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(Chest. 2001;120:S36-S41.)
© 2001 American College of Chest Physicians

Matrilysin in Epithelial Repair and Defense*

William C. Parks, PhD; Yolanda S. López-Boado, PhD and Carole L. Wilson, PhD

* From the Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.

Correspondence to: William C. Parks, PhD, Department of Pediatrics, Box 8208, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110; e-mail: parks_w{at}kids.wustl.edu

Abstract

Repair involves an orderly progression of events to reestablish the integrity of the injured tissue. During each stage in this process, secreted proteinases are needed to remodel extracellular matrix, facilitate cell migration, and process latent proteins, among other functions. In lung epithelium, several of these processes are mediated by matrilysin, a matrix metalloproteinase (MMP). Unlike most MMPs, matrilysin is produced by intact, noninjured airway and peribronchial epithelial cells. In other intact epithelial tissues, namely the small intestine, matrilysin functions in host defense by activating the latent form of defensins, a family of antimicrobial peptides. This metalloproteinase may serve a similar function in the lung. Furthermore, in models of airway injury, matrilysin expression is upregulated in migrating epithelial cells, and the activity of this proteinase is required for repair of airway wounds. These observations indicate that matrilysin serves key functions in both epithelial defense and repair.

Key Words: airway • alveolus • defensin • epithelium • lung • matrilysin • metalloproteinase • wound repair

Abbreviations: CF = cystic fibrosis; MMP = matrix metalloproteinase

The matrix metalloproteinases (MMPs) comprise a family of > 25 related, yet distinct enzymes. MMPs are secreted or anchored to the cell surface, thereby confining their catalytic activity to substrates within the extracellular space. Typically, MMPs are not expressed in normal, healthy, resting tissues, or with notable exceptions, their production and activity are maintained at nearly undetectable levels. In contrast, some level of MMP expression is seen in any repair or remodeling process, in any diseased or inflamed tissue, and essentially in any cell type grown in culture. Although the qualitative pattern and quantitative levels of MMPs vary among tissues, diseases, tumors, inflammatory conditions, and cell lines, a reasonably safe generalization is that activated cells, whether in tissues or in culture dish, express MMPs. Overall, the production of MMPs is carefully regulated, temporally limited, and occurs in response to specific signals.

As their name suggests, MMPs are thought to be responsible for the turnover and degradation of connective tissue proteins, a function that is clearly performed by several family members. However, matrix degradation is not the sole function of these enzymes. After all, MMPs are proteinases, and most proteinases can act on a wide variety of proteins. Indeed, several reports from the past years have suggested or demonstrated that various MMPs can activate a variety of nonmatrix proteins, including cytokines, chemokines, receptors, and antimicrobial peptides. In addition, fragments of matrix proteins released by MMP-mediated proteolysis can act as chemoattractants for distant cells. Thus, MMPs should not be viewed solely as proteinases of matrix catalysis, but also as processing enzymes involved in cell-cell and cell-matrix signaling.

Matrilysin and Epithelial Defense

Matrilysin (MMP-7), the smallest (28 kd) of the known MMPs, has a broad substrate specificity and has been demonstrated in vitro to be able to degrade or process a variety of matrix and nonmatrix proteins.1 Unlike other MMPs, which are expressed or released only in response to injury, disease, or inflammation, matrilysin is expressed by noninjured, noninflamed exocrine and mucosal epithelium in most, if not all, adult tissues. Specifically, matrilysin is produced by all skin and salivary glands and by the ductal or glandular epithelium of the pancreas, liver, breast, intestine, and urogenital tissues.2 3 4 5 In adult human lung, whether normal or diseased, matrilysin is expressed by epithelial cells lining peribronchial glands and conducting airways.6 In peribronchial glands, matrilysin is released by ductal epithelial cells and by secretory serous cells, whereas clear mucous cells produce no detectable matrilysin protein. At all levels of the conducting airways, matrilysin is present in ciliated cells, whereas mucous cells have no signal for matrilysin.

