the growth factors produced by primary human airway epithelial cells, it is IGF-I secreted by these cells that accounts for the majority of the growth-promoting activity directed at lung fibroblasts (16). IGF-I has also been shown to be increased in early-stage IPF with minimal fibrosis and has been colocalized with several cell types, including alveolar macrophages and type II pneumocytes. However, it appears that as IPF progresses, IGF-I is expressed primarily by alveolar macrophages (53).
While IGFs are expected to be involved in the fibrotic process, IGFs in vivo are sequestered by six high-affinity IGF-binding proteins (IGFBPs 1-6), preventing their ability to interact with IGF receptors (23). Studies examining adults and children with IPF and interstitial lung disease show that IGFBP-3 and IGFBP-2 levels are increased in IPF BAL fluid (1, 22). Furthermore, increased IGF levels have been documented in idiopathic pulmonary fibrosis in adults, suggesting that both IGFs and their carrier proteins are overexpressed in interstitial lung disease (6). MMPs have recently been shown to regulate the cleavage of IGFBPs, thereby liberating the complexed ligand to affect IGF actions in target cells. Because IGFBPs bind IGFs with equal or higher affinity than IGF receptors, proteolysis of IGFBPs is thought to play a major role in the regulation of IGF activity (38, 40). Specifically, IGFBP-3 can be cleaved by MMP-1, MMP-2, and MMP-3. In addition, IGFBP-5 is cleaved by MMP-1 and MMP-2 (37, 39, 110). The hypothesis that MMPs may affect IGF bioavailability in vivo has been corroborated by the finding that mice genetically susceptible to developing liver tumors are protected from tumor development through the overexpression of TIMP-1. This phenomenon is associated with increased levels of intact IGFBP-3 and decreased IGF signaling, demonstrating that MMPs are involved in IGF bioavailability and IGF action at the cellular level through modulating the levels of IGFBPs in the tissue compartment (68). The impact of MMP activity on IGF action in the lung is largely unknown. However, recent data from our laboratories have shown that normal human lung secretions contain several MMPs as well as several IGFBPs (Winkler, Folds, Ferguson, and Fowlkes, unpublished data). Furthermore, IGFBP-3 was found in both its intact form as well as multiple fragments, suggesting that IGFBP-3 may be degraded by MMPs in the lung (unpublished data). The interaction of MMPs and IGF action has been demonstrated in airway smooth muscle cells. In this reactive airway disease model, the asthma-associated proinflammatory eicosanoid leukotriene D4 was shown to enhance IGFBP-2 degradation, and the proteinase implicated in the degradation was identified as MMP-1. Furthermore, TIMP-1 and the synthetic inhibitor of MMPs, Batimastat, inhibited the proteolysis of IGFBP-2 (89). In situ studies have also supported that MMPs may be involved in IGFBP proteolysis in the asthmatic lung. MMP-1 has been demonstrated in human airway tissue sections from nonasthmatic and asthmatic subjects with the immunostaining for MMP-1 being 12-fold higher in asthmatics in both the bronchial and tracheal smooth muscle cells compared with normal lung sections. Furthermore, levels of IGFBP-2 and IGFBP-3 were found to be extensively proteolyzed by extracts from asthmatic airway tissues. Interestingly, the IGFBP-degrading proteinase activity in the extracts could be specifically reduced using immunodepletion of MMP-1, suggesting strongly that MMPs are involved in IGFBP processing in the asthmatic lung (88). Indirect evidence also suggests that similar mechanisms may be operative in other conditions associated with pulmonary fibrosis, such as sarcoidosis, in which IGFBP-3 in BAL fluid has been shown to be extensively degraded (1). Although the interactions of MMPs on IGF action in vivo within the lung appear likely, more studies will be necessary to establish such an association. However, findings to date suggest that MMPs may be important regulators of IGF bioavailability, and this level of control may be important in modulating these mitogens, which can increase fibroblast proliferation and collagen production in the pathogenesis of lung fibrosis.TGF-.
TGF-
is expressed as three different isoforms, and knockout
studies examining each isoform have resulted in mice with significantly abnormal lungs, strongly suggesting that TGF-
is important in normal
lung growth and development (92). However, despite its necessary developmental affects, TGF-
1 has been strongly
associated with pulmonary fibrosis and has been demonstrated to be
upregulated in the fibrotic lung at sites of fibrotic foci (24,
61). Furthermore, its administration via gene transfer into
animal models results in severe parenchymal and airway fibrosis
(100). However, normally, TGF-
is secreted in an
inactive form due to its incorporation into a large latent complex with
TGF-
latency-associated protein (LAP) and latent TGF-
binding
proteins, which can tether the latent complex in the ECM
(107). Under homeostatic conditions, very little free,
active TGF-
is available compared with the LAP-bound latent form,
thereby preventing signal transduction and uncontrolled fibrosis. In
order for growth factor action to take place, TGF-
must first be
liberated from these inhibitory proteins, a process generally believed
to occur through proteolytic protein processing (14, 107).
