The 9-kDa N-terminal propeptide domain of MT1-MMP is required for the activation of progelatinase A.
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Amino Acid Sequence↗
Biomedical subjects
M Drews
Publications and source records attributed to M Drews.
Regulation of gelatinases in human airway smooth muscle cells: mechanism of progelatinase A activation.
Matrix metalloproteinases (MMPs) play an important role in tumor metastasis and invasion, inflammatory tissue destruction and remodeling, wound healing, and angiogenesis. The 72-kDa gelatinase A is the most widely distributed of all the MMPs, and along with the 92-kDa gelatinase B, both play an important role in the turnover of basement membrane. The role of MMPs in chronic airway inflammation and remodeling has received scant attention. In this study, we sought to examine the release and activation of gelatinases from human airway smooth muscle (ASM) cells and the effect of tumor necrosis factor-alpha and phorbol 12-myristate 13-acetate (PMA) on this release and activation. The role of membrane type 1 MMP (MT1-MMP) and tissue inhibitor of MMP (TIMP)-2 in activating progelatinase A has been explored. We have demonstrated, using human airway smooth muscle cells in culture, that 1) ASM releases gelatinase A constitutively and when stimulated with PMA and tumor necrosis factor-alpha releases gelatinase B, and the release of gelatinase B is protein kinase C dependent because it is blocked by H-7 and staurosporin; 2) treatment of ASM cells with PMA or concanavalin A failed to activate progelatinase A despite these agents increasing cell expression of MT1-MMP; and 3) the inability of ASM cell membranes to activate progelatinase A is most likely secondary to the high levels of TIMP-2 on the cell membrane. In conclusion, our results demonstrate that human ASM cells constitutively secrete progelatinase A and when stimulated with proinflammatory mediators secrete gelatinase B. The released gelatinases A and B may be important factors in the airway remodeling that occurs in asthma.
Cell Membrane↗
Increased serum stromelysin-1 levels in systemic lupus erythematosus: lack of correlation with disease activity.
OBJECTIVE: In view of evidence that stromelysin-1 and collagenase-1 are involved in tissue injury in inflammatory joint diseases, we sought to determine whether matrix metalloproteinases (MMP) are implicated in the pathophysiology of systemic lupus erythematosus (SLE). METHODS: Seventy-three patients with SLE and 39 healthy subjects were evaluated. Serum levels of MMP and tissue inhibitor of metalloproteinases were measured. RESULTS: Serum stromelysin-1 levels were significantly increased in patients with SLE (416+/-252 ng/ml) compared to healthy subjects (125+/-93 ng/ml). No correlation between serial measurements of stromelysin-1 and disease activity in SLE patients was noted. Serum collagenase-1, gelatinase A, and TIMP-1 levels were not increased in SLE. CONCLUSION: Serum concentrations of stromelysin-1 are increased in SLE, but the levels do not correlate with disease activity.
Disease Progression↗
The propeptide domain of membrane type 1 matrix metalloproteinase is required for binding of tissue inhibitor of metalloproteinases and for activation of pro-gelatinase A.
Activation of secreted latent matrix metalloproteinases (MMPs) is accompanied by cleavage of the N-terminal propeptide, thereby liberating the active zinc from binding to the conserved cysteine in the pro-domain. It has been assumed that an analogous mechanism is responsible for the activation of membrane type 1 MMP (MT1-MMP). Using recombinant wild-type MT1-MMP cDNA and mutant cDNAs transfected into COS-1 cells lacking endogenous MT1-MMP, we have examined the function of the propeptide domain of MT1-MMP. MT1-MMP was characterized by immunoblotting, surface biotinylation, gelatin substrate zymography, and 125I-tissue inhibitor of metalloproteinases 2 (TIMP-2) binding. In contrast to wild-type MT1-MMP-transfected COS-1 cells, transfected COS-1 cells containing a deletion of the N-terminal propeptide domain of MT1-MMP or a chimeric construction (substitution of the pro-domain of MT1-MMP with that of collagenase 3) were functionally inactive in terms of binding of 125I-labeled TIMP-2 to the cell surface and initiating the activation of pro-gelatinase A. These results support the concept that in its native plasma membrane-inserted form, the pro-domain of MT1-MMP plays an essential role in TIMP-2 binding and subsequent activation of pro-gelatinase A.