The expression of matrilysin in noninjured, normal epithelium suggests that this enzyme serves a common homeostatic function among epithelia, and several observations implicate a role for matrilysin in innate immunity among epithelia. All tissues in which matrilysin is "constitutively" expressed are open to the environment and, hence, are vulnerable to bacterial exposure; and matrilysin is prominently upregulated in tissues with a heavy bacterial load, such as in lungs with cystic fibrosis (CF; see below). In addition, both immunohistochemical and cell culture studies demonstrated that the matrilysin protein produced by noninjured epithelium is released into the airway lumen.6 7 Apical secretion of matrilysin indicates that this MMP acts on nonmatrix substrates. Furthermore, in the mouse small intestine, matrilysin is expressed in Paneth cells,5 which are specialized defense cells that secrete defensins, lysozyme, phospholipase A2, and other antimicrobial molecules.8 The most compelling data for a role of matrilysin in mucosal defense are our recent findings showing that matrilysin-null mice have an impaired ability to activate prodefensins and to kill exogenous bacteria in their small intestine.9

An important, common role of mucosal epithelium is to function as an active barrier against the external environment, and the secretion of antibiotic peptides by epithelial cells appears to be an important component of innate immunity.10 The {alpha}- and ß-defensins comprise a family of cationic peptides that kill bacteria by membrane disruption,11 12 and Paneth cells of the small intestine of most mammals produce {alpha}-defensins as prepropeptides.8 The pro segment of {alpha}-defensin precursors maintains them in an inactive state, and proteolysis at some point in the secretion pathway is needed to remove the pro domain.

Because matrilysin is coexpressed with mouse {alpha}-defensin precursors (procryptdins),5 9 we hypothesized that this enzyme activates these defense-related molecules. Indeed, we have recently demonstrated that cryptdins are processed to their active forms by matrilysin and that a deficiency in this enzyme results in impaired bactericidal activity in vitro and in vivo (Fig 1 ). Due to a lack of defensin activation, matrilysin-null mice cannot effectively kill pathogenic Escherichia coli and are themselves killed by doses of Salmonella typhimurium that are not lethal to wild-type mice.9 Thus, matrilysin functions in mucosal immunity by regulating the level of active antimicrobial peptides. We predict that this MMP serves a similar antibacterial role in the lung.



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  		Figure 1.. Association of matrilysin deficiency with a decrease in microbicidal activity. Left, A: Antimicrobial activity in small intestinal protein extracts from wild-type (MAT +/+) and matrilysin knockout (MAT -/-) mice was assayed in agar diffusion antibacterial assay using E coli ML35. Antibacterial activity (zone of inhibition) was determined by subtracting the radius of the well from the total radius of the zone of clearance. Right, B: One thousand log-phase S typhimurium phoP bacteria were combined with supernatants from the indicated number of stimulated crypts. Following incubation for 1 h, colony forming units were determined by plating on nutrient agar. The number of bacteria killed was averaged from results using three mice of each genotype and is expressed as a percentage ( ± SD) of control mice from which crypts were omitted.9

 
Because of role of matrilysin in innate defense, we assessed if the interaction of bacteria with host cells regulates its expression. Indeed, our data demonstrate that matrilysin is strongly induced (> 50-fold) in human and murine mucosal epithelial tissues, including intact human and mouse airway, by bacterial exposure.7 This induction is remarkably potent and sensitive, requiring relatively short exposure and < 10 bacteria per epithelial cell in the initial inoculum. Importantly, this induction is not mediated by lipopolysaccharide.7 Large amounts of matrilysin protein, in both its zymogen and activated forms, are released from infected airway epithelial cells and from normal human trachea (Fig 2 ). Based on messenger RNA levels, matrilysin expression increases as early as 2 h after infection, continues to rise 10 h after bacteria are removed, and remains elevated at 48 h after infection.7 In addition, bacteria-mediated stimulation of matrilysin is restricted to mucosal epithelial cells. Bacterial exposure does not affect the expression of other MMPs examined and does not influence matrilysin expression in other cell types, namely macrophages, fibroblasts, and keratinocytes.