The precise mechanism by which TGF-
activation occurs in vivo is
unclear; however, several molecules, such as plasmin, thrombospondin 1, and integrin may be involved (30, 66, 73), either by
proteolytic cleavage of the latent TGF-
complex, or, as is the case
with plasmin, through conformational changes induced through
protein-protein interactions.
TNF-.
Other growth factors, such as TNF-
, may be expressed as a
membrane-bound protein, requiring proteolytic cleavage to release soluble and active ligand (65). TNF-
is an inflammatory
cytokine that was originally described as being shed from cell surfaces by a cation-dependent proteinase (59). An important role
for TNF-
in interstitial fibrosis of the lung has been established using transgenic mice, which either overexpress or demonstrate a
deficiency of this cytokine. For example, mice transgenically modified
to overexpress TNF-
develop lung fibrosis. In contrast, mice null
for TNF-
or null for both TNF-
and the TNF-
receptor show
marked resistance to bleomycin-induced fibrosis (2, 61). Interestingly, pirfenidone, a novel antifibrotic agent with
anti-TNF-
properties, has now been shown to have some effect in
treating patients with idiopathic pulmonary fibrosis (87).
Recently, two independent groups described simultaneously the cloning
of a metalloproteinase with high homology to MMPs, designated TNF-
converting enzyme or TACE, later designated ADAM-17 (reviewed in Refs.
13 and 14). This proteinase, which
cleaves TNF-
, although not inhibited by TIMP-1 or TIMP-2, is
inhibited by TIMP-3 (41). However, other data suggest that
TACE is not alone in its capacity to cleave TNF-
. Several studies
now suggest that a number of MMPs, including MMP-1, MMP-2, MMP-3,
MMP-7, and MMP-9, may be involved in TNF-
shedding. For instance,
MMP-17 or membrane type 4-MMP (MT4-MMP) expressed in COS-7 cells has
been shown to localize to the cell surface, but not activate pro-MMP-2,
as do other MT-MMPs. However, MT4-MMP is able to cleave a peptide
consisting of the pro-TNF-
cleavage site and is able to shed
pro-TNF-
when cotransfected in COS-7 cells. MT4-MMP has been
detected in monocyte/macrophage cell lines, which in combination with
its fibrinolytic and TNF-
-converting activity suggests a role in
inflammation and its ramifications (41). In vivo, MMP-7
has been associated with the release of TNF-
and the subsequent
upregulation of MMP-3, resulting in degradation of ECM in a model of
herniated intervertebral disks (46). Because MMP-7 is
secreted in airway and peribronchial epithelial cells and is
upregulated in models of airway injury, it is possible that this MMP is
also involved in the release of this profibrotic cytokine in the lung
(78). This is supported by recent studies showing that the
MMP inhibitor Batimastat decreases TNF-
levels in BAL fluid in an
LPS model of acute lung injury (78). These studies suggest
that by modulating MMP activity, the effects of proinflammatory and
profibrotic cytokines, such as TNF-
, may be curtailed by inhibiting
their shedding from cell surfaces.
Conclusions.
The consequences of acute, persistent, or recurrent lung injury and
inflammation can lead to various degrees of pulmonary fibrosis,
alveolar scarring, and chronic lung dysfunction. Although there are
likely many interactions among proinflammatory events within the lung
after injury such as ECM destruction and remodeling, cellular death and
proliferation, and ultimately either adequate repair or dysregulated
reconstruction, we have presented herein support for the idea that
proteinases, primarily of the MMP family, may be critical enzymes not
only in the breakdown and remodeling of lung tissues but also in the
release and/or activation of profibrotic growth factors such as IGFs,
TGF-, and TNF-
. Indeed, there may even be more interplay among
MMPs and growth factors and cytokines than we have detailed because
MMPs appear to be capable also of releasing or activating such
varied mitogens as interleukins, fibroblast growth factor, and
heparin-binding epidermal growth factor-like growth factor (HB-EGF)
(Table 2) (10, 41, 76, 86, 105,
107). A number of these same cytokines and growth factors have been shown to increase MMP production, alter TIMP expression, or enhance MMP activity through promoting an imbalance in
MMP:TIMP ratios favoring MMP action. Therefore, it is possible that a
self-perpetuating cycle may be established within the injured lung
wherein MMPs release cytokines and growth factors, which then enhance
MMP activity, furthering the release and effects of these mitogens on
target cells such as the fibroblasts and myofibroblasts, which comprise
the fibrotic foci.
|
![]() |
ACKNOWLEDGEMENTS |
---|
This work was supported by American Lung Association Grant CG-002-N (to M. K. Winkler) and partially by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-055653 (to J. L. Fowlkes).
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: M. K. Winkler, 1600 7th Ave. S., ACC #504, Birmingham, AL 35233 (E-mail: Mwinkler{at}peds.uab.edu).
10.1152/ajplung.00489.2001
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Allen, JT,
Bloor CA,
Knight RA,
and
Spiteri MA.
