Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently found that polyunsaturated lecithin prevents ethanol from causing cirrhosis in the baboon. Because transformation of lipocytes to transitional cells plays a key role in hepatic fibrogenesis in vivo, and because this process in alcohol-fed baboons was found to be attenuated by polyunsaturated lecithin, we focused on lipocytes to study the mechanism of the protective effect. Rat lipocytes cultured on plastic undergo spontaneous activation, accompanied by expression of alpha-smooth muscle actin isoform and production of substantial amounts of type I collagen. The latter was further increased on incubation with acetaldehyde. This in vitro model was used here to study how acetaldehyde-mediated collagen production and accumulation can be turned off. Addition of polyunsaturated lecithin (10 mumols/L) was found to prevent the acetaldehyde-induced increase in collagen accumulation by 83% (p less than 0.001). By contrast, a saturated phospholipid (10 mumols/L dilauroyl phosphatidylcholine), a monounsaturated one (10 mumols/L linoleoyl-palmitoyl phosphatidylcholine) or linoleic acid (20 mumols/L bound to albumin) had no such effect. Incorporation of [3H]proline into collagen and the expression of alpha-1 (I) procollagen mRNA were increased by acetaldehyde; the latter was not significantly affected by polyunsaturated lecithin. Polyunsaturated lecithin increased lipocyte collagenase activity by 100% (p less than 0.001), whereas dilauroyl phosphatidylcholine, linoleoyl-palmitoyl phosphatidylcholine and linoleic acid had no such action. We concluded that (a) polyunsaturated lecithin selectively prevents the acetaldehyde-induced increase in collagen accumulation in lipocyte cultures, whereas other phospholipids or linoleate have no such effect; and (b) polyunsaturated lecithin does not modify the acetaldehyde-mediated increase in alpha-1 (I) procollagen mRNA, but it increases collagenase activity, suggesting that the protective effect exerted by polyunsaturated lecithin against alcohol induced fibrosis in vivo is due at least in part to stimulation of collagenase activity, which may prevent excess collagen accumulation by offsetting increased collagen production.
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PMID:Polyunsaturated lecithin prevents acetaldehyde-mediated hepatic collagen accumulation by stimulating collagenase activity in cultured lipocytes. 137 80

Chronic iron overload can result in hepatic fibrosis and cirrhosis. Activated lipocytes, through increased production of collagen and extracellular matrix, play an important role in hepatic fibrogenesis in several types of experimental liver injury, but their contribution to hepatic injury after iron overload is unknown. This study examines the effect of iron overload on lipocyte activation, in vivo. Male Sprague-Dawley rats were fed a chow diet supplemented with 1% carbonyl iron for up to 20 mo. Controls were fed the chow diet alone. Lipocytes were prepared by sequential pronase and collagenase perfusion of the livers, followed by density-gradient centrifugation. Lipocyte activation was assessed by immunohistochemistry of liver sections and by Western blot analysis of alpha-smooth muscle actin expression in freshly isolated lipocytes. In addition, to measure the biosynthetic capability of these lipocytes, collagen and noncollagen protein production was determined after 3 days in culture, using [3H]proline incorporation. The hepatic iron concentration was increased by eightfold in the iron-loaded rats, and lipocytes from these animals expressed alpha-smooth muscle actin. Collagen production was increased by 2.5-fold, and noncollagen protein production was elevated by twofold in lipocytes isolated from iron-loaded rats. In the iron-loaded livers, autofluorescent material with the characteristics of lipofusion was present in periportal zones. Chronic iron overload expression results in the activation of lipocytes, as determined by increased expression of alpha-smooth muscle actin and by increased production of both collagen and noncollagen protein. This activation may contribute to iron-induced hepatic fibrogenesis.
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PMID:Chronic iron overload causes activation of rat lipocytes in vivo. 790 Aug 6

