Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Very little is currently known regarding the underlying mechanisms involved in the etiology of intestinal strictures in chronic inflammatory bowel disease. The deposition of extracellular matrix components, especially collagens, is thought to play an important role in the etiology of intestinal strictures. The main goal of this study was therefore to investigate the collagen metabolism in patients with inflammatory bowel disease using the in situ hybridization technique. We determined de novo synthesis of the (pro)-collagen mRNA transcripts alpha 1I, alpha 1III, alpha 1IV, alpha 2V as well as the collagen degrading enzyme mRNA transcripts collagenase type I and IV in Crohn's disease and ulcerative colitis and compared the rate of expression semiquantitatively to healthy controls. We found a significant increase of all (pro)-collagen transcripts tested in Crohn's disease and ulcerative colitis as compared to healthy control tissues, indicating an increased de novo synthesis of all collagens in both inflammatory bowel diseases. However, we observed a significant difference in the expression of the collagenase mRNA transcripts between Crohn's disease and ulcerative colitis. Compared to healthy control subjects we were unable to detect a significant difference in the expression of collagenase type I and IV in Crohn's disease; in contrast, we observed a significant increase in the rate of expression for the collagenases in ulcerative colitis as compared to controls or biopsies from patients with Crohn's disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Indications for different collagen metabolism in Crohn disease and ulcerative colitis]. 849 73

Mucosal inflammation is associated with altered expression of cell membrane molecules. Disaggregation of tissue for flow cytometry may introduce artefactual changes. In an attempt to prevent the induction of artefacts, cells were fixed prior to isolation. The addition of 0.1% buffered formaldehyde to the collagenase/dispase digestion of mucosal biopsy specimens from patients with inflammatory bowel disease enhances detection of CD3, CD11b, CD16, CD63, and CD14. No significant effect was noted for CD19, CD67 or CD45. The expression of CD3, CD11b and CD45 correlated with the degree of endoscopic inflammation. Dilute buffered formaldehyde may be a useful adjunct to the enzymatic isolation of cells from mucosal specimens, by protecting surface antigens from digestion or alterations in expression.
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PMID:Use of buffered formaldehyde in the enzymatic digestion of inflamed mucosa. 865 91

The aim of this study was to investigate the involvement of the monocyte-derived cytokines interleukin 1beta (IL-1beta), interleukin 6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in idiopathic inflammatory bowel disease. Endoscopic biopsies of normal and inflamed intestinal mucosa were obtained from patients with ulcerative colitis (n = 11) and with Crohn's disease (n = 10). Intestinal mucosal cells were isolated by collagenase digestion. Cell viability, morphology and CD14 expression were determined. To measure cell-associated cytokine levels, cells were lysed and analysed for IL-1beta and TNF-alpha in specific radioimmunoassays and for IL-6 using a biological assay. Compared with mucosal cells from control patients without inflammatory bowel disease the inflamed intestine in ulcerative colitis and Crohn's disease displayed markedly enhanced levels of IL-1beta (median 245 pg 10(-6) cells, range 30-1275) and IL-6 (median 22 U 10(-6) cells, range 1-298). Non-inflamed mucosa in patients with ulcerative colitis and Crohn's disease did not show elevated levels of IL-1beta (median 50 pg 10(-6) cells, range 33-90) or IL-6 (mean below detection limit of assay, i.e. 1 U 10(-6) cells). In contrast, no clear cut difference between inflamed and non-inflamed mucosa could be detected for TNF-alpha. High tissue levels of IL-6 were associated with a high endoscopic grade of local inflammation. These results suggest that the monocyte-derived cytokines IL-1beta and IL-6 are mediators of inflammation in inflammatory bowel disease.
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PMID:Elevated cell-associated levels of interleukin 1beta and interleukin 6 in inflamed mucosa of inflammatory bowel disease. 890 20

Inflammatory bowel diseases (IBD) are characterized by a sustained inflammatory cascade that gives rise to the release of mediators capable of degrading and modifying bowel wall structure. Our aims were (i) to measure the production of matrix metalloproteinase-3 (MMP-3), and its tissue inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), by inflamed and uninflamed colonic mucosa in IBD, and (ii) to correlate their production with that of proinflammatory cytokines and the anti-inflammatory cytokine, IL-10. Thirty-eight patients with IBD, including 25 with Crohn's disease and 13 with ulcerative colitis, were included. Ten controls were also studied. Biopsies were taken from inflamed and uninflamed regions and inflammation was graded both macroscopically and histologically. Organ cultures were performed for 18 h. Tumour necrosis factor-alpha (TNF-alpha), IL-6, IL-1beta, IL-10, MMP-3 and TIMP-1 concentrations were measured using specific immunoassays. The production of both MMP-3 and the TIMP-1 were either undetectable or below the sensitivity of our immunoassay in the vast majority of uninflamed samples either from controls or from those with Crohn's disease or ulcerative colitis. In inflamed mucosa, the production of these mediators increased significantly both in Crohn's disease (P < 0.01 and 0.001, respectively) and ulcerative colitis (P < 0.001 and 0.001, respectively). Mediator production in both cases was significantly correlated with the production of proinflammatory cytokines and IL-10, as well as with the degree of macroscopic and microscopic inflammation. Inflamed mucosa of both Crohn's disease and ulcerative colitis show increased production of both MMP-3 and its tissue inhibitor, which correlates very well with production of IL-1beta, IL-6, TNF-alpha and IL-10.
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PMID:Increased production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-1 by inflamed mucosa in inflammatory bowel disease. 1079 71