Enzyme Activation↗
Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase 1 (MT1-MMP).
It has been proposed that tissue inhibitor of metalloproteinase-2 (TIMP-2), in stoichiometric concentrations, serves as an intermediate in progelatinase A activation by binding to activated membrane type 1-matrix metalloproteinase 1 (MT1-MMP) on the plasma membrane. An MT1-MMP-independent cell surface receptor for TIMP-2 has also been postulated. To clarify TIMP-2 binding, we have performed 125I-TIMP-2 binding studies on transfected COS-1 cells and endothelial cells. Specific receptors for TIMP-2 were identified on COS-1 cells transfected with MT1-MMP cDNA, but not on vector-transfected cells. Treatment of MT1-MMP transfected COS-1 cells with a hydroxamic acid inhibitor of MMPs, CT-1746, but not an inactive stereoisomer, CT-1915, produced dose-dependent inhibition of specific TIMP-2 binding comparable with that noted with excess unlabeled TIMP-2. This result suggests that TIMP-2 binds to the zinc catalytic site of MT1-MMP. As demonstrated by the limited competition for binding of C-terminal deleted TIMP-2, the C-terminal domain of TIMP-2 participates in binding to MT1-MMP. Cross-linking studies followed by immunoprecipitation using antibodies to MT1-MMP were employed to identify 125I-TIMP-2.MT1-MMP complexes in MT1-MMP-transfected COS-1 cell membrane extracts. TIMP-2 receptors were also identified on concanavalin A-treated human umbilical vein endothelial cells; inhibition of TIMP-2 binding with CT-1746 was demonstrated.
Amino Acid Sequence↗
The prospective multicenter trial of gastric cancer.
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Adult↗
Prenatal plasma matrix metalloproteinase-9 levels to predict spontaneous preterm birth.
OBJECTIVE: Matrix metalloproteinase-9, a zinc-dependent proteinase, may be important in initiating labor or rupture of membranes. We determined plasma levels of this enzyme in nonpregnant and pregnant women and evaluated whether they predict spontaneous preterm delivery. METHODS: A sandwich enzyme-linked immunosorbent assay (ELISA) was used to measure matrix metalloproteinase-9 levels in plasma samples from 25 nonpregnant women (mean age 39+/-9 years) and in stored plasma samples obtained during a randomized trial of zinc supplementation in pregnancy. Women were selected who delivered following spontaneous labor or premature rupture of membranes at 24-32 weeks (n = 20), 33-36 weeks (n = 29), and greater than 37 weeks (n = 30). Plasma samples were obtained sequentially at 19, 26, 31, and 36 weeks if undelivered and at presentation for delivery. RESULTS: Plasma matrix metalloproteinase-9 levels for non-pregnant women averaged 18.6+/-11.2 (mean +/- standard deviation) ng/mL. Prenatal values averaged 298+/-227 ng/mL from 19 weeks until 36 weeks (not including presentation for delivery) and did not change significantly as the gestational age increased, regardless of whether women ultimately delivered at 24-32, 33-36, or after 37 weeks. Values obtained prior to, but within 1 week of, presentation for delivery (n = 7, 281+/-103 ng/mL) were not significantly different than those obtained earlier in pregnancy (n = 71, 309+/-307 ng/mL, [P = .60]). Plasma matrix metalloproteinase-9 levels for women in spontaneous labor were similar regardless of gestational age and were increased three-fold (852+/-301 ng/mL) compared with those drawn at each prenatal visit (for example, 26 week values = 285+/-144 ng/mL [P < .001]). CONCLUSION: Plasma matrix metalloproteinase-9 levels remain unchanged throughout pregnancy until the onset of spontaneous labor when there is a three-fold increase. Plasma matrix metalloproteinase-9 levels obtained prior to presentation for delivery do not appear to predict spontaneous preterm birth.
