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)

Members of the matrix metalloproteinase family of enzymes degrade specific components of the extracellular matrix. MMP-9 is a type IV/V collagenase necessary for normal osteogenesis and is increased in inflammatory and neoplastic conditions. In such destructive diseases as emphysema and arthritis, and in epithelial cancers, MMP-9 is produced by cells of the monocyte lineage. Fetuin, a prominent serum glycoprotein, binds to and inactivates TGF-beta family members and through this mechanism regulates osteogenesis (Binkert et al., 1999, J Biol Chem 274:28514-28520.). We studied the effects of TGF-beta1 and fetuin on proMMP-9 release by the human monocyte line THP-1. Exogenous TGF-beta1 stimulated proMMP-9 release by THP-1 cells, with half-maximal stimulation at approximately 0.01 ng/ml TGF-beta1. Human fetuin (0.5-2 microM) partially inhibited this stimulation. Human fetuin alone stimulated THP-1 monocyte proMMP-9 release, with half maximal stimulation at approximately 0.25 microM fetuin. Neutralizing antibody specific for TGF-beta1 also stimulated proMMP-9 release, suggesting that endogenously-derived TGF-beta1 has an inhibitory effect. In freshly isolated human peripheral blood monocytes, fetuin stimulated proMMP-9 release with a dose-response curve similar to that observed in THP-1 cells. Human fetuin also activated proMMP-9 present in THP-1 conditioned medium. Taken together, these data suggest that under physiological conditions, fetuin facilitates matrix degradation by monocyte-derived MMP-9, both by opposing the autocrine inhibitory effect of endogenous TGF-beta1 on proMMP-9 release, and by activating proMMP-9 in the pericellular milieu. Conversely, fetuin may limit the stimulation of monocyte proMMP-9 release by high levels of exogenous TGF-beta1. Such modulation could prove important under pathological conditions where TGF-beta1 derived from paracrine sources is abundant, such as in epithelial malignancies.
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PMID:Regulation of human monocyte proMMP-9 production by fetuin, an endogenous TGF-beta antagonist. 1102 39

Disruption of the extracellular matrix is believed to play an important role in the pathogenesis of emphysema. Prior studies have demonstrated that transgenic mice expressing the human tissue collagenase, matrix metalloproteinase 1 (MMP-1), develop emphysema. MMP-1 is a protease with substrate specificity for fibrillar collagen. Type I and III collagens, which are the most abundant proteins within the lungs, are the primary substrates for MMP-1. To assess if type I collagen was indeed the site of action for MMP-1 in these transgenic mice, hybrid mice were generated by crossing the MMP-1 transgenic mice with mice that had degradation-resistant type I collagen. The hybrid mice demonstrated an identical emphysematous phenotype as the MMP-1 transgenic mice, indicating that the degradation of type I collagen was not essential to the development of emphysema in these mice. Immunohistochemical studies in control mice demonstrated that collagen fibers in the alveolar walls and ducts of the normal mouse lungs consist mainly of type III collagen. In the transgenic and hybrid mice, the emphysematous changes, which developed, were associated with a marked decrease in type III collagen in these alveolar structures. These results indicate that MMP-1 generated the emphysematous phenotype via the degradative effect on type III collagen, which is a vital structural element of the alveolar walls. This is the first study to show that a matrix metalloproteinase may cause emphysema via its effects on a specific collagen subtype. As such, it should provide important insight into the mechanisms of this disease in humans.
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PMID:Emphysematous changes are caused by degradation of type III collagen in transgenic mice expressing MMP-1. 1265 12