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  		Figure 2.. Ex vivo infection of human tracheal explants and infection of human tracheal epithelial cells. Top, A: Pieces (1 cm3) of freshly isolated normal adult human trachea were infected with the E coli isolates NU14 (fimH+) and NU14–1 (fimH-) for 90 min and incubated for 24 h in fresh media containing 50 µg/mL gentamicin as described.7 NU14 is an E coli strain isolated from a patient with cystitis and expresses FimH-containing type 1 pili. NU14–1 is a fimH- mutant in which a chloramphenicol cassette was recombined into the fimH gene in the chromosome of NU14.25 FimH is a mannose-binding adhesin that mediates the interaction of type 1-piliated bacteria with mannose-containing glycoproteins on eukaryotic cell surfaces. Released and activated matrilysin was detected by Western analysis. Bottom, B: Human tracheal primary epithelial cells were infected with the type 1-piliated recombinant strains ORN103/pSH2 (fimH+) and ORN103/pUT2002 (fimH-) for 90 min, and allowed to condition fresh media for 48 h. Matrilysin secretion was assessed by immunoblotting.7 Cntl = control; Pro = promatrilysin; Mat = matrilysin.

 
The widespread production of matrilysin in conducting airway epithelium may be initially induced and subsequently sustained by continual, low-level bacterial exposure. Consistent with this idea, matrilysin is seen in adult tissues but is not detected in developed glandular epithelium in utero13 or in fetal or perinatal mouse tissues.5 Furthermore, we have demonstrated that matrilysin protein is not produced at detectable levels in adult germ-free mice but is expressed in mice with a conventional microflora and in ex–germ-free mice colonized with the commensal species Bacteroides thetaiotamicron.7 Thus, bacterial exposure seems to be the physiologic signal that regulates matrilysin expression in intact epithelium.

In accordance with the suggested role of epithelial cells as "sensors" for microbial infection,14 stimulation of matrilysin expression may be part of a more general activation response to bacteria. A growing body of evidence suggests that most epithelial cells, including airway epithelial cells, produce molecules with antimicrobial properties,15 16 17 18 many of which, like matrilysin, are upregulated by bacterial infection.19 Indeed, defensins, cathelicidins, and others are produced as propeptides that require some degree of proteolytic processing to attain full antimicrobial activity.20 21 It is tempting to speculate that the expression of matrilysin in epithelial cells, along with an ever increasing display of epithelial defense molecules, may play a direct role in the first line of defense against infectious microorganisms.

Matrilysin and Epithelial Repair

Repair involves an orderly progression of events to reestablish the integrity of the injured tissue. The initial injury sets off a programmed series of interdependent yet separate responses, such as reepithelialization and epithelial proliferation, inflammation, angiogenesis, fibroplasia, matrix accumulation, and eventually resolution. During each stage in this process, proteinases are needed to remove or remodel extracellular matrix components in both the epithelial and interstitial compartments, in part to accommodate cell migration and other ongoing events. For example, we have shown that the activity of epidermal-derived collagenase-1 (MMP-1) is required for re-epithelialization of cutaneous wounds.22 Using lung as a model, we assessed if MMP-1 in the skin would provide a paradigm of the proteolytic needs of reepithelialization in other tissues. However, our findings demonstrate that matrilysin (MMP-7), which is not expressed in skin wounds, is invariably and prominently expressed in damaged airways and alveoli and is required for repair of lung tissue. These observations indicate that distinct MMPs function in the repair of different epithelial tissues.

In wounded skin, multiple MMPs, specifically collagenase-1, stromelysin-1, stromelysin-2, and 92-kd gelatinase, but not matrilysin, are produced by keratinocytes in response to wounding.23 However, in a survey of numerous and diverse lung conditions, we never detected expression of these MMPs (with the exception of collagenase-1 expression in one area of damaged airway epithelium in one CF sample) in any pulmonary epithelial cell, either in normal, inflamed, or diseased lung.6 Because matrilysin is constitutively produced in airway epithelium, we assessed if its production would be increased in injured lung. For these studies, we examined biopsy samples of lungs from patients with CF, a condition associated with extensive airway injury and obstruction. Compared to normal lung, the expression of matrilysin messenger RNA and protein is markedly increased in the epithelium of upper-airway epithelial cells of CF lungs.6 Most obvious are the high levels of matrilysin messenger RNA expression seen in essentially all epithelial cells at sites of overt damage of airway epithelium.

