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)

In liver fibrosis, activated hepatic stellate cells (HSC) play a major role in the deposition of excess extracellular matrix, including fibrillar collagens type I and type III. In addition to matrix protein synthesis, HSC regulate matrix degradation in the liver. This is mediated via a combination of synthesis of matrix (pro)metalloproteinases, which activate these zymogens via specific mechanisms and by inhibiting the active matrix-degrading enzymes via expression of tissue inhibitors of metalloproteinases (TIMPs). There are currently four members of the TIMP family described and of these, both TIMP-1 and TIMP-2 are synthesised by HSC. These observations have led to the suggestion that inhibition of matrix degradation mediated by a change in HSC-expression of TIMPs relative to metalloproteinases, such as interstitial collagenase, may contribute to progression of liver fibrosis. This hypothesis is supported by studies of human liver disease in which TIMP-1 expression is upregulated 5-fold in cirrhotic compared with normal liver. TIMP-1 and TIMP-2 expression is also upregulated in animal models of progressive fibrosis, whereas expression of collagenase is unchanged. In a model which is characterized by natural resolution of liver fibrosis, degradation of the deposited fibrillar liver matrix is accompanied by rapid down-regulation of TIMP-1 expression. In alcoholic liver disease, the role of TIMPs has not been studied exhaustively, but the evidence currently available supports a role for inhibition of matrix degradation by TIMPs in this progressive fibrotic liver disease.
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PMID:Tissue inhibitors of metalloproteinases: role in liver fibrosis and alcoholic liver disease. 1037 19

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of prevention and therapy, with promising prospects for even more effective treatments. The most successful approaches that one can expect to evolve are those that deal with the fundamental cellular disturbances resulting from excessive alcohol consumption. Two pathologic concepts are emerging as particularly useful therapeutically. Whereas it continues to be important to replenish nutritional deficiencies, when present, it is crucial to recognize that because of the alcohol-induced disease process, some of the nutritional requirements change. This is exemplified by methionine, which normally is one of the essential amino acids for humans, but needs to be activated to S-adenosylmethionine (SAMe), a process impaired by the disease. Thus, SAMe rather than methionine is the compound that must be supplemented in the presence of significant liver disease. Indeed, SAMe was found to attenuate mitochondrial lesions in baboons, replenish glutathione, and significantly reduce mortality in patients with Child A or B cirrhosis. Similarly, polyenylphosphatidylcholine (PPC) corrects the ethanol-induced hepatic phospholipid depletion as well as the decreased phosphatidylethanolamine methyltransferase activity and opposes oxidative stress. It also deactivates hepatic stellate cells, whereas its dilinoleoyl species (DLPC) increases collagenase activity, resulting in prevention of ethanol-induced septal fibrosis and cirrhosis in the baboon. Clinical trials with PPC are ongoing in patients with alcoholic liver disease. Furthermore, enzymes useful for detoxification, such as CYP2E1, when excessively induced, become harmful and should be downregulated. PPC is one of the substances with anti-CYP2E1 properties that is now emerging. Another important aspect is the association of alcoholic liver disease with hepatitis C: a quarter of all patients with alcoholic liver disease also have markers of HCV infection, with an even higher incidence in some urban areas but, at present, no specific therapy is available since interferon is contraindicated in that population. However, in addition to antiviral medications, agents that oppose oxidative stress and fibrosis should also be tested for hepatitis C treatment since these two processes contribute much to the pathology and mortality associated with the virus. In addition to antioxidants (such as PPC, silymarin, alpha-tocopherol and selenium), anti-inflammatory medications (corticosteroids, colchicine, anticytokines) are also being tested as antifibrotics. Transplantation is now accepted treatment in alcoholics who have brought their alcoholism under control and who benefit from adequate social support but organ availability is still the major limiting factor and should be expanded more aggressively. Finally, abstinence from excessive drinking is always indicated; it is difficult to achieve but agents that oppose alcohol craving are becoming available and they should be used more extensively.
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PMID:Alcoholic liver disease: new insights in pathogenesis lead to new treatments. 1072 99