Matrix metalloproteinases (MMPs) have been implicated in the pathobiology of various T-cell-mediated inflammatory disorders of the intestine and skin. Their synthetic inhibitor has been shown to prevent lethal acute graft-versus-host disease in animal models. We intended to determine the expression of MMPs 1, 3, 7, 9, 10, 12, and 19 and tissue inhibitors of metalloproteinases (TIMPs) 1 and 3 in intestinal and cutaneous lesions of patients suffering from graft-versus-host disease after bone marrow transplantation. In situ hybridizations for MMPs 1, 3, 7, 10, and 12 as well as TIMPs 1 and 3 were performed using (35)S-labeled cRNA probes on intestinal (n = 13) and cutaneous specimens (n = 9) from patients with graft-versus-host disease. Immunohistochemical stainings were carried out to localize MMP-9, MMP-19, TIMP-3, and TGF-beta1 proteins, and TUNEL staining, to detect apoptotic cells. TIMP-3 mRNA and protein were detected in cutaneous lesions in areas with vacuolar degeneration of the basal epidermal layer in all skin samples, and they colocalized with apoptotic keratinocytes and partly with staining for TGF-beta. None of the MMPs examined were overexpressed in skin lesions. Signals for MMP-1 and MMP-3 mRNA was found in 10/13 and 5/13 intestinal biopsies, respectively. In the gut, MMP-19-positive epithelial cells, particularly in the crypts, were found in 10/13 samples. Expression of MMPs 7, 9, 10, and 12 was absent or very low. TIMPs 1 and 3 were expressed by stromal cells in 12/13 and 10/13 gut samples, respectively. Whereas TIMP-1 was expressed particularly by subepithelial cells where epithelium had shed away, TIMP-3 was detected in deeper areas. We conclude that MMPs are differentially regulated in the skin and gut lesions of graft-versus-host disease. In agreement with previous data on cancer cells, TIMP-3, induced by TGF-beta1, may contribute to the apoptosis of keratinocytes in cutaneous graft-versus-host disease lesions, leading to typical histopathological changes. We also conclude that MMPs play a less important role as effector molecules in intestinal graft-versus-host disease than in celiac or inflammatory bowel disease.
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PMID:Overexpression of tissue inhibitor of metalloproteinases-3 in intestinal and cutaneous lesions of graft-versus-host disease. 1259 62

Crohn's disease (CD) is a chronic inflammatory bowel disease of still unknown etiology. The aim of our study was to find out whether there are any changes in the colonic wall of CD patients that could give hints for a predisposing disorder concerning the extracellular matrix, especially the collagen metabolism. Eight samples of colonic tissue from patients with Crohn's disease were compared to 14 specimens from patients without Crohn's disease. We performed a sirius red test for the overall collagen content and immunohistochemical studies examining differentiation between" collagen type I and type III and the expression of MMP-1 and MMP-13. In the bowel sections of patients with Crohn's disease, decreased levels of mature collagen type I with a resulting lower ratio of collagen I/III compared to patients without Crohn's disease were found (1.12 +/- 0.29 vs. 1.59 i 0.31). The expression of MMP-1 was significantly increased in the CD group (9.21 i 6.02 vs.6.02 i 1.98), whereas expression of MMP-13 showed no difference in both groups. Our study gives the first indication that preexisting changes of the extracellular matrix in the colonic wall may play a role in the pathogenesis of CD. Further studies have to be done to elucidate these interesting aspect of the pathogenesis in Crohn's disease.
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PMID:Reduced expression of collagen type I and increased expression of matrix metalloproteinases 1 in patients with Crohn's disease. 1580 50

Proteolysis and degradation of extracellular matrix by metalloproteinases (MMPs) may contribute to intestinal injury in inflammatory bowel disease. In the present study, we investigated the pathogenic role of gelatinases (MMP-9 and MMP-2) on transmural colonic injury in a rat model of chronic colitis, which was induced by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS). The activity and expression of MMP-2 and MMP-9 were measured in colonic tissue and peripheral neutrophils by fluorescence, zymography, Western blot, or immunohistochemistry at different time-points. Furthermore, myeloperoxidase content in colonic homogenates was analyzed to evaluate inflammation. Finally, morphological changes were assessed following early or delayed administration of CGS-27023-A, a synthetic inhibitor of MMPs. We found that the induction of colitis led to a significant up-regulation in tissue gelatinase concentration, whereas no changes in collagenase activity were observed. In addition, up-regulation of pro-MMP-9, but not of pro-MMP-2, was found on Days 7 and 10 following the induction of colitis. Furthermore, transmural MMP-9 was detected by immunofluorescent staining in the inflamed tissue. Consistent with tissue samples, neutrophils from colitic rats showed a significantly increased activity of pro-MMP-9. Finally, early but not delayed treatment with CGS-27023-A attenuated colonic mucosal injury in rats with TNBS-induced colitis. In conclusion, up-regulation of MMP-9 in peripheral and colonic neutrophils modulates transmural colonic injury in rats with TNBS-induced colitis.
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PMID:Matrix metalloproteinase-9 modulates intestinal injury in rats with transmural colitis. 1647 19

