In vitro inhibition of matrix metalloproteinase activity in tracheal epithelial lining fluid from horses with recurrent airway obstruction.

OBJECTIVE: To evaluate inhibitory effects of synthetic matrix metalloproteinase (MMP) inhibitors in vitro on gelatinolytic and collagenolytic activities in tracheal epithelial lining fluid (TELF) of horses with recurrent airway obstruction (RAO). ANIMALS: 10 horses with RAO and 5 healthy control horses. PROCEDURES: Substrate-based functional assays, collagen I and gelatin degradation, were used to measure endogenous collagenolytic and gelatinolytic activities in TELF. In vitro inhibition of MMP activity in TELF with 2 chemically modified tetracyclines (CMTs; CMT-3 and CMT-8) and 2 bisphosphonates (BPs; zoledronate and pamidronate) was evaluated. RESULTS: CMT-3, CMT-8, zoledronate, and pamidronate in a dose-dependent manner inhibited TELF type I collagenolytic and gelatinolytic activities, although no complete inhibition of TELF type I collagenolytic and gelatinolytic activities was achieved with the inhibitor concentrations of 25 to 500 microM tested. The CMTs inhibited pathologically induced collagen I degradation more effectively than BPs. Of the tested CMTs, CMT-3 was the most effective inhibitor of gelatinolytic activity, and the efficiency of CMT-3 corresponded with that of the BPs. CONCLUSIONS AND CLINICAL RELEVANCE: An increase in MMP activity in the equine respiratory tract may potentially be inhibited by administration of CMTs or BPs. Distinct synthetic MMP inhibitors may eventually provide an additional means for pharmacologic treatment by decreasing ongoing active tissue destructive inflammation associated with chronic lung disease. The MMP inhibitors such as CMTs and BPs that are targeted to solely inhibit a pathologic increase in MMP activities provide the advantage of minimal adverse effects that are characteristics of other excessively potent MMP inhibitors.

Elevated levels of fragmented laminin-5 gamma2-chain in bronchoalveolar lavage fluid from dogs with pulmonary eosinophilia.

Inflammation causes epithelial cell sloughing and basement membrane (BM) exposure in canine pulmonary eosinophilia (PE), leading to degradation of the epithelial cell attachment component, laminin-5 gamma2-chain, into small molecular weight fragments. The subsidence of inflammation after treatment down-regulates degradation. Laminin-5 gamma2-chain levels and molecular forms in bronchoalveolar lavage fluid (BALF) were analysed semiquantitatively by Western immunoblotting to compare PE affected (n=20) and healthy dogs (n=16) as well as PE dogs (n=6) before and after corticosteroid treatment. PE dogs expressed significantly elevated levels of total (P<0.01), 36 kDa (P<0.05) and 53 kDa (P<0.05) laminin-5 gamma2-fragments. The 36 Da fragment decreased significantly (P<0.05) after treatment. The laminin-5 gamma2-chain degradation products may be linked to epithelial cell sloughing and BM exposure or healing.

Direct activation of gelatinase B (MMP-9) by hay dust suspension and different components of organic dust.

Matrix metalloproteinases (MMPs) are involved in tissue destruction in allergic airway diseases. We studied the ability of various allergenic substances to directly activate recombinant 92kDa proMMP-9. The substances included hay dust suspension (HDS) and its components (supernatant, particulate matter and wash fluid of particulate matter), storage mite extract and two Aspergillus fumigatus extracts. The allergen suspensions were incubated in vitro with proMMP-9. After incubation the conversion of proMMP-9 to 10kDa lower active forms were studied using gelatin zymography and Western immunoblot quantified by computerized densitometry. All studied allergens except HDS significantly and efficiently activated proMMP-9 as compared to a negative control. At the concentrations employed, the most potent activators were A. fumigatus extracts and mite suspension. The greater potency of mite and fungi as proMMP-9 activators suggests that these allergens may be more damaging to airways even at low concentrations.

Gelatinolytic matrix metalloproteinases-2 and -9 in tracheobronchial lavage fluid obtained from calves with concurrent infections of Pasteurella multocida and Mycoplasma bovirhinis.

