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)

Endotoxin sensitivity varies among animal species and appears to correlate with the presence of pulmonary intravascular macrophage (PIM). In rats, which lack PIM, we investigated the hypothesis that chronic cholestatic liver injury leads to induction of PIM and endotoxin sensitivity. Rats were randomized to either common bile duct ligation (BDL) or sham-surgery and studied at 1 wk (acute cholestasis), 2 wk (cholestasis, early cirrhosis), and 4 wk (cholestasis, established cirrhosis) after surgery. Intravascularly injected fluorescent latex microspheres (1 micron diameter) were taken up by large phagocytic cells in lung parenchyma of BDL rats (at 2 and 4 wk), while no uptake was observed in lungs from control rats. Electronmicroscopy revealed accumulation of large, mononuclear, macrophage-like cells containing ingested latex particles within the pulmonary capillaries. Pulmonary intravascular phagocytosis, as reflected in lung uptake of 99mTc microaggregated albumin (Microlite, mean particle diameter = 1 micron), averaged 0.7 +/- 0.1% (mean +/- SEM) of total injected dose in 13 control rats and progressively increased with time after BDL (1 wk, 1.7 +/- 0.2%; 2 wk, 10.0 +/- 3.0%; 4 wk 35.1 +/- 5.9%). Rats with biliary cirrhosis were markedly sensitive to the lethal effects of low dose endotoxin and demonstrated marked lung edema at the time of death. Furthermore, the lung uptake of intravascular 125I-lipopolysaccharide was increased five-fold in cirrhotic rats. We conclude that chronic biliary obstruction leads to the induction of pulmonary intravascular phagocytes and enhances endotoxin sensitivity in rats. Pulmonary intravascular phagocytosis in patients with advanced cirrhosis may account for their increased susceptibility to sepsis-induced adult respiratory distress syndrome.
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PMID:Chronic biliary obstruction induces pulmonary intravascular phagocytosis and endotoxin sensitivity in rats. 796 47

In order to clarify the role of endotoxin in acute tubular necrosis in liver cirrhosis, lipopolysaccharide (LPS) was injected to rats with liver injury with exposure to carbon tetrachloride (CCl4) inhalation. Rats showed liver cirrhosis with ascites retention after 10 weeks' CCl4 treatment and liver fibrosis after 6 weeks' CCl4 treatment. Histopathological grading of kidney injuries after LPS treatment was more severe either in cirrhotic rats or in liver fibrotic rats than in normal rats. All cirrhotic rats had severe acute tubular necrosis after either dose of LPS, but only small necrotic foci of tubuli were seen in a few normal and liver fibrotic rats. The results indicate that endotoxin, which overflows due to disturbance of inactivation in the cirrhotic liver, may contribute to acute tubular necrosis. This effect of endotoxin is supposed to be a direct hemodynamic damage.
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PMID:Endotoxin-induced acute tubular necrosis in cirrhotic rats. 815 14

The steady-state levels of extracellular matrix proteins are regulated by the rates of their synthesis and degradation. Metalloproteinases and their specific inhibitors, tissue inhibitor of metalloproteinases-1 and -2 are believed to play a crucial role in extracellular matrix protein degradation. Here we show that the tissue inhibitor of metalloproteinases-1 is expressed in rat hepatocytes in primary culture and regulated by inflammatory cytokines. Rat hepatocytes constitutively express mRNA of tissue inhibitors of metalloproteinases-1 at a low level. Incubation with conditioned medium from lipopolysaccharide-stimulated human monocytes led to a dramatic induction of mRNA of tissue inhibitors of metalloproteinases-1. The inflammatory cytokines interleukin-1 beta, interleukin-6, interleukin-11, leukemia inhibitory factor and ciliary neurotrophic factor were also capable of stimulating expression of mRNA of tissue inhibitors of metalloproteinases-1. Among these cytokines interleukin-6 was the most potent stimulator. The combination of interleukin-1 beta, interleukin-6 and interleukin-11 synergistically up-regulated mRNA of tissue inhibitors of metalloproteinases-1. The synthetic glucocorticoid dexamethasone dose dependently inhibited constitutive and interleukin-6-induced expression of tissue inhibitors of metalloproteinases-1. A possible involvement of tissue inhibitor of metalloproteinases-1 in the pathogenesis of liver fibrosis and cirrhosis is discussed.
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PMID:Regulation of tissue inhibitor of metalloproteinases-1 gene expression by cytokines and dexamethasone in rat hepatocyte primary cultures. 824 70