Expression of insulin-like growth factor binding proteins in bronchoalveolar lavage fluid of patients with pulmonary sarcoidosis.
Am J Respir Cell Mol Biol
19:
250-258,
1998
2.
Allen, JT,
and
Spiteri MA.
Growth factors in idiopathic pulmonary fibrosis: relative roles.
Respir Res
3:
13,
2002[Medline].
3.
Amour, A,
Slocombe PM,
Webster A,
Butler M,
Knight CG,
Smith BJ,
Stephens PE,
Shelley C,
Hutton M,
Knauper V,
Docherty AJ,
and
Murphy G.
TNF- converting enzyme (TACE) is inhibited by TIMP-3.
FEBS Lett
435:
39-44,
1998[ISI][Medline].
4.
Anderson, WR.
Bronchopulmonary dysplasia: a correlative study by light, scanning, and transmission electron microscopy.
Ultrastruct Pathol
14:
221-232,
1990[ISI][Medline].
5.
Armstrong, L,
Thickett DR,
Mansell JP,
Ionescu M,
Hoyle E,
Billinghurst RC,
Poole AR,
and
Millar AB.
Changes in collagen turnover in early acute respiratory distress syndrome.
Am J Respir Crit Care Med
160:
1910-1915,
1999
6.
Aston, C,
Jagirdar J,
Lee TC,
Hur T,
Hintz RL,
and
Rom WN.
Enhanced insulin-like growth factor molecules in idiopathic pulmonary fibrosis.
Am J Respir Crit Care Med
151:
1597-1603,
1995[Abstract].
7.
Bachofen, M,
and
Weibel ER.
Structural alterations of lung parenchyma in the adult respiratory distress syndrome.
Clin Chest Med
3:
35-56,
1982[ISI][Medline].
8.
Banda, MJ,
Rice AG,
Griffin GL,
and
Senior RM.
1-Proteinase inhibitor is a neutrophil chemoattractant after proteolytic inactivation by macrophage elastase.
J Biol Chem
263:
4481-4484,
1988
9.
Barnes, PJ.
Chronic obstructive pulmonary disease.
N Engl J Med
343:
269-280,
2000
10.
Bergers, G,
Brekken R,
McMahon G,
Vu TH,
Itoh T,
Tamaki K,
Tanzawa K,
Thorpe P,
Itohara S,
Werb Z,
and
Hanahan D.
Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.
Nat Cell Biol
2:
737-744,
2000[ISI][Medline].
11.
Bernard, GR,
Artigas A,
Brigham KL,
Carlet J,
Falke K,
Hudson L,
Lamy M,
Legall JR,
Morris A,
and
Spragg R.
The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination.
Am J Respir Crit Care Med
149:
818-824,
1994[Abstract].
12.
Betsuyaku, T,
Fukuda Y,
Parks WC,
Shipley JM,
and
Senior RM.
Gelatinase B is required for alveolar bronchiolization after intratracheal bleomycin.
Am J Pathol
157:
525-535,
2000
13.
Black, RA,
and
White JM.
ADAMs: focus on the protease domain.
Curr Opin Cell Biol
10:
654-659,
1998[ISI][Medline].
14.
Blobel, CP.
Remarkable roles of proteolysis on and beyond the cell surface.
Curr Opin Cell Biol
12:
606-612,
2000[ISI][Medline].
15.
Brew, K,
Dinakarpandian D,
and
Nagase H.
Tissue inhibitors of metalloproteinases: evolution, structure and function.
Biochim Biophys Acta
1477:
267-283,
2000[ISI][Medline].
16.
Cambrey, AD,
Kwon OJ,
Gray AJ,
Harrison NK,
Yacoub M,
Barnes PJ,
Laurent GJ,
and
Chung KF.
Insulin-like growth factor I is a major fibroblast mitogen produced by primary cultures of human airway epithelial cells.
Clin Sci
89:
611-617,
1995[ISI][Medline].
17.
Carnete-Soler, R,
Litzky L,
Lubensky I,
and
Muschel RJ.
Localization of the 92 kd gelatinase mRNA in squamous cell and adenocarcinomas of the lung using in situ hybridization.
Am J Pathol
144:
518-527,
1994[Abstract].
18.
Carney, DE,
Lutz CJ,
Picone AL,
Gatto LA,
Ramamurthy NS,
Golub LM,
Simon SR,
Searles B,
Paskanik A,
Snyder K,
Finck C,
Schiller HJ,
and
Nieman GF.
Matrix metalloproteinase inhibitor prevents acute lung injury after cardiopulmonary bypass.
Circulation
100:
400-406,
1999
19.
Carney, DE,
McCann UG,
Schiller HJ,
Gatto LA,
Steinberg J,
Picone AL,
and
Nieman GF.
Metalloproteinase inhibition prevents acute respiratory distress syndrome.
J Surg Res
99:
245-252,
2001[ISI][Medline].
20.
Cawston, T,
Carrere S,
Catterall J,
Duggleby R,
Elliott S,
Shingleton B,
and
Rowan A.
