Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The normal structure and function of the human lung is dependent on the maintenance of the connective tissue matrix. These structural macromolecules provide the template for normal parenchymal cell architecture on which efficient gas exchange depends. In addition, the organization and amount of this extracellular matrix accounts for much of the mechanical behavior of the lung parenchyma during the respiratory cycle. The preservation of this intricate connective tissue scaffold depends on the lung's capacity to prevent enzymatic disruption of the component matrix proteins. Specifically, the integrity of the normal connective tissue skeleton of the lung is determined by the maintenance of a balance between proteases capable of cleaving these structural elements and the specific protease inhibitors. The normal extracellular matrix is preserved when the local concentrations of protease inhibitors prohibits expression of active connective tissue proteases within the lung parenchyma. Conversely, the disruption of lung structure during the course of acute and chronic inflammatory diseases of the lung is often associated with an imbalance of protease-antiprotease activity. The consequence is the expression of unimpeded proteolytic attack on the connective tissue matrix of the lung. In this context, the nature of the pulmonary lesion and its physiologic consequences, reflect the specificity of the expressed proteases for the individual connective tissue components. Experimental evidence suggests that the differential expression of collagenase and elastase, prototypes of connective tissue proteases, may determine whether the pathologic outcome is fibrosis (e.g., idiopathic pulmonary fibrosis) or destruction (e.g., emphysema) of the alveolar structures.
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PMID:Role of connective tissue proteases in the pathogenesis of chronic inflammatory lung disease. 632 73

Leukotriene C4 (LTC4), a mediator generated by a variety of inflammatory cells, participates in several physiological and pathological processes. It has been shown that LTC4 stimulates collagen synthesis by fibroblasts, suggesting a role in collagen turnover. However, the possible effect of this mediator on collagen degradation has not been examined. In this study we explored the role of LTC4 in the modulation of fibroblast interstitial collagenase and TIMP-1. Confluent cultures of three human normal lung fibroblast cell lines, and one derived from idiopathic pulmonary fibrosis (IPF) were exposed to LTC4 0.1, 1 and 10 nM, and to IL-1 beta as positive control. Collagenase and TIMP mRNAs expression were analyzed by Northern blot followed by densitometric scanning. Immunoreactive procollagenase was detected by immunoblot, and collagenase activity was measured using [3H]collagen. Our results showed that LTC4 enhanced several-fold collagenase mRNA expression in collagenase-producing fibroblasts, and induced the expression of the enzyme mRNA in collagenase-nonproducing fibroblasts, both in normal and IPF derived cell lines. LTC4 1 nM induced the highest response. Collagenolytic activity and immunoreactive collagenase paralleled collagenase mRNA expression. Interestingly, simultaneous exposure of fibroblasts to LTC4 plus IL-1 failed to show additive effects. Moreover, in two cell lines the combination resulted in a decrease of collagenase mRNA expression compared with both mediators separately. TIMP mRNA levels were not significantly modified by LTC4, nor IL1 beta. Our findings suggest that LTC4 plays a role in the modulation of fibroblast collagenase, and it may participate in extracellular matrix remodeling during lung inflammation.
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PMID:Leukotriene C4 upregulates collagenase expression and synthesis in human lung fibroblasts. 798 Dec 29