In rats with CCl4-induced liver cirrhosis, a twofold decrease of blood clearance rate and a fourfold reduction in number of Kupffer cells taking up colloidal carbon particles has been demonstrated. Zymosan stimulation does not lead to granuloma-like structures in the liver of CCl4-cirrhotic rats. In cirrhotic rats, unlike controls, the cathepsin D activity of liver tissue is very little increased by zymosan treatment and there is virtually no increase in collagenolytic activity. The increase in PGE content in cirrhotic rat liver after prodigiosan stimulation was 2.5 times less than in stimulated control animals. In cirrhotic rats, the IL-1 producing capacity of blood monocytes in vitro in response to lipopolysaccharide drops almost fivefold. The total count of bone marrow-derived myeloid colonies in cirrhotic zymosan-stimulated animals was reduced by 1.5-fold whereas in control animals zymosan induced a 1.8-fold increase in the number of myeloid colonies. The number, uptake and nitroblue tetrazolium-reducing capacities of lung, spleen, peritoneal and bone marrow macrophages in animals with liver cirrhosis were only slightly increased in response to zymosan as compared to control animals. The low response of extrahepatic macrophages to stimuli in cirrhotic animals is thought to be due to their premobilization during the development of cirrhosis.
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PMID:Mononuclear phagocyte system responsiveness in CCl4-induced liver cirrhosis. 833 74

We performed a liver biopsy and measured plasma concentrations of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha), and spontaneous and lipopolysaccharide-stimulated in vitro monocyte production of IL-1 beta and TNF-alpha in 19 obese and 17 age-matched, normal-weight alcoholics admitted for treatment of their alcoholism. Nine healthy normal-weight alcoholics had cirrhosis in their liver biopsy (Fisher's exact test: P=0.031). A histologic score (derived from the sum of fat, necrosis, fibrosis, and inflammation in the biopsy) correlated with body mass index and the percentage body fat, calculated by using the sum of four skinfold-thickness measures. Plasma concentrations and spontaneous in vitro monocyte production of IL-1 beta and TNF-alpha were below detection limits. No significant differences were observed between normal-weight and obese alcoholics with or without cirrhosis and normal control subjects in lipopolysaccharide-stimulated monocyte production of IL-1 beta (6.5 +/- 0.8, 10.1 +/- 2.7, 7.9 +/- 1.6, and 5.28 +/- 4.24 micrograms/L, respectively) or TNF-alpha (2.8 +/- 0.4, 3.7 +/- 1.0, 3.0 +/- 0.44, and 1.97 +/- 1.01 micrograms/L, respectively). However, a positive correlation was found between IL-1 beta production and body mass index (r=0.333, P=0.047), percentage body fat (r=0.412, p=0.013), abdominal circumference (r=0.416, P=0.012), and total histologic score (r=0.331, P=0.049). A multiple-regression model accepted abdominal circumference as the only independent predictor of IL-1 beta production. TNF-alpha did not correlate with any of the above-mentioned indexes. We conclude that obese alcoholics have a higher frequency of histologic liver damage and that IL- 1 beta production by stimulated monocytes is related to abdominal fat accumulation.
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PMID:Interleukin 1 and tumor necrosis factor in obese alcoholics compared with normal-weight patients. 860 95