Extracellular matrix metalloproteinase inducer (EMMPRIN), also called basigin, is present in the lung during development, but its expression in normal adult lung is minimal. Increases of EMMPRIN have been found in various forms of experimental lung injury. To determine whether EMMPRIN might be involved in alveolar injury/repair associated with smoking, we developed an ELISA for EMMPRIN and applied it to bronchoalveolar lavage fluids from never-smokers (n = 7), former smokers (n = 16), and current smokers (n = 58). The smoker groups included subjects with emphysema, as determined by high-resolution chest computed tomography. EMMPRIN levels were significantly elevated in current and former smokers (315 +/- 20 and 175 +/- 15 pg/ml SEM, respectively, compared with 31 +/- 7 pg/ml in never-smokers), but the EMMPRIN levels of smokers with emphysema were not different from smokers without emphysema. Immunohistochemistry of smokers' lung tissue showed EMMPRIN in bronchiolar epithelium and alveolar macrophages, but EMMPRIN mRNA in alveolar macrophages was not different between current and never-smokers. Matrix metalloproteinase-1 was also detectable in the bronchoalveolar lavage fluid from some smokers but not in never-smokers. These findings indicate that smoking is associated with increased intrapulmonary EMMPRIN. Whether EMMPRIN is involved in smoking-induced lung pathology remains to be determined.
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PMID:Extracellular matrix metalloproteinase inducer is increased in smokers' bronchoalveolar lavage fluid. 1271 50

The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue remodeling. Human fibroblast collagenase (MMP-1) was the first vertebrate collagenase purified as a protein and cloned as a cDNA, and is considered the prototype for all the interstitial collagenases. It is synthesized as a zymogen where N-terminal residues are removed by proteolysis and shares with other MMPs a catalytic domain and a carboxy terminal domain with sequence similarity to hemopexin. Importantly, MMP-1 should be considered a multifunctional molecule since it participates not only in the turnover of collagen fibrils in the extracellular space but also in the cleavage of a number of non-matrix substrates and cell surface molecules suggesting a role in the regulation of cellular behaviour. Furthermore, an extensive body of evidence indicates that MMP-1 plays an important role in diverse physiologic processes such as development, tissue morphogenesis, and wound repair. Likewise, it seems to be implicated in a variety of human diseases including cancer, rheumatoid arthritis, pulmonary emphysema and fibrotic disorders, suggesting that its inhibition or stimulation may open therapeutic avenues.
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PMID:MMP-1: the elder of the family. 1547 75

Fibroblast activation protein (FAPalpha) is a member of the cell surface dipeptidyl peptidase (DPP) family of serine proteases. In its dimer form, FAPalpha exhibits gelatinase, collagenase, and DPP activity in vitro. Reactive fibroblasts in healing wounds and stromal fibroblasts associated with epithelial tumors express FAPalpha. Idiopathic pulmonary fibrosis (IPF) is a disease of the lung characterized by progressive fibrosis with no clear etiology or molecular marker for disease activity. Recently, it has been shown that fibroblast FAPalpha expression is induced in liver cirrhosis, with an expression pattern distinct from alpha-smooth muscle actin (alpha-SMA). In this study, we determine whether FAPalpha expression is selectively induced in areas of ongoing tissue remodeling characterized by fibroblast foci in IPF. Human lung tissue was obtained from patients with IPF, centrilobular emphysema, and normal lung. Immunohistochemical studies were performed using anti-FAPalpha antibody and antibodies against alpha-SMA and CD26 (DPPIV), another member of the DPP family. We found that FAPalpha was not expressed in normal human lung tissue or tissue with evidence of centriacinar emphysema, but was induced in all patients with IPF and With a pattern distinct from that of CD26 found primarily on hyperplastic alveolar epithelium. Specifically, FAPalpha was detected in fibroblast foci and in fibrotic interstitium and not in the interstitium of adjacent architecturally normal lung. Alveolar/airway epithelium and vascular smooth muscle did not express FAPalpha. This is the first report of FAPalpha expression in IPF and our results suggest that FAPalpha is selectively induced in fibrotic foci, but not in normal or emphysematous lung. Future studies will address whether FAPalpha may be used as a marker for disease activity in IPF.
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PMID:Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis. 1661 31