OBJECTIVE: To study gelatinolytic matrix metalloproteinases (MMPs) in tracheobronchial lavage fluid (TBLF) obtained from clinically normal calves and calves with Pasteurella multocida infection. SAMPLE POPULATION: Samples of TBLF obtained from 11 calves with clinical signs of respiratory tract disease and growth of P multocida and Mycoplasma spp during culture of TBLF and samples of TBLF from 6 clinically normal calves with no bacterial growth during culture of TBLF. PROCEDURE: MMPs in TBLF were analyzed by use of gelatin zymography. Gelatinases were identified on the basis of molecular weights and inhibition by EDTA. RESULTS: The main gelatinolytic MMPs detected were the proform (90 to 110 kd) and active form (75 to 85 kd) of MMP-9 (gelatinase B) and the proform (67 to 75 kd) and active form (< 65 kd) of MMP-2 (gelatinase A). Increased amounts of active MMP-2 and MMP-9 were detected in TBLF of calves with respiratory tract disease, compared with amounts of active MMP-2 and MMP-9 in TBLF of clinically normal calves. Concurrent infection with Mycoplasma bovirhinis in calves with pneumonia attributable to P multocida was associated with higher concentrations of MMP-9. CONCLUSIONS AND CLINICAL RELEVANCE: The host response to P multocida includes increases in MMP-2 and MMP-9 concentrations in TBLF. Greater amounts of MMPs detected in calves with concurrent M bovirhinis and P multocida infection indicates synergism between these organisms.

Levels and molecular forms of MMP-7 (matrilysin-1) and MMP-8 (collagenase-2) in diseased human peri-implant sulcular fluid.

OBJECTIVES: Matrix metalloproteinases (MMPs) play crucial role in various tissue destructive inflammatory processes by degrading almost all peri-cellular and basement membrane components. MMP-8 (collagenase-2) is the major MMP in periodontitis. MMP-7 (matrilysin-1), in addition to its ability to degrade matrix and basement membrane components, activates other latent pro-MMPs and defensins, host cell-derived antimicrobial cryptidins. The aim of the present study was to characterize the relationship, levels and molecular forms of MMP-8 and MMP-7 in diseased peri-implant sulcular fluid (PISF). MATERIALS AND METHODS: Seventy-two human dental implant fluid samples were collected with filter paper strips from peri-implant sulci from healthy and untreated diseased implant sites. Gingival index (GI) and/or bone resorption (BR) were also recorded. Western immunoblot method with polyclonal anti-human-MMP-8 and monoclonal anti-human-MMP-7 antibodies was used, and immunoreactivities were quantified with computer scanning program. The effects of MMP inhibitors (doxycycline, chemically modified tetracycline-3, clodronate, CTT-peptide and marimastat) were studied on the activity of recombinant human matrilysin-1 (MMP-7) using beta-casein degradation assay. RESULTS: The levels of active forms of MMP-8 and MMP-7 were significantly elevated in diseased PISF in relation to healthy PISF. Furthermore, MMP-8 and MMP-7 levels correlated significantly to each other and GI. MMP-8 was present not only as bands corresponding to 75-kDa polymorphonuclear leukocyte (PMN) -type pro- and 65-kDa active forms, but also as 55-kDa non-PMN-type pro- and 45-kDa active forms. Immunoreactivities > 80 kDa most likely represented dimeric and/or inhibitor-bound MMP-8 complexes and the low molecular weight (< 30 kDa) species were apparently degraded fragments. In diseased PISF, 19-21-kDa active MMP-7 and 28-30-kDa pro-MMP-7 species were detected, and the active 19-21-kDa forms of MMP-7 predominated in diseased PISF. Doxycycline (50 micro m and 250 micro m), chemically modified non-antimicrobial tetracycline (CMT-3) (50 micro m and 100 micro m), clodronate (a bisphosphonate, 20 micro m and 500 micro m) and the cyclic CTT (CTTHWGFTLC)-peptide (125 micro m and 250 micro m), all known broad-spectrum or selective MMP-inhibitors, did not inhibit the activity of human recombinant MMP-7; only marimastat (1 micro m and 5 micro m) inhibited MMP-7. DISCUSSION: Increased immunoreactivities of the active MMP-8 and MMP-7 species in PISF from diseased peri-implantitis lesions eventually reflect the stage and course of peri-implantitis; MMP-7 may potentially act as MMP-8 and defensin activator in diseased PISF. CONCLUSION: The elevated levels of MMP-8 and matrilysin-1/MMP-7 were identified in active forms in diseased PISF, but MMP-7 was less prominent. MMP inhibitors, potential future tissue protective drugs, seemingly do not interfere with the defensive antibacterial action of MMP-7.

