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)

Although it is well recognized that pressure-induced ischemia initiates the formation of pressure ulcers, the many complex mechanisms responsible for the pathogenesis of these ulcers remain poorly understood. It has been reported that chronic ulcers contain an elevated level of proteolytic enzymes, especially neutrophil-derived matrix metalloproteinase-8 and elastase. This evidence suggests that neutrophils are a major component in the pathogenesis of chronic pressure ulcers. Therefore, this study characterized the cellular components of chronic pressure ulcers. Three-millimeter biopsies (6 mm deep) from granulation tissue in pressure ulcers were obtained from 11 patients. A total of 14 biopsies were obtained from these 11 patients for analysis. A portion of each specimen was fixed in formalin for routine histology. Other portions of biopsies were frozen for analysis of myeloperoxidase activity. In addition, cells on the surfaces of the ulcers were collected by lavage for histologic characterization. Routine histologic analysis of all 14 biopsies of the pressure ulcers showed regions near the surface of each that contained dense neutrophil infiltration associated with edema and apparent marked matrix dissociation. In the deeper regions there was an increased density of blood vessels, and many contained rounded endothelial cells surrounded by migrating neutrophils. Cells collected by lavage from the ulcer surface were prepared by Cytospin and found to be greater than 95% neutrophils with occasional large macrophages actively phagocytosing depleted neutrophils. In addition, there was a significant correlation of myeloperoxidase activity with actual neutrophil counts in the ulcer biopsies further confirming the dense presence of neutrophils. These studies directly show that there is extensive neutrophil infiltration in chronic pressure ulcer granulation tissue. Furthermore, the persistence of neutrophils and their destructive enzymes appears responsible for the extensive matrix dissociation and thus contributes to the chronicity of these ulcers.
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PMID:Excessive neutrophils characterize chronic pressure ulcers. 1461 91

Human islet transplantation seems to be a very promising clinical procedure for patients with type I diabetes mellitus. The aim of our study was to investigate the influence of in situ intravascular flushing with University of Wisconsin (UW) solution and intraductal collagenase injection at the time of pancreas procurement on the isolated islets and exocrine tissue injury. Our experiments indicated that in situ perfusion with the UW solution has a beneficial effect on pancreatic islets and intraductal distention results in an increase in the concentration of pancreatic enzymes released into the cold preservation solution during ischemic conditions. Cold ischemia reduced islet yield, but pancreas perfusion with the UW solution showed better ischemic tolerance of isolated islets during glucose static incubation. We conclude that intravascular pancreas flushing has a crucial effect on recovery and yield of pancreatic islets and protects against exocrine tissue injury.
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PMID:Pancreatic islets isolation using different protocols with in situ flushing and intraductal collagenase injection. 1520 41

The selective cyclooxygenase-2 (COX-2) inhibitor has been reported to have antiinflammatory, neuroprotective, and antioxidant effects in ischemia models. In this study, the authors examined whether a selective COX-2 inhibitor (celecoxib) reduces cerebral inflammation and edema after intracerebral hemorrhage (ICH), and whether functional recovery is sustained with longer treatment. ICH was induced using collagenase in adult rats. Celecoxib (10 or 20 mg/kg) was administered intraperitoneally 20 minutes, 6 hours, and 24 hours after ICH and then daily thereafter. Seventy-two hours after ICH induction, the rats were killed for histologic assessment and measurement of brain edema and prostaglandin E2. Behavioral tests were performed before and 1, 7, 14, 21, and 28 days after ICH. The brain water content of celecoxib-treated rats decreased both in lesioned and nonlesioned hemispheres in a dose-dependent manner. Compared with the ICH-only group, the number of TUNEL-positive, myeloperoxidase-positive, or OX42-positive cells was decreased in the periphery of hematoma and brain prostaglandin E2 level was reduced in the celecoxib-treated group. Celecoxib-treated rats recovered better by the behavioral tests at 7 days after ICH throughout the 28-day period, and the earlier the drug was administered, the better the functional recovery. Evidence of similar effects in an autologous blood-injected model showed that direct collagenase toxicity was not the major cause of inflammation or cell death. These data suggest that celecoxib treatment after ICH reduces prostaglandin E2 production, brain edema, inflammation, and perihematomal cell death in the perihematomal zone and induces better functional recovery.
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PMID:Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. 1536 23

