Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mononuclear phagocytes have the capacity to produce an array of MMPs. Several of these proteinases are capable of degrading insoluble elastin, an important component for the structural stability of the lung. Matrilysin is a low molecular weight proteinase with a broad substrate specificity produced at highest levels in in vitro differentiated monocytes. The 92-kD gelatinase is a major product of human alveolar macrophages that is also an elastase. The most newly described member of the MMP family is human macrophage metalloelastase. This enzyme is also expressed in alveolar macrophages derived from cigarette smokers. Determining the contribution of these and other elastolytic proteinases to the pathogenesis of emphysema is a focus of ongoing research.
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PMID:Elastolytic metalloproteinases produced by human mononuclear phagocytes. Potential roles in destructive lung disease. 795 53

Macrophage elastase (ME) was originally named when metal-dependent elastolytic activity was detected in conditioned media of murine macrophages. Subsequent cDNA cloning of the mouse and human enzyme demonstrated that ME is a distinct member of the matrix metalloproteinase family. To date, the catalytic parameters that describe the hydrolysis of elastin by ME have not been quantified and its activity against other matrix proteins have not been described. In this report, we have examined the action of purified recombinant human ME (rHME), produced in Escherichia coli, on elastin and other extracellular matrix proteins. On a molar basis, rHME is approximately 30% as active as human leukocyte elastase in solubilizing elastin. rHME also efficiently degrades alpha1-antitrypsin (alpha1-AT), the primary physiological inhibitor of human leukocyte elastase. In addition, rHME efficiently degrades fibronectin, laminin, entactin, type IV collagen, chondroitan sulfate, and heparan sulfate. These results suggest that HME may be required for macrophages to penetrate basement membranes and remodel injured tissue during inflammation. Moreover, abnormal expression of HME may contribute to destructive processes such as pulmonary emphysema and vascular aneurysm formation. To further understand the specificity of HME, the initial cleavage sites in alpha1-AT have been determined. In addition, the hydrolysis of a series of synthetic peptides with different P'1 residues has been determined. rHME can accept large and small amino acids at the P'1 site, but has a preference for leucine.
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PMID:Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase. 911 92

The aim of this study was to examine the hypothesis that alveolar macrophages represent a significant source of matrix-degrading proteinases in the emphysematous lung. Macrophages from bronchoalveolar lavage fluid of 10 patients with emphysema and 10 normal volunteers were maintained in vitro for 24 h and assessed semiquantitatively for mRNA transcript levels of the matrix metalloproteinases (MMPs) gelatinases A and B, macrophage metalloelastase (MME), and interstitial collagenase. Release of these MMPs into the culture medium and secretion of neutrophil elastaselike activity was also assessed. Elevated levels of mRNA transcripts for gelatinase B (p < 0.0005) and interstitial collagenase (p < 0.0005) were observed in macrophages from emphysematous patients. Increased collagenase (p < 0.01) and neutrophil elastaselike activities (p < 0.001) were also measured in conditioned medium from patient macrophages. With gelatinase B, complexed forms of the enzyme were secreted by patient but not by control macrophages. No difference in transcript levels of gelatinase A or MME was observed between patient and control samples, and neither enzyme was detected in macrophage-conditioned media from either group. These results directly demonstrate that alveolar macrophages from the emphysematous lung produce elevated quantities of matrix-degrading enzymes with both elastolytic and collagenolytic activities.
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PMID:Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. 1021 97

The aim of this study was to investigate the extracellular degrading proteolytic cascade proteins referred to as matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-9, membrane-type matrix metalloproteinase-1 (MT1-MMP), tissue inhibitors of matrix metalloproteinase-1 (TIMP-1), TIMP-2, neutrophil elastase, and alpha1-antitrypsin in human pulmonary emphysema. Localization of MMP-1, MMP-2, MMP-8, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 was verified by immunohistochemical analysis. The results of our study indicated that the immunoreactivity of MMP-1, MMP-8, MMP-9, and TIMP-1 was absent, whereas MT1-MMP and MMP-2 were mainly observed in pneumocytes, fibroblasts, and alveolar macrophages. Although MT1-MMP and MMP-2 were observed both in emphysematous and normal lung tissue, these immunoreactivities were intense in the emphysematous samples. The presence of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 was confirmed at mRNA level by reverse transcription-PCR analysis and enzyme immunoassay (EIA). However, the only statistical difference that was observed was in MMP-2 and MMP-9 (MMP-2: emphysematous samples, 19.1+/-2.1 versus control samples, 5.2+/-0.60 microg/g protein, p < 0.05; MMP-9: emphysematous samples, 18.4+/-5.6 versus control samples, 8.1+/-2.7 microg/g protein, p < 0.05). Results of the neutrophil elastase as analyzed by EIA, and alpha1-antitrypsin levels as detected by laser nephelometric immunoassay, indicated no statistical difference between the emphysematous and control groups. In addition to the presence of mRNA levels, the level of MT1-MMP according to immunoblot analysis increased in the emphysematous samples. Gelatin zymographic analysis confirmed the presence of both pro and active forms of MMP-2, and the increased ratio of the active form of MMP-2 in emphysematous samples (25.9%+/-2.0% versus 11.2%+/-3.3%, p < 0.05), indicated in situ activation of MMP-2 by MT1-MMP. Elastin zymographic analysis showed elastolytic activity by MMP-2 and MMP-9 but not the reported band of macrophage metalloelastase (MMP-12). The data suggest that the MT1-MMP/MMP-2/TIMP-2 system plays a significant role in the MMP-mediated extracellular matrix degradation and tissue remodeling of emphysematous lungs, and thus may contribute to the weakening of lung parenchyma and lead to the formation of emphysema.
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PMID:Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. 975 52

