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Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice.

ABSTRACT: The coagulation cascade has been shown to participate in chronic liver injury and fibrosis, but the contribution of various thrombin targets, such as protease activated receptors (PARs) and fibrin(ogen), has not been fully described. Emerging evidence suggests that in some experimental settings of chronic liver injury, platelets can promote liver repair and inhibit liver fibrosis. However, the precise mechanisms linking coagulation and platelet function to hepatic tissue changes following injury remain poorly defined.To determine the role of PAR-4, a key thrombin receptor on mouse platelets, and fibrin(ogen) engagement of the platelet ?II b ?3 integrin (?IIb ?3 ) in a model of cholestatic liver injury and fibrosis.Biliary and hepatic injury was characterized following 4 week administration of the bile duct toxicant ?-naphthylisothiocyanate (ANIT) (0.025%) in PAR-4-deficient mice, mice expressing a mutant form of fibrin(ogen) incapable of binding integrin ?II b ?3 (Fib?(?5) ), and wild-type mice.Elevated plasma thrombin-antithrombin and serotonin levels, hepatic fibrin deposition, and platelet accumulation in liver accompanied hepatocellular injury and fibrosis in ANIT-treated wild-type mice. PAR-4 deficiency reduced plasma serotonin levels, increased serum bile acid concentration, and exacerbated ANIT-induced hepatocellular injury and peribiliary fibrosis. Compared with PAR-4-deficient mice, ANIT-treated Fib?(?5) mice displayed more widespread hepatocellular necrosis accompanied by marked inflammation, robust fibroblast activation, and extensive liver fibrosis.Collectively, the results indicate that PAR-4 and fibrin-?II b ?3 integrin engagement, pathways coupling coagulation to platelet activation, each exert hepatoprotective effects during chronic cholestasis.

SUBMITTER: Joshi N

PROVIDER: S-EPMC4487795 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice.

Joshi N N Kopec A K AK O'Brien K M KM Towery K L KL Cline-Fedewa H H Williams K J KJ Copple B L BL Flick M J MJ Luyendyk J P JP

Journal of thrombosis and haemostasis : JTH 20141211 1

<h4>Background</h4>The coagulation cascade has been shown to participate in chronic liver injury and fibrosis, but the contribution of various thrombin targets, such as protease activated receptors (PARs) and fibrin(ogen), has not been fully described. Emerging evidence suggests that in some experimental settings of chronic liver injury, platelets can promote liver repair and inhibit liver fibrosis. However, the precise mechanisms linking coagulation and platelet function to hepatic tissue chang ...[more]

PMID: 25353084

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Project description:Adipose tissue-derived stem cell (ADSC) transplantation has been shown to be effective for the management of severe liver disorders. Preactivation of ADSCs enhanced their therapeutic efficacy. However, these effects have not yet been examined in relation to cholestatic liver injury. In the present study, a cholestatic liver injury model was established by bile duct ligation (BDL) in male C57BL/6 mice. Human ADSCs (hADSCs) with or without tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) pretreatment were administrated into the mice via tail vein injections. The efficacy of hADSCs on BDL-induced liver injury was assessed by histological staining, real-time quantitative PCR (RT-qPCR), Western blot, and enzyme-linked immune sorbent assay (ELISA). In vitro, the effects of hADSC conditioned medium on the activation of hepatic stellate cells (HSCs) were investigated. Small interfering RNA (siRNA) was used to knock down cyclooxygenase-2 (COX-2) in hADSCs. TNF-α/IL-1β preconditioning could downregulate immunogenic gene expression and enhance the engraftment efficiency of hADSCs. Compared to control hADSCs (C-hADSCs), TNF-α/IL-1β-pretreated hADSCs (P-hADSCs) significantly alleviated BDL-induced liver injury, as demonstrated by reduced hepatic cell death, attenuated infiltration of Ly6G + neutrophils, and decreased expression of pro-inflammatory cytokines TNF-α, IL-1β, C-X-C motif chemokine ligand 1 (CXCL1), and C-X-C motif chemokine ligand 2 (CXCL2). Moreover, P-hADSCs significantly delayed the development of BDL-induced liver fibrosis. In vitro, conditioned medium from P-hADSCs significantly inhibited HSC activation compared to that from C-hADSCs. Mechanistically, TNF-α/IL-1β upregulated COX-2 expression and increased prostaglandin E2 (PGE2) secretion. The blockage of COX-2 by siRNA transfection reversed the benefits of P-hADSCs for PGE2 production, HSC activation, and liver fibrosis progression. In conclusion, our results suggest that TNF-α/IL-1β pretreatment enhances the efficacy of hADSCs in mice with cholestatic liver injury, partially through the COX-2/PGE2 pathway.

Dataset Information

Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice.

Publications

Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice.

Similar Datasets

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