Metalloproteinase inhibition reduces lung injury and improves survival after cecal ligation and puncture in rats.

BACKGROUND: Neutrophil activation with concomitant matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) release has been implicated in the development of sepsis-induced acute lung injury. We hypothesized that COL-3, a chemically modified tetracycline known to inhibit MMP-2 and MMP-9, would reduce lung injury and improve survival in rats following cecal ligation and puncture (CLP). METHODS: Sprague-Dawley rats were separated into five groups: 1) sham CLP+ carboxymethylcellulose (CMC; vehicle for COL-3, n = 6); 2) sham CLP + COL-3 (n = 6); 3) CLP + CMC (n = 10); 4) CLP + single-dose (SD) COL-3 administered concomitant with CLP (n = 9); and 5) CLP + multiple-dose (MD) COL-3 administered concomitant with CLP and at 24 h after CLP (n = 15). Rats were sacrificed at 168 h (7 days) or immediately after death, with survival defined as hours after CLP. Histological lung assessment was made based on neutrophil infiltration, alveolar wall thickening, and intraalveolar edema fluid. Lung MMP-2 and MMP-9 levels were assessed by immunohistochemistry. MMP-2 and MMP-9 levels were correlated with survival by simple regression analysis. RESULTS: The mortality of rats in the cecal ligation and puncture without treatment group (CLP + CMC) was 70% at 168 h. A single dose of COL-3 in the CLP + COL-3 (SD) group significantly reduced mortality to 54%. Furthermore, with a repeat dose of COL-3 at 24 h after CLP, mortality was significantly reduced to 33%. Pathologic lung changes seen histologically in the CLP + CMC group were significantly reduced by COL-3. A significant reduction in lung tissue levels of MMP-2 and MMP-9 was noted in both groups treated with COL-3. Reduction of MMP-2 and MMP-9 levels correlated with improved survival. CONCLUSION: Inhibition of MMP-2 and MMP-9 by COL-3 in a clinically relevant model of sepsis-induced acute lung injury reduces pulmonary injury and improves survival in a dose-dependent fashion. Our results suggest that prophylactic treatment with COL-3 in high-risk patients may reduce the morbidity and mortality associated with sepsis-induced acute respiratory distress syndrome.

Matrix metalloproteinases process the laminin-5 gamma 2-chain and regulate epithelial cell migration.

Matrix metalloproteinase (MMP)-2 and membrane type 1-MMP can process the laminin-5 (Ln-5) gamma2-chain, revealing a cryptic site inducing epithelial cell migration. We investigated whether other MMPs process the Ln-5 gamma2-chain and related their ability to induce epithelial cell migration. The N-terminal sequences of the MMP-3, -12, -13, and -20 processed 80kDa Ln-5 gamma2x-chains were identical whereas the N-terminus of the 80kDa(MMP-8) Ln-5 gamma2x-chain was not. MMP-3, -13, -14, and -20 induced MCF-7 cell migration over Ln-5 while MMP-8 was a poor inducer of MCF-7 cell migration. In conclusion, several MMPs can process the Ln-5 gamma2-chain and induce epithelial cell migration.

Laminin-5 gamma2-chain and collagenase-2 (MMP-8) in human peri-implant sulcular fluid.

Laminin-5 (LN-5) is an important epithelial cell-derived structural and adhesive component in hemidesmosomes and basement membranes (BM). In peri-implant tissue, gingival BM underlies the junctional epithelium (JE) and reflects the peri-implant health. Matrix metalloproteinase-8 (MMP-8 or collagenase-2) is one of the key mediators of periodontal tissue destruction. Western immunoblotting with image analysis was used to quantitate the molecular forms of LN-5 gamma2-chain and MMP-8 in peri-implant sulcular fluid (PISF) from healthy and diseased implants. These observations were related to the recorded gingival (GI) and bone resorption (BR) indices of the studied sites. Altogether, 72 PISF samples from osseointegrated dental implants were examined. Significantly elevated levels of fragmented LN-5 gamma2-chain species (45 and 70 kDa) and MMP-8 immunoreactivities were observed in diseased PISF in relation to healthy PISF. The elevated levels of both LN-5 gamma2-chain 45 and 70 kDa fragments and MMP-8 in diseased PISF from peri-mucositis (BR = 0) and peri-implantitis (BR >/= 1) lesions strongly correlated with elevated GI. Low levels - almost comparable to those seen in healthy control PISF - were seen in PISF from peri-implantitis lesions (BR >/= 1) with no GI. Activation of 75 kDa neutrophil (PMN)-type proMMP-8 to 10 kDa lower-molecular-size active forms was especially detected in PISF from peri-implantitis with elevated GI. These cross-sectional findings indicate that elevated MMP-8 and LN-5 gamma2-chain fragment levels in PISF can reflect the active phase of the inflammatory peri-implant disease. Longitudinal studies are required to assess their use, either alone or in combination as molecular biochemical PISF markers, to predict the risk of progression of peri-implantitis, as well as to monitor the impact of treatment of the disease.