Angiotensin II (Ang II)-mediated stimulation of fibroblast growth and collagen type I synthesis is believed to be an important component of the cardiac remodeling process in hypertension and chronic ischemia. Ang II-mediated oxidative stress could be important in enhanced fibroblast growth and collagen formation. Accordingly, we postulated that the PPAR-gamma ligand, pioglitazone, which is known to modulate oxidative stress, would alter Ang II-induced formation of collagen type I in cardiac fibroblasts. Cardiac fibroblasts were treated with different concentrations (10(-8) to 10(-6) M) of Ang II for different times (6 hours, 12 hours, and 24 hours). Ang II increased the expression of collagen type I in a concentration- and time-dependent fashion (P<0.01 versus control). Ang II also decreased the expression and activity of matrix metalloproteinase (MMP)-1 (MMP-1, P<0.05 versus control). These effects of Ang II were attenuated by pretreatment of cells with pioglitazone (10 micromol/L). Ang II stimulated the intracellular generation of reactive oxygen species (ROS), and this effect was also attenuated by pioglitazone. Ang II treatment activated the redox-sensitive transcription factor NF-kappaB, and pioglitazone pretreatment blocked this effect of Ang II. Ang II also activated another transcription factor, AP-1, but this effect of Ang II was not modulated by pioglitazone. In other experiments, we observed that trolox, the water soluble analog of vitamin E, attenuated the effects of Ang II on the expression of collagen type I and MMP-1, in a manner similar to pioglitazone. Thus, pioglitazone attenuates Ang II-mediated collagen type I synthesis in cardiac fibroblasts. The effects of pioglitazone are mediated by the modulation of ROS release and redox-sensitive transcription factor NF-kappaB.
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PMID:Angiotensin II regulation of collagen type I expression in cardiac fibroblasts: modulation by PPAR-gamma ligand pioglitazone. 1538 78

Our previous studies indicated that opioid-induced cardioprotection occurs via activation of mitochondrial ATP-sensitive K(+) (K(ATP)) channels. However, other elements of the Met(5)-enkephalin (ME) cardioprotection pathway are not fully characterized. In the present study, we investigated the role of tyrosine kinase, MAPK, and phosphatidylinositol 3-kinase (PI3K) signaling in ME-induced protection. Ca(2+)-tolerant, adult rabbit cardiomyocytes were isolated by collagenase digestion and subjected to simulated ischemia for 180 min. ME was administered 15 min before the 180 min of simulated ischemia; blockers were administered 15 min before ME. Cell death was assessed by trypan blue as a function of time. The epidermal growth factor receptor (EGFR) kinase inhibitor AG-1478 (250 nM) blocked ME-induced protection, but the inactive analog AG-9 (100 microM) did not. Treatment with herbimycin (1 microM) completely eliminated ME-induced protection. To verify that ME activates EGFR and to determine the involvement of Src, Western blotting of EGFR was performed after ME administration with and without herbimycin A. ME resulted in herbimycin-sensitive robust phosphorylation of EGFR at Tyr(992) and Tyr(1068). Administration of the selective MAPK inhibitor PD-98059 (10 nM) and the specific MEK1/2 inhibitor U-0126 (10 microM) also inhibited ME-induced cardioprotection. ME-induced ERK1/2 phosphorylation was significantly reduced by PD-98059, the EGFR kinase inhibitor PD-153035 (10 microM), and chelerythrine (2 microM). The PI3K inhibitor LY-294002 (20 microM) abrogated ME-induced protection, and ME-induced Akt phosphorylation at Ser(473) was suppressed by LY-294002, PD-153035, and chelerythrine. We conclude that ME-induced cardioprotection is mediated via Src-dependent EGFR transactivation and activation of the PI3K and MAPK pathways.
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PMID:Met5-enkephalin-induced cardioprotection occurs via transactivation of EGFR and activation of PI3K. 1556 40