Adult↗
The level of MAP kinase activity in the stomach stump in rats after subtotal gastrectomy.
MAPK (Mitogen-Activated Protein Kinase) is one of the elements of kinase cascades (MAPK, MEK-MAP kinase, kinase, Raf-1, Ras) regulating cellular proliferation and differentiation processes. It seems that the changes in its number and activity may be the factor having influence on carcinogenesis. In some human carcinomas a significant increase of its activity is observed, in others a decrease of its activity is described. Our research aimed at the evaluation of the dynamics of precancerous and cancerous changes in the stomach stump in rats after the experimental, partial stomach resection. Apart from histological and ultrastructural examination we also determined the activity of the sub-unit p42 MAP kinase. The material comprised segments of gastric mucosa of the stomach stump of 15 rats after subtotal gastrectomy. Part of the rats after the procedure were administered carcinogen orally (MNNG). On the histological and ultrastructural examination we used routine methods, the activity of MAP kinase was determined by western-blotting method with the use of IgG against MAPK p42, Santa Cruz #154). In 8 examined rats we observed the increase of MAP kinase activity. We established probable correlation (without statistical analysis, regarding miserly material) between the increase of MAPK activity and histological and ultrastructural changes. Among three cases diagnosed as adenoma tubulare in two we observed the increase of MAPK activity. A clear increase of this kinase was also present in the stomach stump of a rat, which was diagnosed as adenocarcinoma. On the basis of our research carried so far we think that the increase of the MAPK activity may be one of the causes of the neoplasm development. It seems important to obtain the confirmation of our results and to establish a possible usefulness of MAPK activity determination as a prognostic indicator in case of the neoplasm of stomach stump.
Animals↗
Restorative proctocolectomy and ileal pouch in surgical treatment for ulcerative colitis.
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Adenomatous Polyposis Coli↗
Molecular study of sex steroid receptor gene expression in human colon and in colorectal carcinomas.
BACKGROUND: Sex steroid hormones influence function of the human gastrointestinal tract. Although the specific receptor proteins have been identified in surgical specimens of both intestinal mucosa and colorectal carcinomas, it is still unknown whether they are expressed in intestinal epithelial cells. METHODS: Expression of androgen receptor (AR) protein and estrogen receptor (ER) protein was studied by Scatchard analysis and ELISA (for ER only) in surgical specimens of normal-appearing mucosa, colorectal carcinomas, isolated colonocytes, and human colorectal carcinoma cell lines. Northern analysis was applied to identify the appropriate mRNAs, followed by the sensitive technique of reverse transcription-polymerase-chain-reaction (RT-PCR). RESULTS: AR protein was identified in all surgical specimens analyzed and ER protein in 10 out of 13 normal-appearing mucosa specimens and 4 out of 7 colorectal carcinomas. The receptor proteins were not found in isolated colonocytes or in the transformed cell lines. RT-PCR confirmed that none of the isolated normal colonocytes or transformed colorectal carcinoma-derived cells expressed these mRNAs. Intestinal smooth muscle cells and fibroblasts were found to express sex steroid receptor mRNAs. CONCLUSIONS: Both receptors are present in human large intestine but are expressed in stromal cells and not in intestinal epithelial cells. We hypothesize that sex steroids may influence the function of colonocytes indirectly through stromal-epithelial interactions.
Colon↗
Ultrastructural changes in the small bowel epithelium after total gastrectomy.