In the mouse, macrophage elastase is critical to macrophage proteolysis. The use of gene-targeting has uncovered both pathological roles, including destructive effects in aneurysm formation and emphysema, and physiological roles, such as tumor growth inhibition and regulation of inflammation. Translation of findings from mouse to human biology depends upon how well the disease models replicate the human conditions and the similarity of enzyme profile between species. We know that human MMP-12 is associated with these diseases, but as opposed to the mouse, other MMPs may also be of importance (MMP-9, and perhaps MMP-7, in particular). Our interpretation is that findings in mice reflect the critical role of macrophage proteolysis in these disease processes.
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PMID:Diverse roles of macrophage matrix metalloproteinases in tissue destruction and tumor growth. 1060 92

This laboratory has previously described a method of preventing air-space enlargement in experimental pulmonary emphysema using aerosolized hyaluronan (HA). Although it was found that HA preferentially binds to elastic fibers (which undergo breakdown by elastases in emphysema), it remains to be shown that such attachment actually prevents damage to the fibers. In the current study, cell-free radiolabeled extracellular matrices, derived from rat pleural mesothelial cells, were used to test the ability of low molecular weight ( approximately 100 kDa) streptococcal HA to prevent elastolysis. Coating the matrices with HA significantly decreased elastolysis (P<0.05) induced by porcine pancreatic elastase (43%), human neutrophil elastase (53%), and human macrophage metalloelastase (80%). Concomitant in vivo studies examined the ability of an aerosol preparation of the streptococcal HA to prevent experimental emphysema induced by intratracheal administration of porcine pancreatic elastase. As seen with earlier studies involving bovine tracheal HA, a single aerosol exposure significantly decreased elastase-induced airspace enlargement, as measured by the mean linear intercept (107.5 vs 89.6 microm; P < 0. 05). Furthermore, repeated exposure to the HA aerosol for 1 month did not reveal any morphological changes in the lung. The results provide further evidence that aerosolized HA may be an effective means of preventing pulmonary emphysema and perhaps other lung diseases that involve elastic fiber injury.
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PMID:The effect of hyaluronan on elastic fiber injury in vitro and elastase-induced airspace enlargement in vivo. 1099

Macrophage metalloelastase (MMP-12) is implicated in the pathology of many diseases such as emphysema, aortic lesions and cancer. Recently, MMP-12 was cloned and purified from mouse and human macrophages. We report here the expression of the full-length and catalytic domain of rat MMP-12 in Escherichia coli and characterization of the purified enzyme. Inclusion bodies of expressed rat MMP-12 catalytic domain were denatured and refolded using a new method, and then affinity purified to near homogeneity with zinc-chelating Sepharose. The purified rat MMP-12 catalytic domain was highly active in digesting substrates, having a K(m) of 12 microM and optimal pH of 7.5--8.5. During investigation of natural substrate specificity, we found that rat MMP-12 catalytic domain was able to completely degrade collagen-V, partially degrade collagen-I, but it was unable to digest collagen-IV. The enzyme could also degrade osteonectin, vitronectin, and fibronectin, but not laminin and albumin. The catalytic properties and natural substrate specificity of rat MMP-12 catalytic domain differed from those of human MMP-12 catalytic domain.
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PMID:Cloning, expression, purification, and characterization of rat MMP-12. 1123 88