Elevated concentrations of lipopolysaccharide have been found in serum of patients with severe parenchymal liver disease and its toxic effect is thought to involved in hemodynamic disturbances seen in cirrhosis. A soluble form of the receptor (sCD14) for lipopolysaccharide is present in serum and is released by stimulated macrophages, indicating macrophage activation. We investigated sCD14 serum levels and in vitro production by lipopolysaccharide stimulated peripheral blood monocytes in patients with various liver diseases. In acute viral hepatitis serum sCD14 levels were significantly higher during the first 2 weeks after onset of jaundice (n=11; 3.6 +/- 0.9 microg /ml (mean +/- SD)) than in healthy control individuals (n=52; 2.5 +/- 0.7 microg/ml; p<0.001). These elevated serum levels corresponded to enhanced in vitro production of sCD14 by lipopolysaccharide-stimulated peripheral blood monocytes (n=11; 365 +/- 262 ng/ml) as compared to control monocytes (n=52; 228 +/- 74 ng/ml; p=0.02). Similarly, patients with alcoholic cirrhosis had significantly increased sCD14 serum levels (n=31; 4.5 +/- 3.2 microg/ml; p<0.001) and in vitro sCD14 production by lipopolysaccharide-stimulated monocytes (291 +/- 153 ng/ml; p=0.014). Serum sCD14 levles correlated with the severity of disease (Child A: 2.6 +/- 1.0 microg/ml; Child B: 4.4 +/- 2.1 microg/ml; Child C: 7.8 +/- 5.1 micro/ml; Anova: p=0.001). Patients with chronic viral hepatitis had only slightly elevated serum sCD14 levels (n=17; 2.9 +/- 0.7 microg/ml; p=0.01) and increased in vitro production of sCD14 by peripheral blood monocytes (320 +/- 128 ng/ml; p<0.001). The elevated serum concentration of sCD14 in alcoholic cirrhosis and acute and chronic viral hepatitis points to an incrased macrophage activation in these diseases. sCD14 from serum is able to associate with cells not expressing membrane CD14, such as endothelial cells, allowing those cells to bind and respond to lipopolysaccharide. Elevated levels of sCD14 could in this way contribute to the toxic effects of lipopolysaccharide in severe liver disease.
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PMID:Increased in vitro production and serum levels of the soluble lipopolysaccharide receptor sCD14 in liver disease. 865 56

Nitric oxide (NO) is postulated to mediate the peripheral arterial vasodilation in cirrhosis. However, it is not known which isoform of the nitric oxide synthase (NOS) is involved in the increased production of NO. This study was therefore undertaken to examine the expression of the NOS isoforms in arteries of cirrhotic rats compared with controls. Cirrhosis was induced by CCl4, and vessels were harvested for immunoblots using antibodies against inducible NOS (iNOS) and endothelial constitutive NOS (ecNOS). Endothelial cells were used as controls for ecNOS, and vascular smooth muscle cells treated with lipopolysaccharide or septic rats were used for iNOS controls. The results demonstrated an upregulation of ecNOS in both the aortas and mesenteric arteries of cirrhotic compared with control rats. Chronic inhibition of NOS decreased ecNOS in cirrhotic vessels. Although iNOS mRNA was found by reverse transcription-polymerase chain reaction in arteries of cirrhotic rats, iNOS protein was not detectable by immunoblotting compared with septic rats, suggesting a low vascular level of this isoform. In conclusion, the ecNOS seems to play a major role in the increased NO production in cirrhotic rats, whereas the role of iNOS remains elusive.
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PMID:Upregulation of endothelial constitutive NOS: a major role in the increased NO production in cirrhotic rats. 878 Feb 53

Nitric oxide (NO) production via inducible NO synthase (iNOS) is prominent in the liver after stimulation with cytokines and/or lipopolysaccharide. The aim of this study was to investigate the production of NO via iNOS in specific liver cell populations during toxin-mediated and obstructive hepatic injury and fibrogenesis. After a single dose of carbon tetrachloride, iNOS mRNA and nitrite (a metabolic product of NO) were detected only in Kupffer cells. They were not detectable in any cell type after recurrent administration of carbon tetrachloride, including in animals with far advanced cirrhosis (i.e., portal hypertension and/or ascites). After bile duct ligation, a mechanistically different form of liver injury and fibrogenesis, iNOS mRNA and nitrite were identified in all nonparenchymal cells but not in hepatocytes. Twenty-four hours after bile duct ligation, iNOS mRNA and NO production were greatest in Kupffer cells, but after prolonged bile duct ligation, iNOS was found predominantly in sinusoidal endothelial cells. These data indicate that iNOS expression varies temporally and spatially in the liver after injury and also varies with the type of insult.
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PMID:Regulation of inducible nitric oxide synthase and nitric oxide during hepatic injury and fibrogenesis. 925 18