Gelatinase A (MMP-2), collagenase-2 (MMP-8), and laminin-5 gamma2-chain expression in murine inflammatory bowel disease (ulcerative colitis).

Dextran sulfate sodium-induced inflammatory bowel disease in mice resembles human ulcerative colitis. In inflammatory bowel diseases matrix metalloproteinases contribute to tissue degradation. Laminin-5 is an anchoring filament protein in the basement membrane area that can be cleaved by matrix metalloproteinases. We investigated the expression of matrix metalloproteinases-2 and -8 and laminin-5 gamma2-chain in dextran sulfate sodium-induced mice by immunohistochemistry and in situ hybridization. Matrix metalloproteinase-8 expression was evidenced in the colon surface epithelial cells and the protein was more abundant in dextran sulfate sodium-induced mice colon. Matrix metallproteinase-2 and laminin-5 gamma2-chain colocalized in the colon surface epithelial cells and in the basement membrane zone as demonstrated by double immunostaining. In dextran sulfate sodium-induced colon, matrix metalloproteinase-2 immunoreactivity was detected in epithelial cells in the lower parts of the crypt and surrounding the degraded crypts. Matrix metalloproteinase-2 and -8 could participate in the local epithelial inflammatory processes and tissue destruction. The presence of laminin-5 gamma2-chain indicates alternative anchoring mechanisms in the colon, a compartment devoid of hemidesmosomes.

Laminin-5 gamma 2 chain is colocalized with gelatinase-A (MMP-2) and collagenase-3 (MMP-13) in odontogenic keratocysts.

BACKGROUND: Odontogenic keratocyst (KC) differs from other epithelial odontogenic cysts in regard to increased epithelial proliferation and a strong tendency to recur. Laminin-5 (Ln-5) is an epithelial anchoring filament component, which after modulation by certain matrix metalloproteinases (MMPs), like MMP-2 and MMP-13, induces epithelial cell migration. METHODS: Using in situ hybridization and immunohistochemistry, we studied the Ln-5 gamma-2 chain expression related to the expression of MMP-2, -8, and -13 in different odontogenic cysts, including radicular cysts (RC; n = 11), follicular cysts (FC; n = 11), and odontogenic keratocysts (KC; n = 16). RESULTS: Ln-5 mRNA was present in all cysts examined, while less than half of KCs and RCs (33 and 40%, respectively) demonstrated MMP-2 mRNA. MMP-13 mRNA was present in all KC samples. Ln-5 protein was located as a continuous ribbon in BM zone of all KCs, and MMP-2 and MMP-13 immunoreactivities colocated significantly with Ln-5 in that area. MMP-8 was expressed by stromal macrophages and epithelial goblet cells, but never located in BM zone. CONCLUSIONS: Our results indicate that the colocalization of Ln-5 with MMP-2 or MMP-13, but not with MMP-8, in BM zone of KCs, may be related to special characteristics of KC.

Collagenolytic activity in bronchoalveolar lavage fluid in canine pulmonary eosinophilia.

