Direct effects of alcohol on hepatic fibrinolytic balance: Implications for alcoholic liver disease

Seth, Devanshi; Hogg, Philip J.; Gorrell, Mark D.; McCaughan, Geoffrey W.; Haber, Paul S.

doi:10.1016/j.jhep.2007.12.015

Cited by 48 publications

(39 citation statements)

References 37 publications

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“…Alcohol might affect hemostasis by inducing dietary deficiencies which impair megakaryocyte maturation, inhibit platelet aggregation, and reduce global fibrinolytic capacity [51][52][53][54][55]. Definite evidence for impaired fibrinolysis in alcohol misusers is still needed, as previous studies assessed single components of the fibrinolytic system.…”

Section: Factors Tipping the Hemostatic Balance In Cirrhosismentioning

confidence: 99%

Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference

Andriulli

Tripodi

Angeli

et al. 2016

Digestive and Liver Disease

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a b s t r a c tPatients with cirrhosis present with hemostatic alterations secondary to reduced availability of procoagulant and anti-coagulant factors. The net effect of these changes is a rebalanced hemostatic system. The Italian Association of the Study of the Liver (AISF) and the Italian Society of Internal Medicine (SIMI) promoted a consensus conference on the hemostatic balance in patients with cirrhosis. The consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Rome in December 2014. The statements were graded according to quality of evidence and strength of recommendations, and approved by an independent jury. The statements presented here highlight strengths and weaknesses of current laboratory tests to assess bleeding and thrombotic risk in cirrhotic patients, the pathophysiology of hemostatic perturbations in this condition, and outline the optimal management of bleeding and thrombosis in patients with liver cirrhosis.

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Section: Factors Tipping the Hemostatic Balance In Cirrhosismentioning

confidence: 99%

Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference

Andriulli

Tripodi

Angeli

et al. 2016

Digestive and Liver Disease

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“…49 In terms of alcoholic liver diseases, increased parenchymal expression of ANXA2 and its fibrinolytic role were proposed. 13 We found expression of ANXA2 not only in the parenchymal hepatocytes of PBC and CHC liver, but also in the cholangioycytes of PBC. The subcellular localization of ANXA2 to the basolateral cell membrane of cholangiocytes or hepatocytes may be related to the fibrinolytic role of ANXA2 in the injured liver as a consequence of the activation of plasmin, leading to remodeling of the injured bile ducts.…”

Section: Discussionmentioning

confidence: 65%

“…In terms of alcoholic liver diseases, an increase of parenchymal ANXA2 expression and a fibrinolytic role in the liver has been proposed. 13 Apical expression of Cl À /HCO3 À anion exchanger-2 (AE2: SLC4A2 as an official gene symbol) plays a pivotal role in the regulation of the intracellular pH (pH i ) 14 in conjunction with the biliary HCO3 À secretion and bile formation by cholangiocytes. 15 Faint expression of AE2 in the cholangiocytes of PBC livers 16 may suggest some potential roles of AE in the development of PBC, which is further supported by cholangiopathy characterized by portal inflammation and bile duct injury observed in AE-deficient mice.…”

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confidence: 99%

Compensatory role of inducible annexin A2 for impaired biliary epithelial anion-exchange activity of inflammatory cholangiopathy