Matrix metalloproteinases and TIMPs: properties and implications for the treatment of chronic obstructive pulmonary disease.
Novartis Found Symp
234:
205-218,
2001[ISI][Medline].
21.
Cederqvist, K,
Sorsa T,
Tervahartiala T,
Maisi P,
Reunanen K,
Lassus P,
and
Andersson S.
Matrix metalloproteinases-2, -8, and-9 and TIMP-2 in tracheal aspirates from preterm infants with respiratory distress.
Pediatrics
108:
686-692,
2001
22.
Chadelat, K,
Boule M,
Corroyer S,
Fauroux B,
Delaisi B,
Tournier G,
and
Clement A.
Expression of insulin-like growth factors and their binding proteins by bronchoalveolar cells from children with and without interstitial lung disease.
Eur Respir J
11:
1329-1336,
1998
23.
Clemmons, DR.
Role of insulin-like growth factor binding proteins in controlling IGF actions.
Mol Cell Endocrinol
140:
19-24,
1998[ISI][Medline].
24.
Coker, RK,
Laurent GJ,
Shahzeidi S,
Lympany PA,
du Bois RM,
Jeffery PK,
and
McAnujlty RJ.
Transforming growth factor-1, -
2, and -
3 stimulate fibroblast procollagen production in vitro but are differentially expressed during bleomycin-induced lung fibrosis.
Am J Pathol
150:
981-991,
1997[Abstract].
25.
Corbel, M,
Boichot E,
and
Lagente V.
Role of gelatinases MMP-2 and MMP-9 in tissue remodeling following acute lung injury.
Braz J Med Biol Res
33:
749-754,
2000[ISI][Medline].
26.
Corbel, M,
Caulet-Maugendre S,
Germain N,
Molet S,
Lagente V,
and
Boichot E.
Inhibition of bleomycin-induced pulmonary fibrosis in mice by the matrix metalloproteinase inhibitor batimastat.
J Pathol
193:
538-545,
2001[ISI][Medline].
27.
Corbel, M,
Lagente V,
Théret N,
Germain N,
Clément B,
and
Boichot E.
Comparative effects of betamethasone, cyclosporin and nedocromil sodium in acute pulmonary inflammation and metalloproteinase activities in bronchoalveolar lavage fluid from mice exposed to lipopolysaccharide.
Pulm Pharmacol
12:
165-171,
1999[ISI].
28.
Corbel, M,
Lanchou J,
Germain N,
Malledant Y,
Boichot E,
and
Lagente V.
Modulation of airway remodeling-associated mediators by the antifibrotic compound, pirfenidone, and the matrix metalloproteinase inhibitor, batimastat, during acute lung injury in mice.
Eur J Pharmacol
426:
113-121,
2001[ISI][Medline].
29.
Coussens, LM,
Shapiro SD,
Soloway PD,
and
Werb Z.
Models for gain-of-function and loss-of-function of MMPs.
Methods Mol Biol
151:
149-179,
2001[Medline].
30.
Crawford, SE,
Stellmach V,
Murphy-Ullrich JE,
Ribeiro SM,
Lawler J,
Hynes RO,
Boivin GP,
and
Bouck N.
Thrombospondin-1 is a major activator of TGF-1 in vivo.
Cell
93:
1159-1170,
1998[ISI][Medline].
31.
D'Armiento, J,
Dala SS,
Okada Y,
Berg RA,
and
Chada K.
Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema.
Cell
71:
955-961,
1992[ISI][Medline].
32.
Dik, W,
De Krijger R,
Bonekamp L,
Naber B,
Zimmermann L,
and
Versnel M.
Localization and potential role of matrix metalloproteinase-1 and tissue inhibitors of metalloproteinase-1 and -2 in different phases of bronchopulmonary dysplasia.
Pediatr Res
50:
761-766,
2001
33.
D'Ortho, MP,
Jarreau PH,
Delacourt C,
Macquin-Mavier I,
Levame M,
Pezet S,
Harf A,
and
Lafuma C.
Matrix metalloproteinase and elastase activities in LPS-induced acute lung injury in guinea pigs.
Am J Physiol Lung Cell Mol Physiol
266:
L209-L216,
1994
34.
Ferry, G,
Lonchampt M,
Pennel L,
De Nanteuil G,
Canet E,
and
Tucker GC.
Activation of MMP-9 by neutrophil elastase in an in vivo model of acute lung injury.
FEBS Lett
402:
111-115,
1997[ISI][Medline].
35.
Finlay, GA,
Russell KJ,
McMahon KJ,
D'arcy EM,
Masterson JB,
FitzGerald MX,
and
O'Connor CM.
Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients.
Thorax
52:
502-506,
1997[Abstract].
36.
Foda, HD,
Rollo EE,
Drews M,
Conner C,
Appelt K,
Shalinsky DR,
and
Zucker S.
Ventilator-induced lung injury upregulates and activates gelatinases and EMMPRIN. Attenuation by the synthetic matrix metalloproteinase inhibitor, prinomastat (ag3340).
