Accumulation and cellular localization of fibrinogen/fibrin during shortterm and longterm rat liver injury

Neubauer, Katrin; Knittel, Thomas; Armbrust, Thomas; Ramadori, Giuliano

doi:10.1016/0016-5085(95)90211-2

Cited by 119 publications

(106 citation statements)

References 40 publications

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“…Regarding MMP-1, it is expressed at low levels in the liver and is not upregulated in the course of fibrosis. On the other hand, there is evidence that thrombin is generated in fibrotic liver, as evidenced by the presence of fibrin deposition in experimental injury (31) or human disease (28). Thus, although the role of alternative PAR-1 ligands cannot be completely excluded, most evidence points to thrombin as being the active PAR-1 ligand in this setting.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of hemostasis would result in the occurrence of fibrin deposition and microthrombi in the liver parenchyma (31), leading to hypoxia and subsequent fibrogenesis (10,37). However, PAR-1 signaling is known to result in the increased expression of a series of extracellular matrix molecules (7,17) and profibrogenic mediators such as connective tissue growth factor (CTGF) (8) or monocyte chemotactic protein (MCP)-1 (26) and could thus account for the profibrogenic effect of thrombin.…”

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confidence: 99%

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Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis

Rullier

Gillibert-Duplantier²,

Costet³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Thrombin inhibition protects against liver fibrosis. However, it is not known whether the thrombin profibrogenic effect is due to effects on blood coagulation or to signaling via protease-activated receptors (PARs). We took advantage of the lack of blood coagulation defects in PAR-1-knockout mice. Acute carbon tetrachloride (CCl4) toxicity was similar in wild-type (WT), PAR-1−/−, and PAR-1+/−mice as judged by aminotransferase levels, area of liver necrosis, and liver peroxidation measured by Fourier-transformed infrared spectroscopy. Fifteen mice/group received CCl4or its solvent for 6 wk (300 μl/kg, 3 times a week). Fibrosis area was increased 10-fold by CCl4treatment in WT mice. PAR-1 deficiency protected against fibrosis, with 36% and 56% decrease in PAR-1+/−and PAR-1−/−mice, respectively ( P < 0.001). Similar results were obtained for area of activated fibrogenic cells (64% and 79% decrease in PAR-1+/−and PAR-1−/−mice, respectively, P < 0.001). These findings were corroborated by measurements of type I collagen, matrix metalloproteinase-2, and PDGF-β receptor mRNA levels. There was also a significant decrease in T lymphocyte infiltration in PAR-1-deficient mice. Altogether, these results suggest that thrombin profibrogenic effects are independent of effects on blood coagulation and are instead due to direct effects on fibrogenic cells and possibly on T lymphocytes.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis

Rullier

Gillibert-Duplantier²,

Costet³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…9 However, the molecular similarities to the wound-healing process 10,11 and the observation that matrix-producing cells undergo apoptosis 5,12,13 strongly suggested that some matrix deposits might disappear when the damaging noxae are eliminated or inflammation is suppressed as by corticosteroids 2,14-17 ( Figure 1). …”

Section: Liver Damage and Repairmentioning

confidence: 99%

Portal tract fibrogenesis in the liver

Ramadori

Saile

2004

Laboratory Investigation

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171

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The portal area is the 'main entrance' and one of the two main exits of the liver lobule. Through the main entrance portal and arterial blood reach the liver sinusoids. Through the exit the bile flows towards the duodenum. The three main structures, portal vein and artery with their own wall (and vascular smooth muscle cells) and bile duct with its basal membrane, are surrounded by loose myofibroblasts and by the first layer of hepatocytes and non-parenchymal cells. Chronic diseases of the liver can lead to development of liver cirrhosis, characterized by formation of fibrotic septa which can be portal-portal in the case of the chronic biliary damage or portal-central in the case of the chronic viral hepatitis. Central-central septa can also be observed under other pathological conditions. When damaging noxae are introduced to the liver, inflammatory cells are first recruited to the portal field, the first layer of hepatocytes may be destroyed (enlargement of the portal field) and portal (myo)fibroblasts become activated. A similar reaction may take place when the target of inflammation is the bile duct with consecutive reduction of the bile flow, activation of the portal (myo)fibroblasts, proliferation of bile ducts and destruction of the hepatocytes around the portal field. Increased matrix deposition may be the consequence. During the past years several publications dealt with the pathomechanisms of portal fibrogenesis as well as with its resolution. One of the most intriguing observations was that it is not hepatic stellate cells of the hepatic sinusoid, but portal (myo)fibroblasts which rapidly acquire the phenotype of 'activated' (myo)fibroblastas in the early stages of cholestatic fibrosis. These may also become the main mesenchymal cells of the porto-portal or porto-central fibrotic septa. This article reviews the similarities as well as differences between the mesenchymal cells of the portal tract and of the fibrotic septa vs 'activated' stellate cells of the hepatic sinusoids, and discusses the debate over their relative contributions to liver fibrogenesis.

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“…Here, the longstanding yet untested hypothesis in the field is that fibrin matrices formed as a consequence of injury/disease-triggered coagulation, enhance inflammatory cell (ie, leukocyte) activity leading to liver fibrosis. 18 This concept is anchored in the non-hemostatic functions of fibrin polymers, including engagement of the leukocyte integrin a M b 2 , which amplifies inflammation and tissue injury in many other disease settings. [19][20][21][22][23] Notably, however, the precise function of the fibrin(ogen)-leukocyte integrin a M b 2 interaction has never been evaluated in experimental hepatic injury.…”

Section: Introductionmentioning

confidence: 99%

Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism

Joshi¹,

Kopec

Ray

et al. 2016

Blood

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Accumulation and cellular localization of fibrinogen/fibrin during shortterm and longterm rat liver injury

Cited by 119 publications

References 40 publications

Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis

Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis

Portal tract fibrogenesis in the liver

Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism

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