The lining of the lung is divided into two functionally distinct epithelial compartments: the conducting epithelium of the upper airways and the respiratory epithelium of the lower bronchioles and alveoli. In samples of normal lung and in biopsy specimens of pulmonary hypertension, sarcoidosis, and the tumor-free margins of adenocarcinomas, which lack overt disruption of the epithelium, matrilysin is not expressed by intact respiratory epithelium. However, in CF lungs, matrilysin is strongly induced in alveolar type II pneumocytes.6 In addition, we have also seen prominent expression of matrilysin in alveolar pneumocytes in areas of epithelial damage in emphysematous lungs, in fibrotic lungs with diffuse alveolar damage, and in inflamed lungs of patients with idiopathic pneumonia syndrome following bone marrow transplantation (W.C. Parks, PhD; unpublished observations; September, 1997).

Although matrilysin is clearly regulated by bacterial exposure, it is possible that production of this enzyme is also induced in response to injury. Because injury provides an opportunity for infection and infection can lead to injury, some of the epithelial responses associated with either of these events may actually be a key component of both responses. We used an ex vivo wound-repair model to assess directly if injury controls matrilysin expression. For these studies, we incubated small, uniformly sized pieces of normal adult human trachea in antibiotic-containing medium for 0 to 5 days. During this time, epithelial cells migrated over the edge of the cut surface in an attempt to heal the "wounded" tissue. In fresh trachea, low levels of matrilysin protein were seen in the airway epithelial cells and stronger staining was evident in ductal epithelial cells.6 From days 1 to 5, airway epithelial cells at the margin of the tissue samples moved off the basement membrane and migrated progressively along the surface of the adjacent interstitial matrix. Prominent signal for matrilysin protein was seen in all epithelial cells that had migrated away from the wound edge (Fig 3 ). In all samples, matrilysin protein was seen only in basal migrating cells in direct contact with the underlying interstitial matrix and not in the layer of suprabasal cells in the migratory front (Fig 3) . Furthermore, matrilysin was seen being released toward the matrix from some of these strongly positive cells.



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  		Figure 3.. Expression of matrilysin in injured tracheal explant sections of a segment of normal human trachea was incubated in culture medium at 37°C for 5 days (d5) before fixation and immunohistochemistry for matrilysin protein.6 The large arrows mark the edge of the biopsy specimen and the margin of basement membrane, which is the clear area underlying the epithelium. By 5 days after plating, the epithelial cells migrated progressively, and intense staining for matrilysin was seen in these migrating cells, especially those in close contact with the underlying matrix. Release of matrilysin toward the matrix was seen in association with some cells (small arrows). No signal was seen in sections processed with preimmune serum (PI).6 Bar = 20 µm.

 
These observations demonstrate that matrilysin is induced by injury and is prominently expressed by migrating epithelial cells. Although we do not yet know what process or factor induces matrilysin in epithelial cells at the wound edge, candidates would include a loss of specific cell-cell contacts, changes in cytoskeleton, or establishment of new cell-matrix interactions. Furthermore, in the absence of bacteria, wound-induced matrilysin is apparently released basally toward the underlying matrix. Thus, during migration, matrilysin may be acting on an extracellular protein to somehow facilitate cell migration.

Evidence for a functional role of matrilysin in re-epithelialization was obtained by using SC44463, a peptide hydroxamate inhibitor of MMP catalytic activity. This compound is a substrate-based inhibitor containing a hydroxamic acid moiety that chelates the active site zinc cation and renders MMPs catalytically inactive. SC44463 has a inhibition constant (Ki) of about 1 nm for pure MMPs in solution. Uniform wounds were made with a 1.5-mm–wide cell scraper in the center of human tracheal explants, and specimens were kept in cell culture medium. At 24 h after injury, control epithelial wounds were about 70% closed, whereas wounded tracheas cultured in the presence of SS44463 showed essentially no evidence of reepithelialization over the 24-h experiment (Fig 4 , left, A). These data indicate that reepithelialization of airway wounds requires the activity of MMPs. Because other MMPs, namely collagenase-1, stromelysin-1, and 92-kd gelatinase, were not expressed by intact or injured tracheal epithelium, these data support a role for matrilysin in epithelial cell migration following injury. However, because SC44463 blocks the catalytic activity of all MMPs, including other metalloenzymes, we needed more specific reagents to verify that matrilysin is required for re-epithelialization.



