Gene/Protein Disease Symptom Drug Enzyme Compound
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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

Elastase activity directed against lung extracellular matrix is currently believed to be important in the pathogenesis of pulmonary emphysema. Although human alveolar macrophages degrade elastin when in direct contact with this substrate in vitro, studies of free elastase activity in medium conditioned by human alveolar macrophages have yielded variable results. As human alveolar macrophages secrete the tissue inhibitor of metalloproteinases (TIMP), an inhibitor of collagenase and of other connective-tissue-derived mammalian metalloproteinases, we speculated that this inhibitor's effects might extend to macrophage elastase. Using metalloproteinase elastase from the murine macrophagelike cell line P388D1, we observed that human alveolar macrophage conditioned medium inhibits metalloproteinase elastase and that this inhibitory activity could be blocked by specific antibody to TIMP. Alpha 2-macroglobulin, another proteinase inhibitor secreted by alveolar macrophages, also inhibited metalloproteinase elastase, but its inhibitory capacity was not blocked by antibody to TIMP. Because detergents are often included in elastase assays, we examined the effects of sodium dodecyl sulfate (SDS). Buffers containing SDS and SDS-treated elastin were found to exert diverse effects on metalloproteinase elastase, TIMP, and alpha 2-macroglobulin activities, including a marked inhibition of metalloproteinase elastase activity by SDS-containing buffers. These findings suggest that detection of secreted metalloproteinase elastase activity by human alveolar macrophages is complicated by the concomitant release by these cells of inhibitors of metalloproteinases, and that assay conditions can markedly influence the results.
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PMID:Human alveolar macrophages secrete an inhibitor of metalloproteinase elastase. 243 67

An imbalance between proteases and anti-proteases is believed to play an important role in the pathogenesis of emphysema. In this study, we explored the hypothesis that cigarette smoke can alter tissue structure through an effect on the release of matrix metalloproteinase-1 (MMP-1) and type I tissue inhibitor of metalloproteinases (TIMP-1). Cigarette smoke extract (CSE) significantly stimulated pro-MMP-1 production (determined by ELISA and immunoblots) and mRNA expression (by real-time RT-PCR) by human fetal lung fibroblasts (HFL-1) in a concentration-dependent manner (2.5-10%). High concentrations of CSE (10%) could potentially activate the latent form of MMP-1 as the high molecular weight (52 kDa) form was converted into a low molecular weight (42 kDa) form consistent with active MMP-1. TIMP-1 production, however, was not significantly altered by the concentrations of CSE tested. After 30 min exposure, CSE significantly induced ERK1/2 phosphorylation, which then gradually decreased from 90 minutes to 3 hours. PD98059, a specific inhibitor of ERK-MAPK, significantly blocked the CSE effect on ERK1/2 phosphorylation. Furthermore, PD98059 significantly inhibited the CSE effect on MMP-1 production and mRNA expression by fibroblasts. These results suggest that cigarette smoke stimulates production and likely activates MMP-1 through activating ERK1/2 signal transduction pathway. By inducing MMP-1, cigarette smoke may result in excess tissue destruction and contribute to the development of emphysema.
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PMID:Cigarette smoke stimulates MMP-1 production by human lung fibroblasts through the ERK1/2 pathway. 1699 35

The incidence of finding evidence of both emphysema and pulmonary fibrosis in the same patient has received increased attention. Several investigators have found on biopsy the presence of emphysema of the upper zones and diffuse parenchymal disease with fibrosis of the lower zones of the lung, especially associated with current or previous heavy smokers. Believed previously to be two different disease mechanisms, there are now data to implicate some common pathways of cell and molecular activation leading to the different morphologic and physiologic outcomes. According to a current view, emphysema may originate from a protease/antiprotease imbalance, whereas a role for antiproteases has been proposed in the modulation of fibrosis. Overexpression of transforming growth factor beta (TGF-beta) in experimental rodent models leads to progressive pulmonary fibrosis, accompanied with marked up-regulation of protease inhibitors, such as tissue inhibitor of metalloproteinases (TIMP) and plasminogen activator inhibitor-1 (PAI-1) genes, along with excessive matrix accumulation. It may be that a "matrix degrading" pulmonary microenvironment, one in which metalloproteinase activities prevail, favors the development of emphysema, whereas a "matrix nondegrading" microenvironment, with enhanced presence of TIMPs, would lead to matrix accumulation and fibrosis. Surprisingly, although Smad3 null mice, deficient in TGF-beta signal transmission, are resistant to bleomycin- and TGF-beta-mediated fibrosis, they develop spontaneous age-related airspace enlargement, consistent with emphysema, with a lack of ability to repair tissue damage appropriately. A common element is tissue damage and repair, with TGF-beta and the Smad signaling pathway playing prominent molecular roles. Both changes can be followed in experimental models with noninvasive imaging and physiologic measurements.
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PMID:Smad3 signaling involved in pulmonary fibrosis and emphysema. 1706 76

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. While the primary risk factor for COPD is cigarette smoke exposure, vitamin D deficiency has been epidemiologically implicated as a factor in the progressive development of COPD-associated emphysema. Because of difficulties inherent to studies involving multiple risk factors in the progression of COPD in humans, we developed a murine model in which to study the separate and combined effects of vitamin D deficiency and cigarette smoke exposure. During a 16-week period, mice were exposed to one of four conditions, control diet breathing room air (CD-NS), control diet with cigarette smoke exposure (CD-CSE), vitamin D deficient diet breathing room air (VDD-NS) or vitamin D deficient diet with cigarette smoke exposure (VDD-CSE). At the end of the exposure period, the lungs were examined by a pathologist and separately by morphometric analysis. In parallel experiments, mice were anesthetized for pulmonary function testing followed by sacrifice and analysis. Emphysema (determined by an increase in alveolar mean linear intercept length) was more severe in the VDD-CSE mice compared to control animals and animals exposed to VDD or CSE alone. The VDD-CSE and the CD-CSE mice had increased total lung capacity and increased static lung compliance. There was also a significant increase in the matrix metalloproteinase-9: tissue inhibitor of metalloproteinases-1 (TIMP-1) ratio in VDD-CSE mice compared with all controls. Alpha-1 antitrypsin (A1AT) expression was reduced in VDD-CSE mice as well. In summary, vitamin D deficiency, when combined with cigarette smoke exposure, seemed to accelerate the appearance of emphysemas, perhaps by virtue of an increased protease-antiprotease ratio in the combined VDD-CSE animals. These results support the value of our mouse model in the study of COPD.
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PMID:Modeling the influence of vitamin D deficiency on cigarette smoke-induced emphysema. 2378 Dec 5