Fibrosing alveolitis complicating systemic sclerosis (FASSc) carries a better prognosis than lone cryptogenic fibrosing alveolitis (CFA). We wanted to determine whether this improved prognosis is associated with differential neutrophil migration and activation in the lower respiratory tract. We therefore compared bronchoalveolar lavage (BAL) neutrophil numbers and levels of neutrophil-derived enzymes in FASSc, CFA and normal individuals. Bronchoalveolar lavage was performed on 45 subjects (FASSc n = 20; CFA n = 15; normals n = 10); cell counts and levels of neutrophil-derived enzymes, myeloperoxidase, elastase (total elastase and elastase/alpha 1 antitrypsin complexes), collagenase and lactoferrin were measured. Lung function testing was performed in subjects with fibrosing alveolitis. Significant differences in the levels of collagenase, myeloperoxidase and elastase/ alpha 1-antitrypsin complexes were present in the BAL fluid from the three groups. Patients with CFA had significantly higher neutrophil percentages and levels of collagenase and myeloperoxidase than those with FASSc. Disease extent, as judged by lung volumes and gas transfer, was comparable in the CFA and FASSc groups. Forced vital capacity (% predicted) was significantly lower in patients with evidence of increased neutrophil enzyme release than those without. We conclude that: 1) increased neutrophil migration to the lung is accompanied by release both of primary and secondary granule enzymes in cryptogenic fibrosing alveolitis; and 2) the lower amounts of neutrophil products in fibrosing alveolitis complicating systemic sclerosis may account for the improved prognosis, even when disease is as extensive as in cryptogenic fibrosing alveolitis.
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PMID:Neutrophil activation in fibrosing alveolitis: a comparison of lone cryptogenic fibrosing alveolitis and systemic sclerosis. 879 62

In interstitial lung diseases, deposition of extracellular matrix (ECM) in alveoli and degradation of ECM lead to pulmonary structural remodeling. The changes in ECM and the localization of matrix metalloproteinases (MMPs) and a tissue inhibitor of metalloproteinases (TIMP) in the lung tissues of patients with bronchiolitis obliterans organizing pneumonia (BOOP) and idiopathic pulmonary fibrosis (IPF) were investigated. Immunohistochemical analysis for the detection of fibronectin, collagen-I, -III, and -IV, smooth muscle actin, MMP-1 (interstitial collagenase), -2 (gelatinase A), and -9 (gelatinase B), and TIMP-2, and in situ hybridization for the detection of MMP-9 mRNA were performed. Western blotting of lung tissue homogenates was performed for MMP-2 and MMP-9. The gelatinolytic activities of the homogenates were also determined using gelatin zymography. Fibronectin and collagen-I, -III, and -IV were detected in the intra-alveolar fibrosis in addition to the interstitium of these diseases. MMP-1, MMP-2, MMP-9, and TIMP-2 were detected in the regenerated epithelial cells covering intra-alveolar fibrosis. Myofibroblasts in intra-alveolar fibrosis in BOOP showed predominant reaction for MMPs, and they ultrastructurally appeared to be phagocytosing collagen fibrils, and those of IPF showed a predominant reaction for TIMP-2. New vascularization in intra-alveolar fibrosis was exclusively observed in cases of BOOP, and the endothelial cells were positive for MMP-2. Western blotting showed the existence of a latent form of MMP-9 and latent and active forms of MMP-2, and gelatin zymography revealed that the ratio of active/latent forms of MMP-2 in BOOP is significantly larger than that in the control lungs. Predominant MMPs in BOOP may constitute the mechanism of reversibility of fibrotic changes in this disease. TIMP-2 in myofibroblasts in IPF may contribute to the stable ECM deposition and the irreversible pulmonary structural remodeling.
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PMID:Localization of matrix metalloproteinases-1, -2, and -9 and tissue inhibitor of metalloproteinase-2 in interstitial lung diseases. 964 59

The dominant form of human surfactant protein D (SP-D) is a multimeric collagenous glycoprotein composed of monomeric subunits that have a molecular mass of 43 kDa under reducing conditions. However, in evaluating monoclonal antibodies to human SP-D, an additional monomeric subunit was identified with a reduced molecular mass of 50 kDa. This 50-kDa variant was detected in approximately half of the samples evaluated and was found in lavage fluid from normal subjects, patients with alveolar proteinosis or idiopathic pulmonary fibrosis and in amniotic fluid. This 50-kDa variant had the same amino-terminal sequence, amino acid composition and apparent size of the carboxy-terminal collagenase-resistant fragment (20 kDa) as the 43-kDa subunit. The major difference was in the amino-terminal portion of the molecule and was due to altered glycosylation, as determined by carbohydrate staining, chemical deglycosylation, treatment with N-glycanase and neuraminidase and reduced signals for threonine at positions 5, 9 and 10 during amino-terminal sequencing. After gel filtration chromatography, the 50-kDa form was not present in the high molecular weight fraction, which is commonly used in purification of SP-D, but was found only in the smaller molecular weight fraction of monomers and trimers of SP-D. In conclusion, the 50 kDa-form of surfactant protein D is produced by post-translational glycosylation and does not form higher ordered oligomers, but its precise physiological function remains to be determined.
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PMID:A 50-kDa variant form of human surfactant protein D. 986 12