Am J Respir Cell Mol Biol
25:
717-724,
2001
37.
Fowlkes, JL,
Enghild JJ,
Suzuki K,
and
Nagase H.
Matrix metalloproteinases degrade insulin-like growth factor-binding protein-3 in dermal fibroblast cultures.
J Biol Chem
269:
25742-25746,
1994
38.
Fowlkes, JL,
Serra DM,
Nagase H,
and
Thrailkill KM.
MMPs are IGFBP-degrading proteinases: implications for cell proliferation and tissue growth.
Ann NY Acad Sci
878:
696-699,
1999
39.
Fowlkes, JL,
Suzuki K,
Nagase H,
and
Thrailkill KM.
Proteolysis of insulin-like growth factor binding protein-3 during rat pregnancy: a role for matrix metalloproteinases.
Endocrinology
135:
2810-2813,
1994[Abstract].
40.
Fowlkes, JL,
Thrailkill KM,
Suzuki K,
and
Nagase H.
Matrix metalloproteinases as insulin-like growth factor binding protein-degrading proteinases.
Prog Growth Factor Res
6:
255-263,
1995[Medline].
41.
Fowlkes JL and Winkler MK. Exploring the interface between
metalloproteinase activity and growth factor and cytokine
bioavailability. Cytokine Growth Factor Rev. In
press.
42.
Fukuda, Y,
Ishizaki M,
Kudoh S,
Kitaichi M,
and
Yamanaka N.
Localization of matrix metalloproteinases-1, -2, and -9 and tissue inhibitor of metalloproteinase-2 in interstitial lung diseases.
Lab Invest
78:
687-698,
1998[ISI][Medline].
43.
Fukuda, Y,
Ishizaki M,
Masuda Y,
Kimura G,
Kawanami O,
and
Masugi Y.
The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage.
Am J Pathol
126:
171-182,
1987[Abstract].
44.
Giannelli, G,
Falk-Marzillier J,
Schiraldi O,
Stetler-Stevenson WG,
and
Quaranta V.
Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5.
Science
277:
225-228,
1997
45.
Gibbs, DF,
Shanley TP,
Warner RL,
Murphy HS,
Varani J,
and
Johnson KJ.
Role of matrix metalloproteinases in models of macrophage-dependent acute lung injury. Evidence for alveolar macrophage as source of proteinases.
Am J Respir Cell Mol Biol
20:
1145-1154,
1999
46.
Haro, H,
Crawford HC,
Fingleton B,
Shinomiya K,
Spengler DM,
and
Matrisian LM.
Matrix metalloproteinase-7-dependent release of tumor necrosis factor- in a model of herniated disc resorption.
J Clin Invest
105:
143-150,
2000
47.
Hautamaki, RD,
Kobayashi DK,
Senior RM,
and
Shapiro SD.
Macrophage elastase is required for cigarette smoke-induced emphysema in mice.
Science
277:
2002-2004,
1997
48.
Hayashi, T,
Stetler-Stevenson WG,
Fleming MV,
Fishback N,
Koss MN,
Liotta LA,
Ferrans VJ,
and
Travis WD.
Immunohistochemical study of metalloproteinases and their tissue inhibitors in the lungs of patients with diffuse alveolar damage and idiopathic pulmonary fibrosis.
Am J Pathol
149:
1241-1256,
1996[Abstract].
49.
Headley, AS,
Tolley E,
and
Meduri GU.
Infections and the inflammatory response in acute respiratory distress syndrome.
Chest
111:
1306-1321,
1997
50.
Heffner, JE,
Brown LK,
Barbieri CA,
Harpel KS,
and
DeLeo J.
Prospective validation of an acute respiratory distress syndrome predictive score.
Am J Respir Crit Care Med
152:
1518-1526,
1995[Abstract].
51.
Herbert, CA,
Arthur MJP,
and
Robinson C.
Augmentation by eosinophils of gelatinase activity in the airway mucosa: comparative effects as a putative mediator of epithelial injury.
Br J Pharmacol
117:
667-674,
1996[Abstract].
52.
Holgate, ST,
Lackie PM,
Davies DE,
Roche WR,
and
Walls AF.
The bronchial epithelium as a key regulator of airway inflammation and remodeling in asthma.
Clin Exp Allergy
29, Suppl2:
90-95,
1999[ISI][Medline].
53.
Homma, S,
Nagaoka I,
Abe H,
Takahashi K,
Seyama K,
Nukiwa T,
and
Kira S.
Localization of platelet-derived growth factor and insulin-like growth factor I in the fibrotic lung.
Am J Respir Crit Care Med
152:
2084-2089,
1995[Abstract].
54.
Hoshino, M,
Nakamura Y,
Sim J,
Shimojo J,
and
Isogai S.
Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation.
J Allergy Clin Immunol
102:
783-788,
1998[ISI][Medline].
55.
Infeld, MD.
Cell-matrix interactions in gland development in the lung.
Exp Lung Res
23:
161-169,
1997[ISI][Medline].
56.
Jeffery, PK.