In the past, alcoholic liver disease was attributed exclusively to dietary deficiencies, but experimental and judicious clinical studies have now established alcohol's hepatotoxicity. Despite an adequate diet, it can contribute to the entire spectrum of liver diseases, mainly by generating oxidative stress through its microsomal metabolism via cytochrome P4502E1 (CYP2E1). It also interferes with nutrient activation, resulting in changes in nutritional requirements. This is exemplified by methionine, one of the essential amino acids for humans, which needs to be activated to S-adenosylmethionine (SAMe), a process impaired by liver disease. Thus, SAMe rather than methionine is the compound that must be supplemented in the presence of significant liver disease. In baboons, SAMe attenuated mitochondrial lesions and replenished glutathione; it also significantly reduced mortality in patients with Child A or B cirrhosis. Similarly, decreased phosphatidylethanolamine methyltransferase activity is associated with alcoholic liver disease, resulting in phosphatidylcholine depletion and serious consequences for the integrity of membranes. This can be offset by polyenylphosphatidylcholine (PPC), a mixture of polyunsaturated phosphatidylcholines comprising dilinoleoylphosphatidylcholine (DLPC), which has high bioavailability. PPC (and DLPC) opposes major toxic effects of alcohol, with down-regulation of CYP2E1 and reduction of oxidative stress, deactivation of hepatic stellate cells, and increased collagenase activity, which in baboons, results in prevention of ethanol-induced septal fibrosis and cirrhosis. Corresponding clinical trials are ongoing.
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PMID:ALCOHOL: its metabolism and interaction with nutrients. 1094 Mar 40

Background/aims: The liver apoptotic response to chronic alcohol consumption remains poorly characterized. The purpose of this study was to determine in rats the effects of chronic alcohol consumption on the relative magnitude of apoptosis in two major targets of alcohol-induced liver injury: the hepatocyte (Hep) and sinusoidal endothelial cell (SEC). Methods: Rats were fed a liquid diet containing either alcohol or isocaloric amounts of maltose-dextrin for 14 weeks. Hep and SEC were isolated by liver perfusion with collagenase followed by centrifugal elutriation. The state of the liver was assessed on the basis of light microscopic appearance, plasma liver enzymes (alanine and aspartate:2-oxoglutarate amino transferases), and the content of malondialdehyde in Hep. Apoptosis was assessed on the basis of DNA fragmentation in the whole organ (TUNEL), and caspase-3 and -8 activity in isolated cells. A mechanistic approach was also undertaken by measuring mRNA expression and the amount of protein for Fas/CD95, Fas ligand, caspase-3, Bax, Bcl-X(L), and Bcl-2 in the isolated Hep and SEC. Results: The livers of alcohol-fed rats displayed prominent steatosis. Oxidative stress was also present as reflected by an increase in the malondialdehyde content of Hep. Alcohol consumption increased apoptosis in the whole liver assessed on the basis of TUNEL procedure and in Hep and SEC as reflected by significant increase in caspase-3 activity. Of the multiple pro- and anti-apoptotic factors determined in this study, significant changes as assessed by both mRNA expression and the amount of proteins, were observed only in the SEC compartment. Conclusions: The data presented in this study indicate that: (1) chronic alcohol consumption in rats leads to a moderate augmentation of apoptosis in the whole liver and in two liver cell types which are targets for injury in alcoholic liver disease: Hep and SEC; (2) the mechanisms recruited/activated by these two types of liver cells to initiate and execute apoptosis in response to alcohol vary with the cell type.
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PMID:Chronic alcohol exposure of rats exacerbates apoptosis in hepatocytes and sinusoidal endothelial cells. 1125 13

Many patients suffering from end-stage liver disease cannot be transplanted within reasonable time due to the shortage of donor organs. Bioartificial liver support systems may contribute to the liver regeneration or bridging the time until a liver graft for transplantation becomes available. Nonwovens with integrated oxygenation capacity have been developed and manufactured by melt blow technology using thermoplastic polyurethane. Capillary membranes for oxygenation were integrated into the nonwoven during the processing. The polyurethane nonwoven structures with adapted pore size and high pore volume allow high cell densities in the hepatocyte culture. The three-dimensional cell culture was housed by a flow bioreactor system and was integrated in a closed loop circulation with monitoring possibilities for pressure, pH, temperature, ammonia, and oxygen. Hepatocytes were isolated from rats or pigs by collagenase perfusion and infused into the medium-perfused circulation. Cells showed high viability and hepatocyte specific cytochrome P450-dependent metabolic function in culture (MEGX test).
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PMID:Cultivation of porcine hepatocytes in polyurethane nonwovens as part of a biohybrid liver support system. 1245 41