17beta-estradiol reduces cell death after global and focal ischemia and subarachnoid hemorrhage in rodents. Presently, we tested whether estrogen improves outcome after intracerebral hemorrhage (ICH) in male rats. Rats were implanted subcutaneously with 0.05, 0.25, or 0.50 mg pellets of estrogen (21-day release) or subjected to a sham procedure. Two weeks after implantation, they were given a striatal ICH via an infusion of collagenase. The three estrogen groups had significantly smaller lesions at a 7-day survival. Some rats had core temperature measured with an implanted telemetry probe, which also measured whole-body movements. Estrogen did not affect temperature nor activity levels after ICH. A second study with 0.25 mg pellets, administered once or twice, showed persistent histologic protection (30 days) and some functional benefit (e.g., elevated beam). A spectrophotometric hemoglobin assay showed that the 0.25 mg dose significantly reduced hemorrhagic blood volume at 12 hours after ICH. Regardless, estrogen did not lessen cerebral edema at 2 days after ICH and functional benefits were not consistently found on all tests (e.g., cylinder task). In summary, estrogen pretreatment reduces injury after ICH, in part by reducing bleeding. Estrogen may thus lessen injury and improve outcome after ICH in humans.
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PMID:17beta-Estradiol pretreatment reduces bleeding and brain injury after intracerebral hemorrhagic stroke in male rats. 1567 26

Following a severe ischemic injury or myocardial infarction, the extracellular matrix (ECM) of the heart is involved in pathophysiological conditions such as dilatation and cardiac dysfunction. Osteopontin (OPN) has been shown to interact with fibronectin suggesting its possible role in matrix organization, stability and wound healing. There is increased expression of OPN in several tissues in response to injury. Therefore, we tested the hypothesis that acute ischemia (2 h), followed by reperfusion (4 h) may induce early OPN and fibronectin in an isolated hemoperfused working porcine heart model. Twenty hearts were prepared and connected to a perfusion system. After 1 h of perfusion, these hearts were randomized to two groups: ten infarcted (MI, ramus circumflexus) and ten non-infarcted hearts (C). In addition, cardiac fibroblasts derived from infarcted, remote and control myocardium were investigated. In both groups, the heart rate, electrolytes, pH, blood gases, and lactate remained similar. The LVEDP and perfusion pressure of MI hearts increased significantly (P<0.05). The total fibronectin and OPN volume contents were clearly elevated in the infarct area. The matrix metalloproteinases (MMP-1 and MMP-8), fibronectin, OPN, TGF-beta1 proteins and the mRNAs for fibronectin, TGF-beta1, and OPN were significantly elevated in the infarct area as compared to the remote area and the non-infarcted hearts. Simultaneously, circulating carboxyterminal propeptide of type I procollagen (PICP) was released in the perfusion medium (threefold versus C). Fibroblast-like cells originating from the infarct area exhibited an enhanced OPN and fibronectin gene and protein expression compared to fibroblasts derived from control myocardium. Our data demonstrate the early appearance of the MMPs (increased collagen degrading enzymes) and PICP (a collagen synthesis marker) following ischemia and reperfusion. Moreover, OPN, fibronectin and TGF-beta1 protein and gene expression are elevated after ischemia and reperfusion in the ex vivo working hemoperfused porcine heart model.
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PMID:Increase of fibronectin and osteopontin in porcine hearts following ischemia and reperfusion. 1577 Apr 97