The purpose of the study was to analyze ultrastructural changes in the small bowel mucosa in patients after total gastrectomy. We studied mucosal specimens obtained from 25 patients during control gastroscopy. The specimens were routinely processed for examination in transmission electron microscopy. Early after the operation (up to 6 months) we observed marked inflammatory reaction, disordered architecture of the small bowel mucosa epithelium, the presence of dysplasia-like changes and foci of dysplasia. Later on the structure of the mucosa returned to normality. Only a few dysplastic changes were seen. No relationship was found between altered epithelial structure and type of operation. In conclusion, the epithelium of the small bowel does not transform to a gastric type epithelium.
Adult↗
[Analysis of aerobic and anaerobic bacterial flora colonizing drains after surgical abdominal incisions].
Aerobic and anaerobic bacterial flora of post-operative incisions with drainage were examined. From each of 28 patients three specimens were taken; during operation (smear from peritoneal cavity), liquid from drain (taken at 3-th day after operation) and smear from drain taken at the end of drainage. Enterococci, Enterobacteriaceae spp. and anaerobes, especially Bacteroides spp. were most often isolated from specimens taken during operation. Enterococci and coagulase negative Staphylococci-often resistant to methicillin, were most often isolated from specimens taken at the end of drainage.
Abdominal Muscles↗
[Evaluation of bacterial flora in patients after intraabdominal surgical procedures throughout a 12 year period].
UNLABELLED: The aim of this study was to analyse the composition of the bacterial flora in 295 patients who underwent surgical treatment in our clinic throughout the period of 12 years. 448 specimens were bacteriologically examined. Bacterial pathogens were isolated from 390 (87.1%). Among aerobic bacteria, Enterococcus faecalis was the most often isolated (35.6% - from the peritoneum, 17.8% from the wound). Among anaerobic bacteria, Bacteroides fragilis - 44.9% were the most often isolated. 530 aerobic bacterial strains from Enterococcus, Enterobacteriaceae, Staphylococcus and the nonfermentable rods were carefully analysed. Special attention was paid to the development of the resistance to 3 antibiotics (cefoperazone, ciprofloxacin and gentamycin) in 3 time periods: from 1984 to 1987, from 1988 to 1992 and from 1993 to 1996. Resistance of the bacterial strains to cefoperazone was 38.7% in the first time period; 39.5% in the second; and later increased to 53.8%. Resistance to ciprofloxacin was identical in the first two periods - 10.3%; and subsequently, it increased to 22.6%. The increase of resistance to gentamycin was the most significant--it went up from 24.5% to 44.8 and then dropped to 40.3%. CONCLUSION: Constant monitoring of the bacterial flora enables rational antibiotic application, which is essential due to the observed increase of bacteria strain resistance.
Abdomen↗
[Reconstructive surgery of bile ducts from personal material].
In the years 1976-1996, 112 patients were treated surgically for the biliary tract injuries, 156 operations were performed upon them. The long term outcome was assessed in 85 patients along with the effectiveness of different surgical techniques. The best results (86.2%) were achieved when the repair was performed immediately on detecting the lesion, the results were less encouraging for the secondary repair. Perioperative mortality was 8.8%.
Adult↗
[45 years of experience in surgical treatment for cancer of the large intestine].
The aim of the study was to evaluate the results of surgical treatment of colorectal cancer during 45 years of existence of the Department. In this time 1478 cases of rectal cancer and 1008 cases of colon cancer were operated on. Most commonly the diseases occurred between the sixth and seventh decade of live (32.8%). Histology revealed tubular adenocarcinoma in 83.3% of the cases, mucinous adenocarcinoma in 13.5% and other types in 3.2%. The choice of the surgical procedure was based on the individual characteristics of each case, including: localisation of the tumor, histological type, clinical staging, sex of the patient, obesity and overall operative risk. The tumor was localised less then 10 cm above the anal verge in 70% of the patients with rectal cancer. Well differentiated carcinomas (G1) were seen in 32% of the patients, moderately differentiated carcinomas (G2) in 57% and poorly differentiated (G3) in 11%. Curative resections were performed in 64.7% of the patients (1608 cases) and palliative procedures in 35.3% of the patients (878 cases). The mortality rate after curative surgery was 6% and after palliative procedures 5%. The use of combined therapy consisting of surgical treatment and chemo- or radiotherapy allowed for obtaining five years survival rate of 57.4%, local recurrences were seen in 21% of patients. Analysing our own material we evaluated the radicality of different types of operations and the possibility of preserving the sphincter apparatus.