Matrix metalloproteinases (MMPs) are central to tissue remodelling; however, little is known about the temporal pattern and differential regulation of hepatic MMP expression in the course of chronic human liver disease. Using quantitative reverse transcription-PCR ELISA assays, we studied hepatic mRNA expression of MMP-1, -2, -3, -7, -9, -10, -11, -13 and -14 in patients with chronic hepatitis C and hepatitis C virus-induced end-stage liver cirrhosis and controls. Results were compared with histology, hepatic expression of tissue inhibitor of metalloproteinases (TIMP)-1, -2 and -3, procollagen types I and IV, laminin, and with circulating protein levels of hyaluronate, TIMP-1 and -2 and MMP proenzymes, as measured by ELISA. The impact of the MMP-3(-1171) promoter polymorphism on hepatic MMP-3 expression was analysed. Hepatic mRNA expression data identified differentially regulated groups of MMPs during the course of chronic hepatitis C, showing either steadily increasing mRNA expression with disease progression (MMP-1, -2, -7 and -14) or transiently elevated expression (MMP-9, -11 and -13). The first group closely correlated to the parameters of fibrogenesis. Hepatic MMP-3 expression was unrelated to disease stage, but was determined by the MMP-3(-1171) promoter polymorphism. In conclusion, MMP expression during the course of chronic hepatitis C appears to be a closely regulated process, with different clusters of coordinately regulated MMP genes being identified.
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PMID:Expression and coordinated regulation of matrix metalloproteinases in chronic hepatitis C and hepatitis C virus-induced liver cirrhosis. 1276 Jul 42

In laboratory animals, intrasplenic hepatocyte transplantation corrects the physiologic abnormalities associated with decompensated liver disease. The clinical experience with hepatocyte transplantation for cirrhosis has been disappointing when compared with laboratory experience. The route of hepatocyte delivery may influence hepatocyte engraftment and function. Outbred pigs were recipients of allogeneic pig hepatocytes. Donor hepatocytes were isolated by collagenase perfusion and labeled using 5(6)-carboxyfluorescein diacetate succinimidyl-ester (CMFSE). Cells were introduced into pig spleens by infusion through the splenic artery or by direct splenic puncture. Direct intrasplenic injection produced engraftment that was far superior to that obtained using splenic artery infusion. Splenic artery infusion produced a gastric erosion and large areas of splenic necrosis secondary to vascular occlusion with hepatocytes, whereas direct splenic injection was associated with clinically insignificant intraabdominal hemorrhage. The route of hepatocyte delivery may influence hepatocyte engraftment and explain the disparity in efficacy of hepatocyte transplantation between the laboratory and clinic.
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PMID:Route of hepatocyte delivery affects hepatocyte engraftment in the spleen. 1297 19

Alcoholic liver disease is a major cause of illness and death in the United States. In the initial stages of the disease, fat accumulation in hepatocytes leads to the development of fatty liver (steatosis), which is a reversible condition. If alcohol consumption is continued, steatosis may progress to hepatitis and fibrosis, which may lead to liver cirrhosis. Alcoholic fatty liver has long been considered benign; however, increasing evidence supports the idea that it is a pathologic condition. Blunting of the accumulation of fat within the liver during alcohol consumption may block or delay the progression of fatty liver to hepatitis and fibrosis. To achieve this goal, it is important to understand the underlying biochemical and molecular mechanisms by which chronic alcohol consumption leads to fat accumulation in the liver and fatty liver progresses to hepatitis and fibrosis. In addition to alcohol consumption, dietary fatty acids and obesity have been shown to affect the degree of fat accumulation within the liver. Again, it is important to know how these factors modulate the progression of alcoholic liver disease. The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on "Role of Fatty Liver, Dietary Fatty Acid Supplements, and Obesity in the Progression of Alcoholic Liver Disease" in Bethesda, Maryland, USA, October 2003. The following is a summary of the symposium. Alcoholic fatty liver is a pathologic condition that may predispose the liver to further injury (hepatitis and fibrosis) by cytochrome P450 2E1 induction, free radical generation, lipid peroxidation, nuclear factor-kappa B activation, and increased transcription of proinflammatory mediators, including tumor necrosis factor-alpha. Increased acetaldehyde production and lipopolysaccharide-induced Kupffer cell activation may further exacerbate liver injury. Acetaldehyde may promote hepatic fat accumulation by impairing the ability of peroxisome proliferator-activated receptor alpha to bind DNA, and by increasing the synthesis of sterol regulatory binding protein-1. Unsaturated fatty acids (corn oil, fish oil) exacerbate alcoholic liver injury by accentuating oxidative stress, whereas saturated fatty acids are protective. Polyenylphosphatidylcholine may prevent liver injury by down-regulating cytochrome P450 2E1 activity, attenuating oxidative stress, reducing the number of activated hepatic stellate cells, and up-regulating collagenase activity. Nonalcoholic steatohepatitis may develop through several mechanisms, such as oxidative stress, mitochondrial dysfunction and associated impaired fat metabolism, dysregulated cytokine metabolism, insulin resistance, and altered methionine/S-adenosylmethionine/homocysteine metabolism. Obesity (adipose tissue) may contribute to the development of alcoholic liver disease by generating free radicals, increasing tumor necrosis factor-alpha production, inducing insulin resistance, and producing fibrogenic agents, such as angiotensin II, norepinephrine, neuropeptide Y, and leptin. Finally, alcoholic fatty liver transplant failure may be linked to oxidative stress. In vitro treatment of fatty livers with interleukin-6 may render allografts safer for clinical transplantation.
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PMID:Role of fatty liver, dietary fatty acid supplements, and obesity in the progression of alcoholic liver disease: introduction and summary of the symposium. 1567 Jun 59