Kido

Fukushima

Ueno

et al. 2009

Laboratory Investigation

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The peribiliary inflammation of cholangiopathy affects the physiological properties of biliary epithelial cells (cholangiocyte), including bicarbonate-rich ductular secretion. We revealed the upregulation of annexin A2 (ANXA2) in cholangiocytes in primary biliary cirrhosis (PBC) by a proteomics approach and evaluated its physiological significance. Global protein expression profiles of a normal human cholangiocyte line (H69) in response to interferon-g (IFNg) were obtained by two-dimensional electrophoresis followed by MALDI-TOF-MS. Histological expression patterns of the identified molecules in PBC liver were confirmed by immunostaining. H69 cells stably transfected with doxycyclin-inducible ANXA2 were subjected to physiological evaluation. Recovery of the intracellular pH after acute alkalinization was measured consecutively by a pH indicator with a specific inhibitor of anion exchanger (AE), 4,4 0 -diisothiocyanatostilbene-2,2 0 -disulfonic acid (DIDS). Protein kinase-C (PKC) activation was measured by PepTag Assay and immunoblotting. Twenty spots that included ANXA2 were identified as IFNg-responsive molecules. Cholangiocytes of PBC liver were decorated by the unique membranous overexpression of ANXA2. Apical ANXA2 of small ducts of PBC was directly correlated with the clinical cholestatic markers and transaminases. Controlled induction of ANXA2 resulted in significant increase of the DIDS-inhibitory fraction of AE activity of H69, which was accompanied by modulation of PKC activity. We, therefore, identified ANXA2 as an IFNg-inducible gene in cholangiocytes that could serve as a potential histological marker of inflammatory cholangiopathy, including PBC. We conclude that inducible ANXA2 expression in cholangiocytes may play a compensatory role for the impaired AE activity of cholangiocytes in PBC in terms of bicarbonate-rich ductular secretion and bile formation through modulation of the PKC activity.

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“…Regulation of plasmin homeostasis through PAI-1 (Arteel, 2008;Seth et al, 2008) and other fibrinolysis regulating molecules, such as osteopontin (Opn) (Apte et al, 2005b;Seth et al, 2006a,b) are also some of the recent discoveries that provide insights in the common mechanisms involved in alcohol-induced organ injury. More recently, Opn is also suspected to have a role in alcohol-mediated lipid accumulation in the hepatocytes by modulating peroxisome-proliferator activated receptor alpha (PPAR-a) (Nath and Szabo, 2009).…”

Section: Novel Mechanisms Of Alcohol Injury In Diverse Organs and Tismentioning

confidence: 99%

“…The data from their study suggest a pro-fibrinolytic profile with exposure to low dose alcohol and a propensity for antifibrinolytic response with high-dose alcohol presumably, due to several log-fold increase in PAI-1 expression . Similarly, PAI-1 is strongly induced and is known to regulate ECM remodeling in experimental models of alcoholic as well as other forms of liver injury (Arteel, 2008;Bergheim et al, 2006;Seth et al, 2008). PAI-1 affects activity of MMPs further contributing to ECM remodeling (Bergheim et al, 2006;Ramos-DeSimone et al, 1999).…”

Section: Alcohol-induced Fibrogenesis Modulated Via Plasmin-plasminogmentioning

confidence: 99%

Alcohol, Signaling, and ECM Turnover

Seth

El-Guindy

Apte

et al. 2009

Alcoholism Clin & Exp Res

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Alcohol is recognized as a direct hepatotoxin, but the precise molecular pathways that are important for the initiation and progression of alcohol-induced tissue injury are not completely understood. The current understanding of alcohol toxicity to organs suggests that alcohol initiates injury by generation of oxidative and nonoxidative ethanol metabolites and via translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. With continuing alcohol abuse, the injury progresses through impairment of tissue regeneration and extracellular matrix (ECM) turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, the predominant being stellate cells, macrophages, and parenchymal cells. In response to alcohol, growth factors and cytokines activate many signaling cascades that regulate fibrogenesis. This mini-review brings together research focusing on the underlying mechanisms of alcohol-mediated injury in a number of organs. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, susceptibility to infection, ECM turnover and fibrogenesis in the liver, pancreas, and lung triggered by alcohol abuse.

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Direct effects of alcohol on hepatic fibrinolytic balance: Implications for alcoholic liver disease

Cited by 48 publications

References 37 publications

Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference

Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference

Compensatory role of inducible annexin A2 for impaired biliary epithelial anion-exchange activity of inflammatory cholangiopathy

Alcohol, Signaling, and ECM Turnover

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