Laparoscopic techniques are increasingly applied for the treatment of diverse gastrointestinal diseases. With regard to reports of a pronounced decrease of intra-abdominal blood flow with increasing intra-abdominal pressure, the present study investigates the impact of pressure and gas type on ischemia in small bowel anastomoses in the rat model. Laparotomy and ileoileal anastomosis were performed in 39 male Sprague-Dawley rats. A CO2 or helium pneumoperitoneum of 3 mm Hg or of 6 mm Hg was maintained before and after anastomoses. Rats in the control group received no pneumoperitoneum. Animals were sacrificed after 5 d, and the anastomotic region was explanted for subsequent histopathological examinations. In hematoxylin and eosin (HE)-stained sections, the Chiu score, villi configuration, and number of goblet cells were analyzed. Proliferation (Ki67) and expression of a matrix metalloproteinase (MMP-8) were examined by immunohistochemistry. Mucosal damage according to the scoring system by Chiu, the number of goblet cells, the villus length, the proliferation (Ki67), and the submucosal expression of MMP-8 was similar in all groups. Our results suggest that within a certain range of pressures and time, laparoscopic assisted surgery using CO2 pneumoperitoneum can be performed safely. Helium gas offers no advantages over CO2.
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PMID:Influence of pneumoperitoneum on small bowel anastomoses: a histological analysis in the rat model. 1603 74

Extracellular matrix (ECM) metabolism and homeostasis is sensitive to changes in oxygen tension manifest in ischemia. We hypothesize that in chronically ischemic limbs, abnormalities in uninjured skin, secondary to hypoxia, predispose to dermal breakdown. Paired biopsies of uninjured distal ischemic and proximal non-ischemic skin were harvested at below knee amputation from 14 patients with peripheral vascular disease following quantification of ischemia. Age- and site-matched controls were taken at total knee replacement (TKR) and varicose vein (VV) operations. Matrix metalloproteinase (MMP)-2 and -9 expression was determined using gelatin zymography, MMP-1 by western blotting and ELISA and tissue inhibitor of MMP (TIMP) by reverse zymography. Collagen content was measured by determining hydroxyproline levels, and collagen type I synthesis by ELISA. Collagen type I synthesis was upregulated in ischemic tissue compared with non-ischemic matched pairs (p<0.001) and both TKR and VV controls, however, there was no increase in collagen deposition. Levels of MMP-2 (p<0.0005) and TIMP-2 (p<0.01), were elevated in ischemic samples. MMP-9 was unaltered, signifying no inflammatory changes. Tissue ischemia was linked to elevated ECM turnover, associated with matrix failure when compounded with problems of matrix stabilization, likely in ischemia. This represents a potential mechanism for ulcer formation.
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PMID:Abnormal extracellular matrix metabolism in chronically ischemic skin: a mechanism for dermal failure in leg ulcers. 1609 24

We analyzed the preexisting donor factors and isolation variables that affected isolation of human islets of Langerhans. Sixty-nine pancreata from cadaveric donors were analyzed for donor factors of age, gender, body mass index, cause of death as well as graft factors of cold ischemia time, pancreas status, distensibility during intraductal collagenase distension and time of collagenase expansion and digestion. Islet isolations that recovered >100,000 IEQ (n = 53) were compared to those generating less than 100,000 IEQ (n = 16) to analyze the factors affecting islet yield during donor harvest and isolation procedures. The mean islet recovery was 216.0 x 10(3) (IEQ) or 2840 (IEQ) per gram of pancreas. Mean purity was 54%. The success rate of islet isolation was 76%. Mean age was 31 years, and mean cold ischemia time was 6.9 hours. In univariate analysis, the status of the pancreas was the only significant factor for successful isolation, and gender, time of collagenase expansion and digestion were marginal factors. In stepwise multivariate logistic regression analysis of donor and isolation-related factors, donor gender, pancreas status and digestion time were significant factors. During the same period we performed three cases of clinical islet allotransplantation and one autotransplantation. This study confirmed that the same donor factors and variables in the isolation process can affect the ability to obtain successful human islet isolation. Enough experience and pertinent review of donor and isolation factors can make islet isolation consistent, supporting clinical islet transplantation without unnecessary cost.
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PMID:Analysis on donor and isolation-related factors of successful isolation of human islet of Langerhans from human cadaveric donors. 1629 7


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