Matrix Metalloproteinase 1 (MMP1, collagenase-1) expression is implicated in a number of diseased states including emphysema and malignant tumors. The cigarette-smoke induced expression of this interstitial collegenase has been studied extensively and its inhibition proposed as a novel therapeutic treatment for tobacco related diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer. However, a limitation in MMP1 research is the inability to take advantage of natural in vivo studies as most research has been performed in vitro or via animal models expressing human forms of the gene due to the lack of a rodent ortholog of MMP1. The present study examines the function of two possible mouse orthologs of human MMP1 known as Mmp1a and Mmp1b. Using genomic sequence analysis and expression analysis of these enzymes, the data demonstrate that neither MMP1a nor MMP1b behave in the same manner as human MMP1 in the presence of cigarette smoke. These findings establish that the two commonly proposed orthologs of MMP1, Mmp1a and Mmp1b, provide substantial limitations for use in examining MMP1 induced lung disease in mouse models of cigarette smoke emphysema.
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PMID:Mmp1a and Mmp1b are not functional orthologs to human MMP1 in cigarette smoke induced lung disease. 2549 7

Matrix metalloprotease 13 (MMP13) deficiency in pulmonary fibrosis has described contradictory phenotypes on inflammatory and fibrotic responses after lung injury, and its role during lung fibrosis resolution is still undefined. MMP13 has been considered the main collagenase in rodents, and the remodeling of fibrillar collagen is widely attributed to the action of this enzyme. In this study we aimed to explore the role of MMP13 during lung fibrosis progression and resolution. Lung fibrosis was induced by intratracheal instillation, and inflammatory, fibrotic, and resolution stages were evaluated in Mmp13-null and wild-type (WT) mice. Bronchoalveolar lavage fluid was taken for cytokine array analysis and activity of gelatinases. Our results showed that MMP13 is upregulated mainly during two stages after lung injury, inflammation and resolution of fibrosis, and it is mainly expressed by alveolar and interstitial macrophages. Mmp13-null mice exhibited more extensive inflammation at 7 days after bleomycin treatment, and it was characterized by increased macrophage infiltration and significant alterations in proinflammatory cytokines. We also documented that Mmp13-deficient mice experienced more severe and prolonged lung fibrosis compared with WT mice. Delayed resolution in Mmp13-deficient lungs was characterized by a decreased overall collagenolytic activity and persistent fibrotic foci associated with emphysema-like areas. Together, our findings indicate that MMP13 plays an antifibrotic role and its activity is crucial in lung repair and restoration of tissue integrity during fibrosis resolution.
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PMID:Delayed resolution of bleomycin-induced pulmonary fibrosis in absence of MMP13 (collagenase 3). 3078 43

In this study, we present a method to experimentally quantify and numerically identify the constituent-specific material behavior of soft biological tissues. This allows the clear identification of the individual contributions of major load-bearing constituents and their interactions in the constitutive law. While the overall approach is applicable for many tissues, here it will be presented for the identification of a sophisticated constituent-specific material model of viable lung parenchyma. This material model will help to better model the effects of various lung diseases that feature altered fiber content in the lungs, such as emphysema or fibrosis. To experimentally quantify the mechanical properties of collagen, elastin, collagen-elastin-fiber interactions, and ground substance, we examined 18 collagenase and elastase treated rat lung parenchymal slices. The mechanical contributions of the collagen and elastin fibers in the living tissue were inferred from uniaxial tension tests comparing the behavior before and after the selective digestion of the respective fibers. In order to also obtain the mechanical influence of the ground substance, we consecutively treated the samples with both proteases. Collagen and elastin fibers are morphologically interconnected. Thus, a mechanical interaction between these fibers appears likely, but has not yet been experimentally verified. In this paper, we propose an experimental method to quantitatively assess the mechanical behavior of these collagen-elastin-fiber interactions. Based on our experiments, we have identified individual material models within a nonlinear continuum mechanics framework for each load-bearing component via an inverse analysis. The proposed constituent-specific material law can be incorporated into computational models of the respiratory system to simulate and even predict the behavior and alteration of the individual constituents and their effect on the whole respiratory system during normal and artificial breathing, in particular in the case of diseases that alter the fibers in the tissue.
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PMID:Constituent-specific material behavior of soft biological tissue: experimental quantification and numerical identification for lung parenchyma. 3105 28


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