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  		Figure 4.. Reepithelialization is blocked by MMP inhibitor and in matrilysin-null mice. Normal human (left, A) and matrilysin-null and wild-type mice (right, B) trachea were isolated, wounded in their centers with a 1.5-mm–wide cell scraper. Human explants were placed into culture medium and incubated in the presence (+) or absence (-) of 25 µM SC44463, an MMP hydroxamate inhibitor, for 18 h or 24 h. For both human and mouse tissues, reepithelialization was quantified as the distance between opposing epithelial margins. For human trachea (left, A), the data are the mean ± SEM of four sections per time point from three separate tracheal pieces. For mice (right, B), the data (mean ± SEM) were collected from two experiments using three of each mouse line.6

 
As we saw in human tissue, matrilysin was expressed in airway epithelial cells that had migrated over the cut edges of dissected mouse tracheas. To specifically implicate matrilysin in airway reepithelialization, we wounded tracheas from wild-type and matrilysin-null mice using a 1.5-mm–wide cell scraper, just as we did with the human specimens. In tracheas from wild-type mice, reepithelialization progressed rapidly and was nearly complete by 24 h after injury (Fig 4 , right, B). In contrast, wounds in tracheas from matrilysin-null mice showed no evidence of epithelial migration, and the size of the wound opening did not change significantly over the 24-h course of the experiment. In fact, matrilysin-deficient mice have shown the most severe wound-repair defect among the MMP knockout mice generated to date.

The marked inhibition of tracheal reepithelialization in both models, but especially in the matrilysin knockout mice, indicates that the catalytic activity of matrilysin produced by migrating airway epithelial cells is necessary for cell migration following injury. We do not yet know if matrilysin is required for remodeling of a matrix component or for processing of some factor that may provoke cell proliferation or migration or for cleavage of cell surface molecules, such as integrins,24 to allow cell movement. In skin wounds, we demonstrated that the activity of collagenase-1 is needed to loosen tight cell-matrix contacts,22 and matrilysin may serve a similar function in injured airway. Thus, the composition of the underlying interstitial matrix may dictate the pattern of MMP expression between skin and mucosa. Whereas collagenase-1 facilitates migration of keratinocytes over the collagen-rich matrix of dermis, matrilysin would be a more appropriate proteinase to remodel components of the airway interstitium, which include elastin, adhesive glycoproteins, and proteoglycans, all of which are substrates for this MMP. The observation that matrilysin is secreted basally by migrating cells in aseptic wounds (Fig 3) supports the idea that this epithelial MMP acts on matrix proteins during repair.

Conclusion

Collectively, our findings indicate that matrilysin serves different functions. In other words, this MMP acts on different substrates, depending on whether it is secreted apically (defensin activation) or basally (cell migration). Because matrilysin can vigorously degrade all sorts of matrix proteins, overexpression of this proteinase may contribute to severe lung damage, such as seen in CF. Several studies have shown that excessive levels of many MMPs are present in ulcerations and in chronically inflamed tissues throughout the body. These observations have led to the often held concept that excessive proteolysis damages tissues and impairs healing. Indeed, unregulated, excessive proteolysis is likely responsible for the destruction of matrix proteins in arthritis, aneurysms, and other conditions of structural tissues. However, it seems presumptuous to conclude that all proteinases expressed in diseased tissue contribute to disease pathogenesis. Based on the mechanisms uncovered in matrilysin-null mice,6 9 overexpression of this MMP in CF may reflect its beneficial roles in epithelial cell migration and in mucosal defense against bacteria. Because MMPs can both break down and activate proteins, we cannot conclude by their presence alone if a specific proteinase in an inflammatory or injury setting is contributing to a reparative or disease process.

Acknowledgements

We thank Drs. Sarah Dunsmore, Scott Hultgren, Qinglang Li, Jouko Lohi, Lynn Matrisian, John McGuire, Andre Ouellette, Jill Roby, Ulpu Saarialho-Kere, and Howard Welgus for their valuable contributions to our studies.

Footnotes

Our research on these topics has been supported by grants from the National Institutes of Health (HL29594 and HL56419) and the Barnes-Jewish Hospital Research Foundation.

References

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