Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Schistosomiasis mansoni is characterized by granulomatous inflammations, deposition of collagen, and irreversible liver fibrosis. In chronic infections fibrosis is cumulative, while collagen synthesis and degradation are diminished. In the present study, we compared collagenase, elastase, and nonspecific neutral protease (NP) activities in isolated vigorous (8-week infection) and immunomodulated (18-20-week infection) liver granulomas. Enzyme activity was localized in the adherent macrophage (greater than 90% purity) and nonadherent eosinophil-rich (greater than 70% purity) cell fractions of the disaggregated granulomas. Collagenase levels were approximately two times higher in granuloma extracts and explant culture supernates of the vigorous as compared with the immunoregulated lesions. However, macrophages and eosinophil-rich cells derived from either type of granuloma secreted similar enzyme levels. Elastase and NP levels in granuloma extracts and secretions of adherent macrophage and eosinophil-rich cell populations were the same in vigorous or immunomodulated lesions but were significantly greater in vigorous granuloma culture supernates. In addition to active collagenase, trypsin activatable latent collagenase was also present in both types of granuloma extracts, explants and eosinophil-rich cell culture supernates. Latent elastase was also detected in granuloma extracts or explant supernates but was absent from secretions of granuloma cells. These results suggest that the presence of active neutral proteases within granulomas may play an important role in the regulation of tissue repair and remodeling during the fibrotic process.
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PMID:Collagenase, elastase, and nonspecific protease production by vigorous or immunomodulated liver granulomas and granuloma macrophages/eosinophils of S mansoni-infected mice. 299 60

Schistosomiasis mansoni is a tropical helminthic disease characterized by parasite egg-induced granulomatous inflammation and cumulative fibrosis. Because fibrosis is influenced by the imbalance between degradative matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), we analysed the resorption of fibrous tissue and MMP/TIMP expression in the livers of S. mansoni-infected and praziquantel-cured mice. Worm elimination significantly enhanced survival rate, ameliorated the granulomatous pathology and reduced collagen I, III and IV gene expression at 6 and 12 months post-treatment. Compared to 6 months infected, untreated controls, liver fibrous tissue was resorbed by 71.4% at 12 months after treatment. At 3 months post-treatment, expression of the MMP-2, -3, -8, -10, -13, -14 and -16 genes decreased compared with untreated controls. By 6 months, a highly significant increase in MMP-10 gene expression was manifest. At 12 months, messages for all MMP genes decreased in relation to untreated controls. TIMP-1, -2 and -3 gene expression drastically decreased between 3 and 6 months. At 1 year, only TIMP-1 expression was significantly diminished. Overall, profibrogenic tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta and inducible nitric oxide synthase (iNOS) gene expression decreased. Antigen-stimulated splenocytes secreted significantly higher levels of interleukin (IL)-4, IL-5, IL-10 and IL-13 cytokines between 3 and 12 months after treatment. Production of interferon (IFN)-gamma was higher than in untreated controls 3 and 6 months after treatment. In conclusion, praziquantel-treated mice showed a slow resorption of liver fibrous tissue. Resorption is attributed to the precipitous drop in TIMP-1 gene expression level, which shifted the balance in favour of MMP message expression and presumed enhanced collagenase activity.
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PMID:Expression of matrix metalloproteinases and their inhibitors during the resorption of schistosome egg-induced fibrosis in praziquantel-treated mice. 1500 36

