Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that monocyte aryl hydrocarbon hydroxylase (AHH) activity is depressed in patients with liver disease and is decreased more in cirrhosis than in early stage liver disease. To determine if monocyte AHH activity reflects liver AHH activity, we studied an animal model of cirrhosis, i.e., yellow phosphorus induced cirrhosis in the pig. AHH activity was detectable in monocytes isolated from peripheral blood of normal pigs (0.32 +/- 0.13 nmol.mg-1 P.h-1, n = 11) and was comparable to the level of AHH activity in hepatic Kupffer cells isolated from wedge or needle biopsies of livers of normal pigs (0.38 +/- 0.21, n = 7). The AHH level in pig Kupffer cells was approximately 10% of the AHH level in hepatocytes and microsomes. To induce liver disease, pigs were administered yellow phosphorus (0.6 mg/kg) 5 days per week for 16 weeks. At 4 weeks of treatment, monocyte AHH activity was not different from control and liver histology was normal. Depression of monocyte AHH activity was evident at 8 weeks of treatment when liver fibrosis was seen histologically. At 12 weeks of treatment when histology revealed extensive liver fibrosis and collagen levels were elevated, the level of monocyte AHH activity was decreased 67% compared with controls. Similar changes were observed at 12 weeks in Kupffer cell AHH activity (86% decrease) and hepatocyte AHH activity (70% decrease) compared with controls. These results suggest that monocyte AHH activity reflects liver AHH activity and may be a good indicator of change in liver enzyme function in liver disease in the pig model of cirrhosis.
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PMID:Monocyte aryl hydrocarbon hydroxylase (AHH) activity mimics Kupffer cell and hepatocyte AHH activity in an animal model of liver disease. 180 52

Liver fibrosis is a complex process characterized by two major events: fibroproliferation and increased collagen synthesis. The exact role of cytokines in the pathogenesis of hepatic fibrosis remains to be established, but platelet-derived growth factor clearly stimulates proliferation of fibroblasts and increases collagen synthesis. In in vitro studies, pentoxifylline, a methylxanthine, significantly reduced platelet-derived growth factor-driven proliferation of fibroblasts. Platelet-derived growth factor has also been identified as a fibroproliferative factor produced spontaneously by monocytes obtained from patients with liver disease. Long-term administration of pentoxifylline (16 mg/kg orally, 5 days/wk for 12 wk) in an animal model of liver fibrosis prevented elevations in gamma-glutamyl transpeptidase and alkaline phosphatase levels and prevented the reduction in serum albumin level normally observed in this animal model of liver disease. The animal model used was a long-term, low-dose yellow phosphorus--induced model in pigs that reproducibly results in extensive fibrosis after 10 to 12 wk of treatment. Long-term administration of pentoxifylline also prevented the histological changes characteristic of fibrosis in this animal model. Collagen concentration was significantly elevated in liver sections obtained from animals receiving yellow phosphorus, compared with controls. Long-term pentoxifylline treatment resulted in significantly lower collagen concentrations in liver sections from animals receiving yellow phosphorus than in sections from animals receiving yellow phosphorus alone; this was supported by histological observation. Therefore administration of pentoxifylline prevented the biochemical and histological changes associated with an animal model of liver disease. Pentoxifylline will likely have an important therapeutic role in liver fibrosis.
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PMID:Pentoxifylline prevents fibrosis in an animal model and inhibits platelet-derived growth factor-driven proliferation of fibroblasts. 809 47

Fibroblast proliferation and extracellular matrix accumulation are two major events occurring in fibrosis. Hepatic stellate cells are the major collagen-producing cells of the liver and are transformed into proliferative myofibroblasts following activation. Whether proliferation and extracellular matrix production are regulated by the same cytokines is not known. Monocyte-conditioned medium obtained from pigs with yellow phosphorus-induced hepatic fibrosis increased the collagen production by cultured procine myofibroblasts. Liver biopsies from these same fibrotic animals had increased levels of collagen alpha 1(I) and alpha 1(III) mRNA compared to control animals. Preincubation with platelet-derived growth factor (PDGF) B/B antibody significantly reduced the collagen-stimulating ability of the monocyte-conditioned medium. Recombinant PDGF stimulated proliferation in nonconfluent myofibroblasts and stimulated collagen production in confluent cultures of myofibroblasts without increasing cell number, suggesting that these events can occur independent of each other. Pentoxifylline and one of its active metabolites (metabolite-1) inhibited PDGF-stimulated collagen production in cultured porcine myofibroblasts. These results demonstrate the importance of PDGF in the pathogenesis of liver fibrosis and provide evidence that pentoxifylline interferes with PDGF-mediated events during experimental liver fibrosis.
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PMID:Platelet-derived growth factor and pentoxifylline modulation of collagen synthesis in myofibroblasts. 951 34