Remodeling in asthma and chronic obstructive lung disease.
Am J Respir Crit Care Med
164:
S28-S38,
2001
57.
Keatings, VM,
Collins PD,
Scott DM,
and
Barnes PJ.
Differences in interleukins-8 and tumor necrosis factor- in induced sputum from patients with chronic obstructive pulmonary disease or asthma.
Am J Respir Crit Care Med
153:
530-534,
1996[Abstract].
58.
Kelly, EA,
Busse WW,
and
Jarjour NN.
Increased matrix metalloproteinase-9 in the airway after allergen challenge.
Am J Respir Crit Care Med
162:
1157-1161,
2000
59.
Killar, L,
White J,
Black R,
and
Peschon J.
Adamalysins. A family of metzincins including TNF- converting enzyme (TACE).
Ann NY Acad Sci
878:
442-452,
1999
60.
Kunugi, S,
Fukuda Y,
Ishizaki M,
and
Yamanaka N.
Role of MMP-2 in alveolar epithelial cell repair after bleomycin administration in rabbits.
Lab Invest
81:
1309-1318,
2001[ISI][Medline].
61.
Lasky, JA,
and
Brody AR.
Interstitial fibrosis and growth factors.
Environ Health Perspect
108:
S751-S762,
2000.
62.
Leco, KJ,
Waterhouse P,
Sanchez OH,
Gowing KL,
Poole AR,
Wakeham A,
Mak TW,
and
Khokha R.
Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3).
J Clin Invest
108:
817-829,
2001
63.
Lee, CG,
Homer RJ,
Zhu Z,
Lanone S,
Wang X,
Koteliansky V,
Shipley JM,
Gotwals P,
Noble P,
Chen Q,
Senior R,
and
Elias JA.
Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor 1.
J Exp Med
194:
809-821,
2001
64.
Lemjabbar, H,
Gosset P,
Lechapt-Zalcman E,
Franco-Montoya ML,
Wallaert B,
Harf A,
and
Lafuma C.
Overexpression of alveolar macrophage gelatinase B (MMP-9) in patients with idiopathic pulmonary fibrosis: effects of steroid and immunosuppressive treatment.
Am J Respir Cell Mol Biol
20:
903-913,
1999
65.
Locksley, RM,
Killeen N,
and
Lenardo MJ.
The TNF and TNF receptor superfamilies: integrating mammalian biology.
Cell
104:
487-501,
2000[ISI].
66.
Lyons, RM,
Gentry LE,
Purchio AF,
and
Moses HL.
Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin.
J Cell Biol
10:
1361-1367,
1990.
67.
Martin, C,
Papazian L,
Payan MJ,
Saux P,
and
Gouin F.
Pulmonary fibrosis correlates with outcome in adult respiratory distress syndrome: a study in mechanically ventilated patients.
Chest
107:
196-200,
1995
68.
Martin, DC,
Fowlkes JL,
Babic B,
and
Khokha R.
Insulin-like growth factor II signaling in neoplastic proliferation is blocked by transgenic expression of the metalloproteinase inhibitor TIMP-1.
J Cell Biol
146:
881-892,
1999
69.
Martinet, Y,
Menard O,
Vaillant P,
Vignaud JM,
and
Martinet N.
Cytokines in human lung fibrosis.
Arch Toxicol Suppl
18:
127-139,
1996[Medline].
70.
McAnulty, RJ,
Guerreiro D,
Cambrey AD,
and
Laurent GJ.
Growth factor activity in the lung during compensatory growth after pneumonectomy evidence of a role for IGF-1.
Eur Respir J
5:
739-747,
1992[Abstract].
71.
McCawley, LJ,
and
Matrisian LM.
Matrix metalloproteinases: they're not just for matrix anymore!
Curr Opin Cell Biol
13:
534-540,
2001[ISI][Medline].
72.
Moon, J,
du Bois BR,
Colby TV,
Hansell DM,
and
Nicholson AG.
Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking related interstitial lung disease.
Thorax
54:
1009-1014,
1999
73.
Munger, JS,
Huang X,
Kawakatsu H,
Griffiths MJ,
Dalton SL,
Wu J,
Pittet JF,
Kaminski N,
Garat C,
Matthay MA,
Rifkin DB,
and
Sheppard D.
The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis.
Cell
96:
319-328,
1999[ISI][Medline].
74.
Nagase, H,
and
Woessner JF, Jr.
Matrix metalloproteinases.
J Biol Chem
274:
21491-21494,
1999
75.
Noe, V,
Fingleton B,
Jacobs K,
Crawford HC,
Vermeulen S,
Steelant W,
Bruyneel E,
Matrisian LM,
and
Mareel M.
Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1.
J Cell Sci
114:
111-118,
2001
76.
Opdenakker, G,
Van den Steen PE,
Dubois B,
Nelissen I,
Van Coillie E,
Masure S,
Proost P,
and
Van Damme J.
Gelatinase B functions as regulator and effector in leukocyte biology.
J Leukoc Biol
69:
851-859,
2001
77.