Immunohistochemistry and image analysis were used to quantify alterations in the Kupffer cell and 'activated' perisinusoidal cell populations in the different stages of primary biliary cirrhosis. Anti-CD68 macrophage antibodies were used to detect Kupffer cells, and anti-alpha-smooth muscle actin (alpha-SMA), PR 2D3 and anti-desmin antibodies to detect perisinusoidal cells. Liver biopsy material was available from 26 patients with primary biliary cirrhosis and 23 patients with histologically normal liver. Increased Kupffer cell numbers were observed in periportal/periseptal zones of stage 3 primary biliary cirrhosis (n = 9), and in random parenchymal areas of stage 3 and stage 4 cases. Significantly increased 'activated' perisinusoidal cell numbers were seen only in periportal/periseptal zones of stage 3 and stage 4 primary biliary cirrhosis. Neither Kupffer cell nor perisinusoidal cell numbers altered significantly in stage 1 and 2 primary biliary cirrhosis (n = 6). PR 2D3 positivity and increased alpha-SMA immunoreactivity by perisinusoidal cells in primary biliary cirrhosis support myofibroblastic differentiation of these cells. Human perisinusoidal cells, unlike their rodent counterparts, did not express desmin in primary biliary cirrhosis or control liver. Kupffer cells and 'activated' perisinusoidal cell accumulation in periportal/periseptal zones of the precirrhotic and cirrhotic primary biliary cirrhosis liver support the concept of Kupffer cell-mediated stimulation of perisinusoidal cells. Furthermore, these findings indicate that Kupffer cell-perisinusoidal interactions play an important role in the development of liver fibrosis and cirrhosis in primary biliary cirrhosis.
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PMID:Quantitative analysis of macrophages and perisinusoidal cells in primary biliary cirrhosis. 795 47

The main pathological feature of liver fibrosis is the accumulation of extracellular matrix associated with hyperplasia and activation of perisinusoidal (Ito) cells (PSC) to myofibroblast-like cells. Interleukin-1 enhances collagen synthesis by increasing the proliferative activity of cultured PSC and has been implicated in the pathogenesis of hepatic fibrosis. Interleukin-1 receptor antagonist (IL-1ra) can block the binding of IL-1 to its receptors and act as a natural inhibitor of IL-1. We have examined whether the administration of IL-1ra can interfere with the development of experimental cirrhosis induced by dimethylnitrosamine (DMN). Rats were divided in three groups and received respectively DMN, DMN + IL-1ra and IL-1ra. For each group the collagen content of the hepatic tissue and the volume density of the inflammatory infiltrate were measured. Immunostaining for laminin and alpha-smooth muscle actin were also performed. In animals given DMN + IL-1ra we observed a decreased deposition of laminin and collagen, and a decreased number of laminin-positive PSC and of alpha-smooth muscle actin reactive cells, compared with animals receiving DMN alone. The present findings suggest that the early activation of PSC in vivo is at least in part mediated by IL-1 and confirm that the administration of IL-1ra may be of interest in modifying the biological effects of IL-1.
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PMID:An interleukin-1 receptor antagonist decreases fibrosis induced by dimethylnitrosamine in rat liver. 798

To evaluate the distribution of alpha-smooth muscle actin (alpha-SMA) positive cells in various liver diseases, we undertook an immunohistochemical study of liver diseases including chronic persistent hepatitis, chronic active hepatitis, liver cirrhosis, intrahepatic cholelithiasis and hepatocellular carcinoma. As a control, fetal livers (gestational age: 22-26 weeks) showed alpha-SMA positive cells along the blood vessels of the portal area, terminal hepatic venules and at perisinusoidal spaces. Perisinusoidal alpha-SMA positive cells were bipolar shaped and had round nuclei. In chronic persistent hepatitis, a few alpha-SMA positive cells were admixed with the inflammatory infiltrates mostly along the intact limiting plate. They were also detected multifocally in a linear pattern along the dilated sinusoid. In chronic active hepatitis, very strong alpha-SMA staining was detected at the site of piecemeal necrosis and adjacent lobules. A-SMA expression was decreased in some cases after interferon treatment. In cases of transplanted liver biopsies, expression of intralobular alpha-SMA was diffusely increased but showed no correlation with degree of acute rejection. Cirrhotic livers revealed strong alpha-SMA positivity in fibrous septae as well as in the perisinusoidal space of intact hepatocytes at the leading edge of fibrosis. Interlobular bile ducts were concentrically circumscribed by alpha-SMA positive cells in cases of intrahepatic cholelithiasis. In trabecular type hepatocellular carcinomas, most sinusoidal lining cells were positive for alpha-SMA. Most intralobular alpha-SMA positive cells represent, if not all, perisinusoidal cells (PSCs) which are involved in intralobular fibrogenesis in various liver diseases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of alpha-smooth muscle actin in liver diseases. 830 44

