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)

Tissue inhibitor of metalloproteinases (TIMP) is the major inhibitor of collagenase, gelatinase, proteoglycanase, stromelysin, and metalloelastases. An imbalance between proteases and inhibitors has been implicated in numerous disease processes including tumor invasion, rheumatoid arthritis, emphysema, and aortic aneurysm disease. The purpose of this investigation was to develop a polyclonal antibody to recombinant TIMP and establish an immunoassay to measure immunoreactive protein in normal and diseased tissues. A polyclonal antibody was produced in rabbit against recombinant human TIMP which was characterized and used to establish a radioimmunoassay. The assay was used to measure immunoreactive protein in fibroblast conditioned medium, human serum, and aortic extracts. There was more immunoreactive TIMP in matrix associated urea extracts than soluble salt extracts from human aorta, suggesting that TIMP is matrix associated. The sensitivity of the assay enables the specific measurement of this inhibitor in serum, fibroblast culture medium, and tissue extracts.
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PMID:Tissue inhibitor of metalloproteases (TIMP) is matrix associated in aortic tissue: report of a radioimmunoassay. 232 85

Proteolytic degradation of extracellular matrix is thought to play an important role both in emphysema and in tissue development and repair. Retinoic acid has been suggested to modify tissue injury, and in an animal model of emphysema may induce alveolar repair. Since cytokines can induce matrix metalloproteinase (MMP) production in fibroblasts and neutrophil elastase (NE) can activate MMPs, we hypothesized that retinoic acid could attenuate collagen degradation by modifying MMP production and activation. To evaluate this, human lung fibroblasts were cast into native type I collagen gels and floated in medium containing cytomix (TNF-alpha, IL-1beta, and IFN-gamma) alone or in combination with NE in the presence and absence of retinoic acid (1 microM). After 5 d, cytomix with elastase induced significant degradation of the collagen gels assessed by quantifying total hydroxyproline (41.6 +/- 1.6 microg versus 3.3 +/- 1.5 microg, P < 0.01). Retinoic acid significantly inhibited this degradation (23.3 +/- 1.5 microg versus 3.3 +/- 1.5 microg, P < 0.01). Gelatin zymography and Western blot revealed that MMP-1, MMP-3, and MMP-9 were induced by cytomix and that co-exposure to NE resulted in increased production of activated forms of these enzymes. Retinoic acid attenuated the induction and activation of MMP-1 and MMP-3. The current study, therefore, suggests that in addition to stimulating anabolic effects, retinoic acid may modulate proteolytic processes thought to contribute to tissue destruction in emphysema.
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PMID:Retinoic acid attenuates cytokine-driven fibroblast degradation of extracellular matrix in three-dimensional culture. 1171 5

Tissue remodeling is an important process in many inflammatory and fibrotic lung disorders. RBC may in these conditions interact with extracellular matrix (ECM). Fibroblasts can produce and secrete matrix components, matrix-degrading enzymes (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Imbalance in matrix synthesis/degradation may result in rearrangement of tissue architecture and lead to diseases such as emphysema or fibrosis. Neutrophil elastase (NE), a protease released by neutrophils, is known to activate MMP. We hypothesized that RBC can stimulate secretion of MMPs from human lung fibroblasts and that NE can augment this effect. Human fetal lung fibroblasts were cultured in floating collagen gels with or without RBC. After 4 days, the culture medium was analyzed with gelatin zymography, Western blot, and ELISA for MMP-1, -2, -3 and TIMP-1, -2. RBC augmented NE-induced fibroblast-mediated collagen gel contraction compared with NE alone (18.4+/-1.6%, 23.7+/-1.4% of initial gel area, respectively). A pan-MMP inhibitor (GM-6001) completely abolished the stimulating effect of NE. Gelatin zymography showed that RBC stimulated MMP-2 activity and that NE enhanced conversion to the active form. Addition of GM-6001 completely inhibited MMP-2 activity in controls, whereas it only partially altered RBC-induced MMP activity. Western blot confirmed the presence of MMP-1 and MMP-3 in fibroblasts stimulated with RBC, and ELISA confirmed increased concentrations of pro-MMP-1. We conclude that stimulation of MMP secretion by fibroblasts may explain the ability of RBC to augment fibroblast-mediated collagen gel contraction. This might be a potential mechanism by which hemorrhage in inflammatory conditions leads to ECM remodeling.
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PMID:Red blood cells increase secretion of matrix metalloproteinases from human lung fibroblasts in vitro. 1640 42

Macrophage metalloelastase or matrix metalloproteinase-12 (MMP-12) appears to exacerbate atherosclerosis, emphysema, aortic aneurysm, rheumatoid arthritis, and inflammatory bowel disease. An inactivating E219A mutation, validated by crystallography and NMR spectra, prevents autolysis of MMP-12 and allows us to determine its NMR structure without an inhibitor. The structural ensemble of the catalytic domain without an inhibitor is based on 2813 nuclear Overhauser effects (NOEs) and has an average RMSD to the mean structure of 0.25 A for the backbone and 0.61 A for all heavy atoms for residues Trp109-Gly263. Compared to crystal structures of MMP-12, helix B (hB) at the active site is unexpectedly more deeply recessed under the beta-sheet. This opens a pocket between hB and beta-strand IV in the active-site cleft. Both hB and an internal cavity are shifted toward beta-strand I, beta-strand III, and helix A on the back side of the protease. About 25 internal NOE contacts distinguish the inhibitor-free solution structure and indicate hB's greater depth and proximity to the sheet and helix A. Line broadening and multiplicity of amide proton NMR peaks from hB are consistent with hB undergoing a slow conformational exchange among subtly different environments. Inhibitor-binding-induced perturbations of the NMR spectra of MMP-1 and MMP-3 map to similar locations across MMP-12 and encompass the internal conformational adjustments. Evolutionary trace analysis suggests a functionally important network of residues that encompasses most of the locations adjusting in conformation, including 18 residues with NOE contacts unique to inhibitor-free MMP-12. The conformational change, sequence analysis, and inhibitor perturbations of NMR spectra agree on the network they identify between structural scaffold and the active site of MMPs.
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PMID:Solution structure of inhibitor-free human metalloelastase (MMP-12) indicates an internal conformational adjustment. 1799 11