Pardo, A,
Ridge K,
Uhal B,
Sznajder JI,
and
Selman M.
Lung alveolar epithelial cells synthesize interstitial collagenase and gelatinases A and B in vitro.
Int J Biochem Cell Biol
29:
901-910,
1997[ISI][Medline].
78.
Parks, WC,
Lopez-Boado YS,
and
Wilson CL.
Matrilysin in epithelial repair and defense.
Chest
20:
36S-341S,
2001.
79.
Parks, WC,
and
Shapiro SD.
Matrix metalloproteinases in lung biology.
Respir Res
2:
10-19,
2002[ISI].
80.
Pilcher, BK,
Sudbeck BD,
Dumin JA,
Welgus HG,
and
Parks WC.
Collagenase-1 and collagen in epidermal repair.
Arch Dermatol Res
290:
S37-S46,
1998[ISI][Medline].
81.
Planus, E,
Galiacy S,
Matthay M,
Laurent V,
Gavrilovic J,
Murphy G,
Clerici C,
Isabey D,
Lafuma C,
and
d'Ortho MP.
Role of collagenase in mediating in vitro alveolar epithelial wound repair.
J Cell Sci
112:
243-252,
1999
82.
Platten, M,
Wild-Bode C,
Wick W,
Leitlein J,
Dichgans J,
and
Weller M.
N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) inhibits transforming growth factor-beta release and reduces migration and invasiveness of human malignant glioma cells.
Int J Cancer
93:
53-61,
2001[ISI][Medline].
83.
Pratt, PC,
Vollmer RT,
Shelburne JD,
and
Crapo JD.
Pulmonary morphology in a multihospital collaborative extracorporeal membrane oxygenation project. I. Light microscopy.
Am J Pathol
95:
191-214,
1979[Abstract].
84.
Powell, WC,
Fingleton B,
Wilson CL,
Boothby M,
and
Matrisian LM.
The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis.
Curr Biol
9:
1441-1447,
1999[ISI][Medline].
85.
Puddicombe, SM,
Polosa R,
Richter A,
Krishna MT,
Howarth PH,
Holgate ST,
and
Davies DE.
Involvement of the epidermal growth factor receptor in epithelial repair in asthma.
FASEB J
14:
1362-1374,
2000
86.
Raab, G,
and
Klagsbrun M.
Heparin-binding EGF-like growth factor.
Biochim Biophys Acta
1333:
F179-F199,
1997[ISI][Medline].
87.
Raghu, G,
Johnson WC,
Lockhart D,
and
Mageto Y.
Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study.
Am J Respir Crit Care Med
159:
1061-1069,
1999
88.
Rajah, R,
Nachajon RV,
Collins MH,
Hakonarson H,
Grunstein MM,
and
Cohen P.
Elevated levels of the IGF-binding protein protease MMP-1 in asthmatic airway smooth muscle.
Am J Respir Cell Mol Biol
20:
199-208,
1999
89.
Rajah, R,
Nunn SE,
Herrick DJ,
Grunstein MM,
and
Cohen P.
Leukotriene D4 induces MMP-1, which functions as an IGFBP protease in human airway smooth muscle cells.
Am J Physiol Lung Cell Mol Physiol
271:
L1014-L1022,
1996
90.
Ramos, C,
Montano M,
Garcia-Alvarez J,
Ruiz V,
Uhal B,
Selman M,
and
Pardo A.
Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis and tissue inhibitor of metalloproteinases expression.
Am J Respir Cell Mol Biol
24:
591-598,
2001
91.
Saetta, M.
CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med
157:
822-826,
1998
92.
Sanford, LP,
Ormsby I,
Gittenberger-de Groot AC,
Sariola H,
Friedman R,
Boivin GP,
Cardell EL,
and
Doetschman T.
TGF2 knockout mice have multiple developmental defects that are non-overlapping with other TGF
knockout phenotypes.
Development
124:
2659-2670,
1997
93.
Segura-Valdez, L,
Pardo A,
Gaxiola M,
Uhal BD,
Becerril C,
and
Selman M.
Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD.
Chest
117:
684-694,
2000
94.
Selman, M,
King TE,
and
Pardo A.
Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.
Ann Intern Med
134:
136-151,
2001
95.
Selman, M,
Ruiz V,
Cabrera S,
Segura L,
Ramirez R,
Barrios R,
and
Pardo A.
TIMP 1, 2, 3 and 4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment?
Am J Physiol Lung Cell Mol Physiol
279:
L562-L574,
2000
96.
Shapiro, SD.
Diverse roles of macrophage matrix metalloproteinases in tissue destruction and tumor growth.
Thromb Haemost
82:
846-849,
1999[ISI][Medline].
97.
Shapiro, SD.
Evolving concepts in the pathogenesis of chronic obstructive pulmonary disease.
Clin Chest Med
21:
621-632,
2000[ISI][Medline].
98.
Shapiro, SD,
Campbell EJ,
Kobayashi DK,
and
Welgus HG.