We investigated the response of macrophages and perisinusoidal (Ito) cells (PSCs) during the development of secondary biliary cirrhosis after ligation and division of the common bile duct. Liver tissue was obtained from three groups of male Wistar rats: 1) untreated controls (n = 3); 2) common bile duct-ligated (CBDL) animals (n = 15); and 3) sham-operated controls (n = 15). Material from animal groups 2 and 3 was obtained on days 3, 7, 14, 21, and 28 after operation; in all animals 5-bromo-2-deoxyuridine was administered intraperitoneally before death. Monocytes and macrophages were detected using the monoclonal antibody ED1 and tissue macrophages using the antibody ED2. Cell proliferation within the macrophage population was demonstrated by double labeling for ED2 and incorporated 5-bromo-2-deoxyuridine. PSCs were demonstrated in tissue sections by immunolocalization of desmin; proliferating PSCs were identified by double labeling for desmin and incorporated 5-bromo-2-deoxyuridine. Evidence of phenotypic modulation of PSCs was sought using anti-alpha-smooth muscle actin (alpha-SMA) antibody. Increased numbers of ED1- and ED2-positive cells were seen in CBDL animals at all time points. Local proliferation of macrophages could be identified and reached a peak at day 3, thereafter falling toward control values. Compared with those of controls, livers of CBDL animals showed increased numbers of desmin-positive PSCs in periportal zones from day 3 on, reaching a peak at day 14 (127.8 +/- 10.99 cells/0.635 mm2) and followed by a plateau. PSC proliferation peaked at days 3 and 7 (labeling indices 11.2% and 11.2%, respectively) and thereafter fell toward control values; no expansion of the PSC population was seen in sham-operated rats. Increased alpha-SMA-positive cells were also noted from day 3, with a peak at day 21 (231.1 +/- 11.52 cells/0.635 mm2) and followed by a plateau. En face labeling experiments in days 14, 21, and 28 CBDL animals showed cells co-expressing alpha-SMA and desmin and cells expressing alpha-SMA alone. These results indicate that in response to chronic cholestatic liver injury, PSCs proliferate and undergo phenotypic modulation toward "myofibroblast-like" cells. The kinetics of the response are similar to those of the ED2-positive cell population in keeping with a hypothesis that PSC proliferation and activation may be mediated by factors released by macrophages in response to various forms of liver injury. We conclude that the responses of macrophages and PSCs to cholestatic injury are similar to those after toxin-induced hepatocyte necrosis.
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PMID:In vivo responses of macrophages and perisinusoidal cells to cholestatic liver injury. 843 46

Circulating hyaluronan is mostly derived from lymph, fibroblast and Ito cells in the liver, and more than 90% of hyaluronan is degraded in hepatic sinusoidal endothelial cells. Thus, elevated serum hyaluronan is regarded as an indication of hepatic fibrosis with activated Ito cells and dysfunctional sinusoidal endothelial cells. We studied the distribution of hyaluronan in human liver sinusoids to determine the influences on elevated hyaluronan levels in sera. Histochemical examination was made using hyaluronan-binding protein (HABP) and serial sections of liver tissue for staining of alpha-smooth muscle actin (ASMA) (an indicator of activated Ito cells) and of ulex europaeus agglutinin I lectin (UEA-1) (closely related to hepatic sinusoidal capillarization). Positive staining, indicating the presence of hyaluronan, was noted in fibrous regions around the portal tracts, areas of focal necrosis in the liver parenchyma, and walls of the sinusoids in chronic hepatitis. In this group, hyaluronan-positive areas corresponded to positive ASMA staining and faint staining of UEA-1. On the contrary, in liver cirrhosis, UEA-1-positive areas were essentially identical to hyaluronan-positive areas and to ASMA-negative areas in sinusoidal walls. Hyaluronan and ASMA could be detected in the same areas of sinusoidal walls in chronic hepatitis, but not in liver cirrhosis. Hyaluronan appears to be mainly related to the staining of activated Ito cells in chronic hepatitis. Therefore, we concluded that in chronic hepatitis, the production of hyaluronan was accelerated in Ito cells; however, degradation of hyaluronan by sinusoidal endothelial cells continued. On the contrary, in liver cirrhosis, hyaluronan production decreased in Ito cells, and a marked transformation of sinusoidal endothelial cells with hepatic sinusoidal capillarization indicated loss of the ability to degrade hyaluronan. These different mechanisms in chronic hepatitis and liver cirrhosis may operate in the sinusoidal walls and may cause the elevation of hyaluronan in sera.
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PMID:Localization of hyaluronan in human liver sinusoids: a histochemical study using hyaluronan-binding protein. 902 14