Adenocarcinoma↗
[Combined treatment of large bowel cancer].
During the years 1989 to 1994, in the Department of General Surgery we performed surgery on 800 cases of large bowel cancer. The cases comprised 412 men (51.5%) and 388 women (48.5%), aged 25 to 85, the most numerous age group ranging from 50 to 70 (60%). Radical surgery was carried out on 501 cases (62.7%) and palliative surgery on 299 cases (37.3%). In cases with histopathological evaluation pTNM-T1N0M0 or T2N0M0 we refrained from chemo- and radiotherapy. In cases of rectal cancer with advanced staging T3N1M0 or T4N2M1 we applied radiotherapy, whereas in cases of cancer localized on other parts of large bowel we had recourse to chemotherapy as combined treatment. Radiotherapy was applied irrespective of grading, whereas chemotherapy was applied in cases of cancer with grading G2 and G3. Radiative energy was used in 65 cases and chemotherapy in 120 cases. Postoperational mortality amounted to 6%. Five years survival after radical surgery achieved 57.4%. Local recurrence took place in 21% of the cases. The control group consisted of the cases subjected to surgery in the years 1984-1989 when only surgery was performed and 5-years survival after radical surgery amounted to 48% and local recurrence was found in 30% of the cases.
Adult↗
[Personal experiments in treating rectal rumors with the TEM technique].
Transanal Endoscopic Microsurgery (TEM) was introduced to clinical practice by Buess in 1983. After several years of gaining experience technique has been used for the excisions of rectal tumours. TEM enables excisions of the tumours localised in the rectum and distal portion of the sigmoid colon from 5 to 25 cm from the anal verge. Until now 13 patients have been operated using TEM method. The group includes also rectal cancers classified as pT-1 and G-1. Preliminary results are encouraging. The patients left the hospital four days after the procedure and started professional activity two weeks postoperatively. All the patients are followed-up: patients who had adenomas once a year and those with pT-1 low-risk rectal cancer-every three months in their first postoperative year and then in six month intervals. Local excision of the adenomas and early cancers of the rectum with the use of TEM proves to be an effective method of surgical treatment in a selected group of patients.
Adenocarcinoma↗
[Removal of rectal adenoma with the TEM technique].
The paper presents the operation of local excision of a rectal polyp using TEM technique. The operation was performed at our Department on the 12th of April 1996 with the instruments for transanal endoscopic microsurgery made by Wolf Company according to professor Buess. The patient was 49 year old woman, in whom rectoscopy revealed at 8 cm above the dantate line a cauliflower like lesion, 3 cm in diameter, bleeding on touch and not fixed to the underlying tissues. Transrectal sonography showed the tumor was confined to the mucosa with the absence of muscularis propria infiltration. During the operation the polyp was removed with the full thickness portion of rectal wall. Wound edges were approximated with Vicryl 3-0. Histopathology confirmed villous papillary adenoma with a mild focal epithelial dysplasia. The excision was complete. The postoperative course was free of any complications and the patient being appointed for a control, was discharged from the hospital four days after the surgery. On the follow ups she presented with no complaints. When preparing the instruments, it is important to fix the apparatus properly allowing enough room for the operator's hands and getting used to the stereoscopic view. A very helpful device is the instrument for monopolar coagulation, bipolar cutting, suction and flushing, lately introduced by professor Buess.
Adenoma↗