We studied and characterized the collagenolytic matrix metalloproteinases (MMP-8 and MMP-13) in the pathogenesis of canine pulmonary eosinophilia (PE). Twenty dogs with PE and 16 healthy control dogs underwent similar clinical examination and collection of bronchoalveolar lavage fluid (BALF). Analyses of total cell and differential cell counts and collagen I degradation with and without aminophenyl mercuric acetate (APMA) treatment were performed. Correlations between cell counts and percentage of degraded collagen I in BALF were studied. Collagenase activity detected in BALF was characterized by Western immunoblotting for collagenase-2 (MMP-8) and collagenase-3 (MMP-13), and their cellular location was studied by immunocytochemical means. Collagenolytic activity was significantly increased in cell-free and native BALF of PE dogs compared to healthy controls. APMA treatment had no significant effect on BALF collagenase activity, indicating that collagenolytic activity occurred in diseased BALF in vivo in active form. Western immunoblotting identified the presence of MMP-8 and MMP-13 immunoreactivities, of which the latter was converted to active form. Major immunoreactivity for MMP-8 was observed in macrophages and epithelial cells, and major immunoreactivity for MMP-13 was observed in macrophages. A significant positive correlation was noted between the percentage of degraded collagen I and the counts of eosinophils, macrophages, lymphocytes, and mast cells. These findings suggest that the up-regulation of collagenolysis eventually contributes to pulmonary tissue destruction in canine PE.

Airway obstruction correlates with collagenase-2 (MMP-8) expression and activation in bronchial asthma.

Matrix metalloproteinases (MMPs) contribute to extracellular matrix and basement membrane degradation in asthma. The present study analyzed molecular forms and degree of activation and expression of MMP-8 in bronchoalveolar lavage fluid (BALF), BALF cells, and bronchial tissue specimens from 14 steroid-naive asthma patients, 13 uncontrolled severe asthma patients, 13 controlled asthma patients, and 14 healthy subjects by Western immunoblotting, immunohistochemistry, and in situ hybridization. Immunohistochemistry and in situ hybridization revealed a prominent MMP-8 immunoreactivity in submucosal inflammatory, glandular, and shed, but not in intact bronchial epithelial cells of asthma patients. In BALF cytospins, both MMP-8 protein and mRNA expression were observed in epithelial cells, macrophages, and polymorphonuclear leukocytes (PMNs). MMP-8 was present in BALFs asthma patients in complex, pro- and active PMN-type, and pro- and active non-PMN-type forms. BALF MMP-8 was significantly converted to active form only in BALFs from steroid-naive and uncontrolled severe asthma patients, but not in BALFs from well-controlled asthma patients or healthy controls. A significant inverse correlation between BALF MMP-8 levels and FEV1 (r = -0.283, p = 0.04), and BALF activated MMP-8 forms and FEV1 (r = -0.427, p = 0.001) was detected. Overall, these data suggest that MMP-8 and its activation has an important role in the airway destruction, healing, remodeling, and treatment response in asthma.

Clinical findings, bronchoalveolar lavage fluid cytology and matrix metalloproteinase-2 and -9 in canine pulmonary eosinophilia.

We characterized clinical and clinicopathological features, and the involvement of gelatinolytic matrix metalloproteinases (MMP-2 and -9) in canine pulmonary eosinophilia (PE). Study material consisted of 20 PE dogs and 16 healthy beagles. All dogs underwent a similar clinical examination and bronchoalveolar lavage (BAL). Analysis for cell count and differential cell count of BAL fluid (BALF), arterial blood gas analysis before and after BAL, and thoracic radiographs before BAL and after treatment were obtained. Twelve dogs were re-evaluated and six relavaged. MMP-2 and MMP-9 in BALF were analysed by zymography, Western immunoblotting and immunocytochemistry. In the PE dogs, BALF, cell count, number and percentage of eosinophils, and numbers of macrophages, lymphocytes, neutrophils, mast cells and epithelial cells were all significantly elevated. Blood eosinophilia was detected in half of the PE dogs. Three PE dogs had mild hypoxaemia. The BAL procedure had an equal effect on PE and healthy dogs' arterial blood gas values. Bronchointerstitial densities were seen in PE dogs' radiographs. Treatment of PE decreased BALF cell count, eosinophil count and percentage and diminished radiographic changes. Gelatinolytic activity was higher in PE dogs' BALF. BALF macrophages and epithelial cells were the principal sources of the MMP-9.

Bisphosphonates inhibit stromelysin-1 (MMP-3), matrix metalloelastase (MMP-12), collagenase-3 (MMP-13) and enamelysin (MMP-20), but not urokinase-type plasminogen activator, and diminish invasion and migration of human malignant and endothelial cell lines.