The hepatic stellate (Ito) cell lies within the space of Disse and has a variety of functions. Stellate cells store vitamin A in characteristic lipid droplets. In the normal human liver, the cells can be identified by the presence of these lipid droplets; in addition, many stellate cells in the normal liver express alpha-smooth muscle actin. In acute liver injury, there is an expansion of the stellate cell population with increased alpha-smooth muscle actin expression; stellate cells appear to play a role in extracellular matrix remodelling after recovery from injury. In chronic liver injury, the stellate cell differentiates into a myofibroblast-like cell with marked expression of alpha-smooth muscle actin and occasional expression of desmin. Myofibroblast-like cells have a high fibrogenic capacity in the chronically diseased liver and are also involved in matrix degradation. In vitamin A intoxication, hypertrophy and proliferation of the stellate and myofibroblast-like cells may lead to non-cirrhotic portal hypertension, fibrosis and cirrhosis. In liver tumours, myofibroblast-like cells are involved in the capsule formation around the tumour and in the production of extracellular matrix within it. The transition of stellate cells into myofibroblast-like cells is regulated by an intricate network of intercellular communication between stellate cells and activated Kupffer cells, damaged hepatocytes, platelets, endothelial and inflammatory cells, involving cytokines and nonpeptide mediators such as reactive oxygen species, eicosanoids and acetaldehyde. The findings suggest that the stellate cell plays an active role in a number of human liver diseases, with a particular reactivity pattern in fibrotic liver disorders.
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PMID:The hepatic stellate (Ito) cell: its role in human liver disease. 909 76

In the liver of humans, guinea pigs, cats, and tupaia, nerve endings are distributed all over the hepatic lobules from the portal spaces to the centralobular spaces. Nerve endings in the intralobular spaces are located mainly in the space of Disse, and are closely related to lipocytes. In the human liver, various neurotransmitters such as substance P (SP) exist in the nerve endings. Lipocytes are believed to contract through these substances. In fact, the contraction of lipocytes is induced by SP. Moreover, lipocytes possess endothelin (ET) receptors (ETA, ETB), and the cells are contracted by ET-1 by way of ET receptors in the autocrine or paracrine mechanism. Contraction of lipocytes seems to be related to the enhancement of the intracellular Ca2+ and inositol phosphates. In addition, alpha-smooth muscle actin, which is a contractile protein, exists in the cytoplasm of lipocytes. Lipocyte contractility may be similar to that of vascular smooth muscle cells. On the other hand, prostaglandin E2, Iloprost, and adrenomedullin cause the elevation of c-AMP levels in lipocytes and relax the cells. In addition, lipocytes produce nitric oxide (NO) and inhibit contractility by an autocrine mechanism related to NO. In this way, lipocytes appear to be associated with the regulation of hepatic sinusoidal microcirculation by contraction and relaxation. In the cirrhotic liver, intralobular innervation is decreased or absent, but ET-1 and NO are overexpressed. These phenomena indicate that lipocytes may play an important role in the sinusoidal microcirculation through these agents rather than through intralobular innervation in liver cirrhosis.
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PMID:Intralobular innervation and lipocyte contractility in the liver. 910 92

Patients with chronic viral hepatitis are at high risk of developing cirrhosis, but the outcome of the disease in a given patient is unpredictable. Hepatic stellate cells have been demonstrated to be the most important cell type involved in hepatic fibrogenesis, regardless of the cause of the liver injury. The alpha isotype of actin (a phenotypic marker of smooth muscle cells) may be expressed by hepatic stellate cells, reflecting their "activation" to myofibroblast-like cells. The present study aimed to analyze the expression of alpha-smooth muscle actin-positive hepatic stellate cells in liver allografts with recurrent viral hepatitis, and to evaluate whether and how such expression may be related to the outcome of the disease. Using immunohistochemistry and a semi-quantitative scoring system, the expression of a-smooth muscle actin in hepatic stellate cells was analyzed in liver allografts of 17 patients with recurrent viral hepatitis. They included nine patients who developed cirrhosis at the end of follow-up (mean time 23.6 months), and eight patients with no cirrhosis at the end of a comparable follow-up time (mean 30.1 months). In all patients, liver biopsy specimens were obtained between 3 and 6 months (t1) and between 10 and 15 months (t2) after transplantation. Preperfusion biopsy specimens of donor livers served as a baseline (t0). By comparison with the baseline biopsy, an increased number of alpha-smooth muscle actin-expressing hepatic stellate cells was observed in all cases in t1 biopsies. An increase in the amount of alpha-smooth muscle actin-positive hepatic stellate cells in zone 1 at t1 was significantly (P < .006) related to subsequent cirrhotic evolution. In conclusion, in liver allografts with recurrent viral hepatitis, the activation of hepatic stellate cells is an early event. An increased number of alpha-smooth muscle actin-positive hepatic stellate cells in zone 1 may represent an unfavorable event related to cirrhotic evolution.
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PMID:Hepatic stellate cell immunodetection and cirrhotic evolution of viral hepatitis in liver allografts. 925 39


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