Pulmonary emphysema is believed to result from an imbalance between proteolytic enzymes and their inhibitors. Multiple studies have examined the presence of various proteases within the bronchoalveolar lavage fluid from patients with chronic obstructive pulmonary disease (COPD). However, to date extensive examination of the lung parenchyma for the expression of destructive enzymes has not yet been determined. The following study examines the lung parenchyma of 23 patients with emphysema and 8 normal control samples for the expression of matrix matalloproteinase-1 (MMP-1), MMP-12, and MMP-9. We report here that interstitial collagenase (MMP-1) RNA, protein, and activity are present in the lung parenchyma of patients with emphysema and not in the lung of normal control subjects. In contrast, metalloelastase (MMP-12) expression is absent in these samples. Immunohistochemistry studies localized MMP-1 to the Type II pneumocyte in patients with emphysema and not normal control subjects or smokers without emphysema. This observation demonstrates that the lung is altered in emphysema such that the Type II pneumocyte secretes MMP-1 and suggests that MMP-1 may be an important enzyme involved in the destruction of the lung in the human disease. In addition, the induction of a proteolytic enzyme within the Type II pneumocyte suggests that the cells within the lung itself are capable of producing degradative enzymes in this disease process.
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PMID:Human collagenase (matrix metalloproteinase-1) expression in the lungs of patients with emphysema. 1125 39

The macrophage elastase enzyme (MMP-12) expressed mainly in alveolar macrophages has been identified in the mouse lung as the main destructive agent associated with cigarette smoking, which gives rise to emphysema, both directly via elastin degradation and indirectly by disturbing the proteinase/antiproteinase balance via inactivation of the alpha1-proteinase inhibitor (alpha1-PI), the antagonist of the leukocyte elastase. The catalytic domain of human recombinant MMP-12 has been crystallized in complex with the broad-specificity inhibitor batimastat (BB-94). The crystal structure analysis of this complex, determined using X-ray data to 1.1 A and refined to an R-value of 0.165, reveals an overall fold similar to that of other MMPs. However, the S-shaped double loop connecting strands III and IV is fixed closer to the beta-sheet and projects its His172 side-chain further into the rather hydrophobic active-site cleft, defining the S3 and the S1-pockets and separating them from each other to a larger extent than is observed in other MMPs. The S2-site is planar, while the characteristic S1'-subsite is a continuous tube rather than a pocket, in which the MMP-12-specific Thr215 replaces a Val residue otherwise highly conserved in almost all other MMPs. This alteration might allow MMP-12 to accept P1' Arg residues, making it unique among MMPs. The active-site cleft of MMP-12 is well equipped to bind and efficiently cleave the AlaMetPhe-LeuGluAla sequence in the reactive-site loop of alpha1-PI, as occurs experimentally. Similarities in contouring and particularly a common surface hydrophobicity both inside and distant from the active-site cleft explain why MMP-12 shares many substrates with matrilysin (MMP-7). The MMP-12 structure is an excellent template for the structure-based design of specific inhibitors for emphysema therapy and for the construction of mutants to clarify the role of this MMP.
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PMID:Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 A crystal structure. 1157 28

Human macrophage elastase (MMP-12) is a member of the family of matrix metalloproteinases (MMPs) that plays, like other members of the family, an important role in inflammatory processes contributing to tissue remodelling and destruction. In particular, a prominent role of MMP-12 in the destruction of elastin in the lung alveolar wall and the pathogenesis of emphysema has been suggested. It is therefore an attractive therapeutic target. We describe here the crystal structure of the catalytic domain of MMP-12 in complex with a hydroxamic acid inhibitor, CGS27023A. MMP-12 adopts the typical MMP fold and binds a structural zinc ion and three calcium ions in addition to the catalytic zinc ion. The enzyme structure shows an ordered N terminus close to the active site that is identical in conformation with the superactivated form of MMP-8. The S1'-specificity pocket is large and extends into a channel through the protein, which puts MMP-12 into the class of MMPs 3, 8 and 13 with large and open specificity pockets. The two crystallographically independent molecules adopt different conformations of the S1'-loop and its neighbouring loop due to differing crystal packing environments, suggesting that flexibility or the possibility of structural adjustments of these loop segments are intrinsic features of the MMP-12 structure and probably a common feature for all MMPs. The inhibitor binds in a bidentate fashion to the catalytic zinc ion. Its polar groups form hydrogen bonds in a substrate-like manner with beta-strand sIV of the enzyme, while the hydrophobic substituents are either positioned on the protein surface and are solvent-exposed or fill the upper part of the specificity pocket. The present structure enables us to aid the design of potent and selective inhibitors for MMP-12.
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PMID:Crystal structure of human macrophage elastase (MMP-12) in complex with a hydroxamic acid inhibitor. 1157 29


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