Bisphosphonates (clodronate, alendronate, pamidronate and zoledronate) at therapeutically attainable non-cytotoxic concentrations inhibited MMP-3, -12, -13 and -20 as well as MMP-1, -2, -8 and -9, but not urokinase-type plasminogen activator (uPA), a serine proteinase and a pro-MMP activator. Dose-dependent inhibition was shown by three independent MMP assays. The inhibition was reduced in the presence of an increased concentration of Ca(2+) when compared to physiologic Ca(2+) concentration. Alendronate inhibited the in vitro invasion (Matrigel) of human HT1080 fibrosarcoma and C8161 melanoma cells, and the random migration of these malignant and endothelial cell lines capable of expressing MMPs and uPA. The concentration of alendronate required to inhibit 50% of the activity (IC(50)=40-70 microM) of MMPs corresponded to the IC(50) of down-regulation of in vitro invasion and migration. The ability of bisphosphonates to down-regulate the in vitro invasion and random migration was comparable or slightly better in relation to the selective gelatinase inhibitor CTTHWGFTLC peptide. Alendronate but not CTTHWGFTLC peptide promoted the adhesion of HT1080 fibrosarcoma and C8161 melanoma cell lines on fibronectin. Bisphosphonates are broad-spectrum MMP inhibitors and this inhibition involves cation chelation. Bisphosphonates further exert antimetastatic, anti-invasive and cell adhesion-promoting properties, which may prevent metastases not only into hard tissues but also to soft tissues.

Chemically modified tetracycline (CMT-8) and estrogen promote wound healing in ovariectomized rats: effects on matrix metalloproteinase-2, membrane type 1 matrix metalloproteinase, and laminin-5 gamma2-chain.

Estrogen deficiency is associated with impaired cutaneous wound healing. Remodeling of the extracellular matrix in wound healing involves the action of matrix metalloproteinases on basement membrane zone components, especially laminin-5. We studied the effects of estrogen and a potent matrix metalloproteinase inhibitor, chemically modified non-antimicrobial tetracycline, CMT-8, on wound healing in ovariectomized rats. At the tissue level, laminin-5 gamma2-chain expression was decreased and the migration-inductive 80 kDa form of laminin-5 gamma2-chain was absent in ovariectomized rats when compared with sham and CMT-8- or estrogen-treated ovariectomized animals as detected by Western blotting. The highest levels of gelatinolytic activity (matrix metalloproteinase-2 and -9) were found in sham animals. Levels were reduced in ovariectomized rats and were lowest after treating ovariectomized rats with CMT-8 or estrogen as analyzed by functional activity assay and zymography. The total amount of membrane type 1-matrix metalloproteinase was unchanged in all groups. We conclude that CMT-8 and estrogen can promote wound healing in ovariectomized rats, not only by normalizing wound bed total collagen content and structure, but also by recovering the expression and processing of key molecules in wound healing, i.e., laminin-5 gamma2-chain. This study shows, for the first time, the role of estrogen and CMT-8 in laminin-5 gamma2-chain modulation in vivo.

Soluble membrane-type 1 matrix metalloproteinase (MT1-MMP) and gelatinase A (MMP-2) in induced sputum and bronchoalveolar lavage fluid of human bronchial asthma and bronchiectasis.

The aim of this study was to investigate the involvement of the MT1-MMP/MMP-2 cascade in induced sputum (IS) and bronchoalveolar lavage fluid (BALF) from bronchial asthma (BA) and bronchiectasis (BE) patients and healthy controls. The molecular forms and cellular origins of MT1-MMP and MMP-2 were determined by Western immunoblotting, immunohistochemistry and in situ hybridization. Elevated levels of soluble activated and autocatalyzed MT1-MMP species as well as activated forms of MMP-2 in IS and BALF samples from BA and BE patients were evidenced. The activation degrees of soluble MT1-MMP and MMP-2 were significantly correlated in BA and BE IS and BALF. Only low levels of both these MMPs were observed in healthy control IS and BALF. The co-expression of MMP-2 with MT1-MMP was evidenced by double immunostaining in bronchial epithelial cells, submucosal glandular cells, smooth muscle cells and monocyte/macrophages. The MT1-MMP/MMP-2 cascade is present and active in human inflammatory lung disease fluid and tissue samples. This cascade seemingly reflects the active destructive phases of these chronic lung diseases.