In vivo lung-targeted VEGF gene inactivation results in pulmonary cell apoptosis, airspace enlargement, and increased lung compliance consistent with an emphysema-like phenotype. The predominant hypothesis for the cause of lung destruction in emphysema is an imbalance between active lung protease and anti-protease molecules. Therefore, we investigated the role of protease (e.g., matrix metalloproteinases--MMPs) and anti-protease (e.g., tissue inhibitors of metalloproteinases--TIMPs) expression in contributing to the lung structural remodeling observed in pulmonary-VEGF-deficient mice. VEGFLoxP mice instilled through the trachea with an adeno-associated virus expressing Cre recombinase (AAV/Cre) manifest airspace enlargement and a greater (P < 0.05) mean linear intercept (MLI: 44.2 +/- 4.2 microm) compared to mice instilled with a control virus expressing LacZ (31.3 +/- 2.5 microm). Airspace enlargement was prevented by the continuous administration of the general MMP inhibitor, doxycycline (Dox) (Cre + Dox: 32.6 +/- 2.5 microm), and MLI values were not different from either control (LacZ + Dox: 30.5 +/- 1.2 microm). In situ magnetic resonance imaging of VEGF gene inactivated mouse lungs revealed uneven inflation, residual trapped gas volumes upon oxygen absorption deflation/re-inflation, and loss of parenchymal structure; effects that were largely prevented by Dox. Five weeks after AAV/Cre infection Western blot revealed a 9.9-fold increase in pulmonary MMP-3, and 2-fold increases in MMP-9 and TIMP-2. However, the increase in MMP-3 was prevented by Dox administration and was associated with a 2-fold increase in serpin b5 (Maspin) expression. These results suggest that doxycycline treatment largely prevents the aberrant lung remodeling response observed in VEGF-deficient mouse lungs and is associated with changes in protease and anti-protease expression.
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PMID:Doxycycline treatment prevents alveolar destruction in VEGF-deficient mouse lung. 1818 Dec 12

Long-term exposure to cigarette smoke (CS) results in alveolar parenchyma destruction due to chronic inflammatory response and the imbalance between oxidants and antioxidants, and proteases and antiproteases. Emphysema is the main symptom of chronic obstructive pulmonary disease. Current treatment focuses on relieving respiratory symptoms, and inflammation resolution failure is an important pathophysiological element of the disease. Specialized pro-resolving mediators (SPMs) synthesized endogenously during resolution processes demonstrated beneficial effects in murine models of airway inflammation. Here, we aimed to test the SPM AT-RvD1 in a murine model of CS-induced emphysema. AT-RvD1 restored elastic fibers and lung morphology, with reduction in MMP-3, neutrophils, and myeloperoxidase activity and increases in macrophages and IL-10 levels. AT-RvD1 also decreased levels of oxidative stress markers and ROS via upregulation of the Nrf2/Keap1 pathway. Therefore, we suggest that AT-RvD1 causes pro-resolutive action in our murine model of CS-induced emphysema by upregulation of the Nrf2/Keap1 pathway.
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PMID:AT-RVD1 repairs mouse lung after cigarette smoke-induced emphysema via downregulation of oxidative stress by NRF2/KEAP1 pathway. 2943 39

S100 calcium-binding protein A9 (S100A9), is elevated in plasma and bronchoalveolar lavage fluid (BALF) of COPD patients and aging enhances S100A9 expression in several tissues. Currently, the direct impact of S100A9-mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated S100A9 levels in human BALF correlated with age. Elevated lung levels of S100A9 were higher in older mice compared to young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced S100A9 levels in age-matched mice. To examine the direct role of S100A9 on the development of COPD, S100a9-/- mice or inhibited activity with paquinimod, and exposed the models to chronic cigarette smoke S100A9 depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and FEV0.05/FVC, compared to age-matched wild type or vehicle administered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK, and c-RAF phosphorylation, MMP-3, MMP-9, MCP-1, IL-6, and KC release into the airways. Paquinimod administered to non-smoked aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor, LY3214996, or the c-RAF inhibitor, GW5074, resulting in less S100A9-induced MMP-3, MMP-9, MCP-1, IL-6, and IL-8. Silencing TLR4, RAGE or EMMPRIN prevented S100A9-induced phosphorylation of ERK and c-RAF. Our data suggest that S100A9 signaling contributes to the progression of smoke and age-related COPD.
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PMID:Cigarette smoke induction of S100A9 contributes to chronic obstructive pulmonary disease. 3296 23