Fibroblast proliferation and extracellular matrix accumulation characterize idiopathic pulmonary fibrosis (IPF). We evaluated the presence of tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4; collagenase-1, -2, and -3; gelatinases A and B; and membrane type 1 matrix metalloproteinase (MMP) in 12 IPF and 6 control lungs. TIMP-1 was found in interstitial macrophages and TIMP-2 in fibroblast foci. TIMP-3 revealed an intense staining mainly decorating the elastic lamina in vessels. TIMP-4 was expressed in IPF lungs by epithelial and plasma cells. TIMP-2 colocalized with Ki67 in fibroblasts, whereas TIMP-3 colocalized with p27 in inflammatory and epithelial cells. Collagenase-1 was localized in macrophages and alveolar epithelial cells, collagenase-2 was localized in a few neutrophils, and collagenase-3 was not detected. MMP-9 was found in neutrophils and subepithelial myofibroblasts. Myofibroblast expression of MMP-9 was corroborated in vitro by RT-PCR. MMP-2 was noticed in myofibroblasts, some of them close to areas of basement membrane disruption, and membrane type 1 MMP was noticed in interstitial macrophages. These findings suggest that in IPF there is higher expression of TIMPs compared with collagenases, supporting the hypothesis that a nondegrading fibrillar collagen microenvironment is prevailing.
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PMID:TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? 1095 32

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder characterized by fibroblast proliferation and extracellular matrix accumulation. However, studies on fibroblast growth rate and collagen synthesis have given contradictory results. Here we analyzed fibroblast growth rate by a formazan-based chromogenic assay; fibroblast apoptosis by in situ end labeling (ISEL) and propidium iodide staining; percent of alpha-smooth muscle actin (alpha-SMA) positive cells by fluorescence-activated cell sorter; and alpha1-(I) collagen, transforming growth factor (TGF)-beta1, collagenase-1, gelatinases A and B, and tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4 expression by reverse transcriptase/polymerase chain reaction in fibroblasts derived from IPF and control lungs. Growth rate was significantly lower in IPF fibroblasts compared with controls (13.3 +/- 38.5% versus 294.6 +/- 57%, P < 0.0001 at 13 d). Conversely, a significantly higher percentage of apoptotic cells was observed in IPF-derived fibroblasts (ISEL: 31.9 +/- 7.0% versus 15.5 +/- 7.6% from controls; P < 0.008). alpha-SMA analysis revealed a significantly higher percentage of myofibroblasts in IPF samples (62.8 +/- 25.2% versus 14.8 +/- 11.7% from controls; P < 0.01). IPF fibroblasts were characterized by an increase in pro-alpha1-(I) collagen, TGF-beta1, gelatinase B, and all TIMPs' gene expression, whereas collagenase-1 and gelatinase A expression showed no differences. These results suggest that fibroblasts from IPF exhibit a profibrotic secretory phenotype, with lower growth rate and increased spontaneous apoptosis.
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PMID:Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression. 1135 Aug 29