In schistosomiasis mansoni, granulomatous inflammation and fibrotic resolution are the major pathogenetic factors. The outcome of fibrosis is influenced by the deposition of collagen and degradation mediated by matrix metalloproteinases (MMP). There is a dearth of data on the expression of MMP and the tissue inhibitors of metalloproteinase (TIMP) during the fibrosis associated with schistosomiasis. In this study, the dynamics of collagen, MMP and TIMP gene expression were analysed during murine Schistosoma mansoni infection. Expression within the granulomatous liver tissue of the genes coding for collagen of types I, III and IV was up-regulated at the onset of granuloma development, and the dominant type-I expression peaked at the chronic, fibrotic stage. The amount of deposited hepatic collagen increased with the chronicity of the infection, indicating cumulative fibrosis. Collagenase, gelatinase, stromelysin, matrilysin-specific gene activities were similarly up-regulated, but only MMP-8 (collagenase-2) expression peaked at the height of fibrosis. TIMP-1 gene expression gradually increased during the course of the disease and, along with TIMP-2, peaked at the chronic, fibrotic stage. Granuloma myofibroblasts expressed both MMP and TIMP-1 genes. In ELISA of the splenic cytokines, high levels of fibrogenic interleukin-13 and moderate production of transforming growth factor-beta were found to be concurrent with fibrosis. These data indicate that an imbalance in MMP:TIMP expression and fibrogenic cytokine production are associated with cumulative fibrosis.
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PMID:Dynamics of collagen, MMP and TIMP gene expression during the granulomatous, fibrotic process induced by Schistosoma mansoni eggs. 1532 65

Schistosomiasis mansoni disseminated worm eggs in mice and humans induce granulomatous inflammations and cumulative fibrosis causing morbidity and possibly mortality. In this study, intrahepatic and I.V. injections of a double-stranded oligodeoxynucleotide decoy containing the TGF-beta regulatory element found in the distal promoter of the COL1A1 gene into worm-infected mice suppressed TGF-beta1, COL1A1, tissue inhibitor of metalloproteinase-1, and decreased COL3A1 mRNAs to a lesser extent. Sequence comparisons within the mouse genome found homologous sequences within the COL3A1, TGF-beta1, and TIMP-1 5' flanking regions. Cold competition gel mobility shift assays using these homologous sequences with 5' and 3' flanking regions found in the natural COL1A1 gene showed competition. Competitive gel mobility assays in a separate experiment showed no competition using a 5-base mutated or scrambled sequence. Explanted liver granulomas from saline-injected mice incorporated 10.45 +/- 1.7% (3)H-proline into newly synthesized collagen, whereas decoy-treated mice showed no collagen synthesis. Compared with the saline control schistosomiasis mice phosphorothioate double-stranded oligodeoxynucleotide treatment decreased total liver collagen content (i.e. hydroxy-4-proline) by 34%. This novel molecular approach has the potential to be employed as a novel antifibrotic treatment modality.
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PMID:A novel nonsteroidal antifibrotic oligo decoy containing the TGF-beta element found in the COL1A1 gene which regulates murine schistosomiasis liver fibrosis. 1588 Mar 83

Schistosomiasis mansoni is a major helminthic disease of the tropics characterised by chronic hepatic and intestinal granulomatous inflammation and fibrosis. The fibrotic response is regulated by the amount of collagen deposited in the tissues and the degradation of that collagen by matrix metalloproteinases (MMP). In the murine model of the disease, although hepatic granuloma formation and the ensuing fibrosis have been thoroughly examined, there is a dearth of information on the intestinal fibrotic process. The expression of fibrosis-related genes in the colons of chronically infected mice has therefore been investigated. Compared with that seen in uninfected mice, the expression of the genes coding for collagen of types I, III and IV was upregulated. Similarly, the messages for MMP-2, MMP-3 and MMP-8 were elevated, indicating the potential for collagen degradation. The genes for two tissue inhibitors of metalloproteinases (TIMP), TIMP-1 and TIMP-4, were, however, expressed at higher levels than those coding for the MMP. As a corollary, expression of the genes coding for three fibrogenic cytokines, transforming growth factor-beta, tumour necrosis factor and interleukin-4, was elevated. These data indicate that an imbalance in MMP:TIMP expression and enhanced levels of the messages for fibrogenic cytokines underlie the mechanism(s) of the colonic fibrosis seen in mice chronically infected with Schistosoma mansoni.
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PMID:Differential expression of collagen, MMP, TIMP and fibrogenic-cytokine genes in the granulomatous colon of Schistosoma mansoni-infected mice. 1698 87