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

Interleukin-11 (IL-11) is a cytokine which interacts with a variety of haemopoietic and non-haemopoietic cell types. Recombinant human IL-11 (rhIL-11; oprelvekin) is produced in Escherichia coli and differs from the naturally occurring protein only in the absence of the amino-terminal proline residue. In synergy with other factors, rhIL-11 stimulates the growth of myeloid, erythroid, and megakaryocyte progenitor cells in vitro. In vivo, rhIL-11 is active in mice, rats, dogs, guinea pigs, hamsters and non-human primates, where the principal activity measured was stimulation of megakaryocytopoiesis and thrombopoiesis. rhIL-11 has shown benefit in 2 clinical trials by significantly reducing severe chemotherapy-induced thrombocytopenia. In addition to its thrombopoietic activity, rhIL-11 has also shown activity in models of acute gastrointestinal mucosal damage. rhIL-11 enhanced survival in mice following cytoablative therapy and in a hamster model of chemotherapy-induced oral mucositis, where treatment with rhIL-11 was associated with decreased mucosal damage, accelerated healing and reduced numbers of deaths. rhIL-11 is currently in clinical trials for the treatment of chemotherapy-induced mucositis. In rat models of acute colonic injury and inflammatory bowel disease, rhIL-11 treatment reduced intestinal mucosal damage and alleviated clinical signs. rhIL-11 has direct effects on activated macrophages to reduce the production of pro-inflammatory mediators. In animal models of endotoxaemia, rhIL-11 treatment reduced serum levels of pro-inflammatory cytokines and blocked hypotension. rhIL-11 increased survival in models of Gram-negative sepsis and toxic shock. Based on these studies, rhIL-11 is currently in clinical trials for treatment of Crohn's disease. Other inflammatory conditions are being further evaluated. Mechanistically, rhIL-11 functions at many levels to control inflammation, ameliorate tissue damage and maintain haemostasis in the face of trauma or infection. rhIL-11 has direct effects on hepatocytes, inducing the production of acute phase reactant proteins, haem oxygenase and tissue inhibitor of metalloproteinase-1 (TIMP-1). TIMP-1 expression can also be induced in synoviocytes and chondrocytes by treatment with rhIL-11. rhIL-11 administration has been associated with increased plasma levels of von Willebrand factor and fibrinogen. rhIL-11 treatment potentially offers multiple benefits for cancer chemotherapy patients, such as prevention of thrombocytopenia, gastrointestinal epithelial protection and subsequent reduction of mucositis, and amelioration of inflammatory complications. In addition, rhIL-11 is being evaluated further in the treatment of inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and sepsis.
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PMID:Interleukin-11. 1803 Nov 4

Matrix metalloproteinases (MMPs) have been implicated in tissue damage associated with inflammatory bowel disease (IBD).As the role of the intestinal epithelium in this process is unknown, we determined MMP expression and enzyme activity in human colonic epithelial cells (CEC). MMP mRNA expression was assessed by reverse transcription-polymerase chain reaction in HT-29 and DLD-1 cells and in CEC isolated from biopsies from IBD and control patients. Total MMP activity in the cells was measured by a functional assay, based on degradation of a fluorescent synthetic peptide containing the specific bond for MMP cleavage. HT-29 and DLD-1 expressed several MMPs and levels of MMP-3, -10 and -13 mRNA expression were increased significantly by tumour necrosis factor (TNF)-alpha exposure. Transcripts of MMP-1, -3, -7, -9, -10 and -12 were detected in CECs and all, except MMP12, at significantly increased levels in cells from inflamed IBD mucosa. MMP-2 and -8 mRNA were expressed inconsistently and MMP-11, -13 and -14 mRNA undetectable. Proteolytic MMP activity was detected in CEC supernatants and the level was increased significantly in inflamed IBD epithelium. The enzyme activity was inhibited strongly by a specific MMP inhibitor (GM 6001). A significant TNF-alpha-mediated increase in MMP enzyme activity was also detected in HT-29 cells in vitro. In conclusion, the expression of several MMPs as well as the level of functional MMPactivity is increased in CEC from patients with active IBD. The results suggest that MMPs released by the intestinal epithelium may be involved in the pathogenesis of IBD by promoting local mucosal damage.
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PMID:Spontaneous and cytokine induced expression and activity of matrix metalloproteinases in human colonic epithelium. 1913 36


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