Activated hepatic stellate cells (HSC) participate in matrix remodeling and deposition in liver fibrosis. The present study demonstrates that interleukin (IL)-10 is expressed by HSC upon activation in vitro or in vivo and that autocrine effects of this cytokine include inhibition of collagen production. Culture activation of HSC caused a distinct increase in IL-10 mRNA level compared with freshly isolated quiescent HSC. Treatment of cultured HSC with tumor necrosis factor-alpha, transforming growth factor-beta, or lipopolysaccharide further increased IL-10 mRNA by 2-fold and resulted in the release of IL-10 protein into the medium. HSC isolated from rats after bile duct ligation (BDL) showed prominent increases in IL-10 mRNA (x 100) and protein (x 30) levels at 7 days after BDL, but such induction disappeared in advanced liver fibrosis (19 days after BDL). IL-10 expression correlated positively with mRNA expression of interstitial collagenase and inversely with that of alpha1(I) collagen. Addition of anti-IL-10 IgG to cultured HSC caused enhanced collagen production under a basal or stimulated condition with TGF-beta, tumor necrosis factor-alpha, or lipopolysaccharide. These effects were associated with increased alpha1(I) collagen mRNA and reciprocally reduced collagenase mRNA levels. Co-transfection of HSC with an IL-10 expression vector and collagen reporter genes showed a 40% inhibition of alpha1(I) collagen promoter activity. These results demonstrate that activation of HSC causes enhanced autocrine expression of IL-10 which possesses a negative autoregulatory effect on HSC collagen production mediated at least in part by alpha1(I) collagen transcriptional inhibition and stimulation of collagenase expression. These findings, along with the demonstrated early induction of HSC IL-10 expression and its late disappearance during biliary liver fibrosis, suggest its in vivo role in matrix remodeling and a possibility that failure for HSC to sustain IL-10 expression underlies pathologic progression to liver cirrhosis.
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PMID:Expression of interleukin-10 by in vitro and in vivo activated hepatic stellate cells. 941 80

Kupffer cells (KC) play a central role in the initiation and perpetuation of hepatic inflammation, which, if uncontrolled, can result in tissue damage, fibrosis, and cirrhosis. Interleukin-10 (IL-10) can inhibit a range of macrophage functions. We hypothesized that the transcription, synthesis, and release of IL-10 may influence the development of liver injury. Rat KC were activated in vitro with lipopolysaccharide (LPS), and expression of IL-10 mRNA compared with IL-13 and IL-1beta by reverse-transcription polymerase chain reaction (RT-PCR). The effects of pretreatment with recombinant IL-10 (rIL-10) on KC phagocytosis, production of superoxide (SO), and tumor necrosis factor (TNF-) were examined by fluorescent activated cell sorter (FACS), reduction of ferricytochrome C, and bioassay, respectively. Rats were administered intraperitoneal carbon tetrachloride (CCl4), and expression of IL-10 mRNA and protein in vivo compared with IL-13 and IL-1beta by RT-PCR and immunoblotting. Results were correlated with histological inflammatory changes. Finally, IL-10 gene-deleted (IL-10-/-) mice and wild-type (WT) controls were administered intraperitoneal CCl4 biweekly for up to 70 days, and the development of inflammation and fibrosis compared by scoring histological changes. IL-10 mRNA was up-regulated early, both in KC in vitro and in whole liver in vivo, concurrent with that of IL-1beta. IL-10 was able to inhibit KC production of both SO and TNF- in vitro, and this was achieved more effectively than IL-4 or IL-13; no such effects were seen on KC phagocytosis. After 70 days of treatment with CCl4, IL-10-/- mice showed significantly more severe fibrosis and exhibited higher hepatic TNF- levels than WT controls. These results suggest that IL-10 synthesized during the course of liver inflammation and fibrosis may modulate KC actions, and influence subsequent progression of fibrosis.
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PMID:Interleukin-10 expression and function in experimental murine liver inflammation and fibrosis. 982 39


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