Hepatocyte transplantation is being investigated as an alternative to orthotopic liver transplantation in patients with liver-based metabolic disorders. The progress made in this field to date is reviewed. Protocols have been developed using collagenase perfusion to isolate human hepatocytes from unused donor liver tissue. Hepatocytes with a high viability can often be obtained and can be cryopreserved for later use, though with loss of function on thawing. For clinical use, hepatocytes must be prepared in clean GMP conditions with cells meeting criteria of function and lack of microbial contamination before patient use. Hepatocytes are infused intraportally into the patient's liver, where a proportion of cells will engraft and replace the deficient metabolic function without the need for major surgery. Twenty patients have now received hepatocyte transplantation, including eight children at King's College Hospital. There was a range of aetiologies of liver disease: familial hypercholesterolaemia, Crigler-Najjar syndrome type 1, urea cycle defects, infantile Refsum disease, glycogen storage disease type Ia, inherited factor VII deficiency and progressive familial intrahepatic cholestasis type 2. Clinical improvement and partial correction of the metabolic abnormality was observed in most cases. Considerable progress has been made in developing the technique, but hepatocyte transplantation is limited by the available supply of liver tissue. Hepatocytes derived from stem cells could provide alternative sources of cells in the future.
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PMID:Hepatocyte transplantation for liver-based metabolic disorders. 1676 14

The disease manifestations of schistosomiasis arise from the mammalian host-mediated type 2 T-helper cell-induced (Th2) fibro-granulomatous inflammatory response to eggs trapped within host tissues. Activated hepatic stellate cells are well described as the effector cells of hepatic fibrosis in a variety of human diseases and rodent models. The aim of this study was to further understand the mechanism of fibrosis and the role of hepatic stellate cells in hepatic schistosomiasis progression. Groups of female CBA mice, which produce an intermediate degree of Schistosoma japonicum-induced liver fibrosis, were infected with S. japonicum, perfused at fortnightly time points and the liver tissue and contained egg granulomas examined by immunohistochemistry and cytokine and chemokine analysis using quantitative PCR. Immunohistochemistry demonstrated the presence of activated hepatic stellate cells in the periphery of egg granulomas, adjacent to fibrotic areas. Time course analysis demonstrated that the transcription of smooth muscle actin-alpha type 1 collagen, IL-4, IL-13, IL-13Ralpha2 and tissue inhibitor of metalloproteinase-1 mirrored the initial increase and subsequent down-modulation of granuloma diameter in mice. However, the transcription of monocyte chemo-attractant protein-1, Regulated upon Activation Normal T Cell Expressed and Secreted (RANTES), TNF-alpha, IFN-gamma and matrix metalloproteinase-9 paralleled the evolution of the total liver disease burden. Transforming growth factor-beta1 transcription did not appear to be of biological significance in this mouse model. Immunohistochemical analysis of human hepatic granulomas showed close association of smooth muscle actin-alpha-expressing cells with fibrosis in five available cases of end-stage (advanced) schistosomiasis japonica. We conclude that activated hepatic stellate cells play a contributory role in the granulomatous, fibrotic process induced by S. japonicum eggs, both in the murine model and in human disease.
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PMID:A contributory role for activated hepatic stellate cells in the dynamics of Schistosoma japonicum egg-induced fibrosis. 1680 22


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