Dexamethasone selectively modulates basal and lipopolysaccharide-induced metalloproteinase and tissue inhibitor of metalloproteinase production by human alveolar macrophages.
J Immunol
146:
2724-2729,
1991
99.
Shapiro, SD,
and
Senior RM.
Matrix metalloproteinases: matrix degradation and more.
Am J Respir Cell Mol Biol
20:
1100-1102,
1999
100.
Sime, PJ,
Xing Z,
Graham FL,
Csaky KG,
and
Gauldie J.
Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung.
J Clin Invest
100:
768-776,
1997
101.
Stamenkovic, I.
Matrix metalloproteinases in tumor invasion and metastasis.
Semin Cancer Biol
10:
415-433,
2000[ISI][Medline].
102.
Sternlicht, MD,
and
Werb Z.
How matrix metalloproteinases regulate cell behavior.
Ann Rev Cell Dev Biol
17:
463-516,
2001[ISI][Medline].
103.
Stockley, RA.
Proteases and antiproteases.
Novartis Found Symp
234:
189-199,
2001[ISI][Medline].
104.
Suga, M,
Iyonaga K,
Okamoto T,
Gushima Y,
Miyakawa H,
Akaike T,
and
Ando M.
Characteristic elevation of matrix metalloproteinase activity in idiopathic interstitial pneumonias.
Am J Respir Crit Care Med
162:
1949-1956,
2000
105.
Suzuki, M,
Raab G,
Moses MA,
Fernandez CA,
and
Klagsbrun M.
Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site.
J Biol Chem
272:
31730-31737,
1997
106.
Sweet, DG,
McMahon KJ,
Curley AE,
O'Connor CM,
and
Halliday HL.
Type I collagenases in bronchoalveolar lavage fluid from preterm babies at risk of developing chronic lung disease.
Arch Dis Child Fetal Neonatal Ed
84:
F168-F171,
2001[Medline].
107.
Taipale, J,
and
Keski-Oja J.
Growth factors in the extracellular matrix.
FASEB J
11:
51-59,
1997
108.
Takizawa, H,
Tanaka M,
Takami K,
Ohtoshi T,
Ito K,
Satoh M,
Okada Y,
Yamasawa F,
and
Umeda A.
Increased expression of inflammatory mediators in small-airway epithelium from tobacco smokers.
Am J Physiol Lung Cell Mol Physiol
278:
L906-L913,
2000
109.
Tanaka, H,
Miyazaki N,
Oashi K,
Tanaka S,
Ohmichi M,
and
Abe S.
Sputum matrix metalloproteinase-9: tissue inhibitor of metalloproteinase-1 ratio in acute asthma.
J Allergy Clin Immunol
105:
900-905,
2000[ISI][Medline].
110.
Thrailkill, KM,
Quarles LD,
Nagase H,
Suzuki K,
Serra DM,
and
Fowlkes JL.
Characterization of insulin-like growth factor-binding protein 5-degrading proteases produced throughout murine osteoblast differentiation.
Endocrinology
136:
3527-35233,
1995[Abstract].
111.
Van Helden, HP,
Kuijpers WC,
Steenvoorden D,
Go C,
Bruijnzeel PL,
Van Eijk M,
and
Haagsman HP.
Intratracheal aerosolization of endotoxin (LPS) in the rat: a comprehensive animal model to study adult (acute) respiratory syndrome.
Exp Lung Res
23:
297-316,
1997[ISI][Medline].
112.
Vu, TH,
and
Werb Z.
Matrix metalloproteinases: effectors of development and normal physiology.
Genes Dev
14:
2123-2133,
2000
113.
Ward, PA,
and
Hunninghake GW.
Lung inflammation and fibrosis.
Am J Respir Crit Care Med
157:
S123-S129,
1998[ISI][Medline].
114.
Ware, LB,
and
Matthay MA.
Medical progress: the acute respiratory distress syndrome.
N Engl J Med
342:
1334-1349,
2000
115.
Warner, RL,
Beltran L,
Younkin EM,
Lewis CS,
Weiss SJ,
Varani J,
and
Johnson KJ.
Role of stromelysin 1 and gelatinase B in experimental acute lung injury.
Am J Respir Cell Mol Biol
24:
537-544,
2001
116.
Werb, Z.
ECM and cell surface proteolysis: regulating cellular ecology.
Cell
91:
439-442,
1997[ISI][Medline].
117.
Yao, PM,
Buhler JM,
D'Ortho MP,
Lebargy F,
Delclaux C,
Harf A,
and
Lafuma C.
Expression of matrix metalloproteinase gelatinases A and B by cultured epithelial cells from human bronchial explants.
J Biol Chem
271:
15580-15589,
1996
118.
Yu, Q,
and
Stamenkovic I.
Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis.
Genes Dev
14:
163-176,
2000
119.
Zucker, S,
Hymowitz M,
Conner C,
Zarrabi HM,
Hurewitz AN,
Martrisian L,
Boyd D,
Nicolson G,
and
Montana S.
Measurements of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues.
Ann NY Acad Sci
878:
212-227,
1999