The purpose of this study was to examine the role of interstitial collagenases, members of the family of matrix metalloproteinases, in the development of pulmonary fibrosis. The activity, levels and molecular forms of collagenases (matrix metalloproteinases (MMP)-1, -8 and -13), gelatinase B (MM P-9) and its main endogenous inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) and sarcoidosis patients with varying degrees of pulmonary parenchymal involvement. Collagenase activity was elevated in IPF and group 3 sarcoidosis patients. A positive correlation between BALF collagenase activity and MMP-8 levels was also observed. Western immunoblotting revealed the presence of two isoforms of MMP-8 in patient samples; an 80 kD form representing latent enzyme from polymorphonuclear neutrophils and a 55 kD form representing the fibroblast-type proform. MMP-9 levels were also elevated in both IPF and group 3 sarcoidosis patients, while TIMP-1 levels remained normal, indicating a shift in the balance between the enzyme and inhibitor, favouring MMP-9. Matrix metalloproteinase-8 is the major contributor to the bronchoalveolar lavage fluid collagenase activity in the airways of patients with idiopathic pulmonary fibrosis and sarcoidosis and may initiate collagen destruction and remodelling leading to the development of pulmonary fibrosis.
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PMID:Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF. 1244 77

Diverse interstitial lung diseases (ILD) demonstrate mesenchymal infiltration by an abundance of activated mast cells whose role in parenchymal fibrogenesis remains unclear. Since mast cells differentiate in a dynamic, tissue-specific manner via signals transduced by c-Kit receptor, we examined the effect of ILD microenvironments on c-Kit expression and metalloproteinase phenotypes of mesenchymal mast cell populations. Immunohistochemical and flow cytometric analyses characterized surface expression of c-Kit on mast cells in tissues obtained from patients with idiopathic pulmonary fibrosis, systemic sclerosis, sarcoidosis, and lymphangioleiomyomatosis, thus identifying a unique immunophenotype not shared by normal lung mast cells. Isolation of c-Kit+/FcepsilonRI+/CD34- mast cells via immunocytometric sorting of heterogeneous cell populations from mechanically disaggregated lung tissues permitted analysis of gene expression patterns by two-step real-time polymerase chain reaction. Transcriptional profiling identified expression of c-Kit and the neutral serine proteases, tryptase and chymase, establishing the identity of sorted populations as mature mast cells. Mast cells harvested from ILD tissues demonstrated characteristic metalloproteinase phenotypes which included expression of matrix metalloproteinase (MMP)-1 and a disintegrin and metalloproteinase (ADAM)-9, -10, and -17. Immunohistochemical co-localization guided by gene profiling data confirmed expression of chymase, MMP-1, and ADAM-17 protein in subpopulations of mast cells in remodelling interstitium. Gene profiling of harvested mast cells also showed increased transcript copy numbers for TNFalpha and CC chemokine receptor 2, which play critical roles in lung injury. We conclude that ILD microenvironments induce unique c-Kit receptor and metalloproteinase mast cell phenotypes.
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PMID:c-Kit immunophenotyping and metalloproteinase expression profiles of mast cells in interstitial lung diseases. 1588 94

Plasmin is a potent protease related to tissue repair/remodeling not by fibrinolysis alone but also by activation of cytokines such as transforming growth factor and hepatocyte growth factor and by activation of matrix metalloproteases. We examined whether matrix matalloproteinase-1 was activated via plasminogen activation on surfaces of cultured alveolar epithelial cells (A-549). Cells were cultured overnight with plasminogen, pro-matrix metalloproteinase-1, and type I collagen as a substrate. Sodium dodecil sulfate-polyacrylamide gel electrophoresis was used to detect type I collagen degradation in culture supernatant. Collagen degradation corresponded to cell surface plasmin generation. No such finding was seen in the absence of cells or plasminogen. Alveolar epithelial plasminogen activation is important in matrix metalloproteinase-1 activation and thus presumably in tissue remodeling in pulmonary fibrosing pulmonary diseases such as idiopathic pulmonary fibrosis.
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PMID:Matrix metalloproteinase-1 activation via plasmin generated on alveolar epithelial cell surfaces. 1659 47


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