Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces. Hepatology 2015 Feb;61(2):648-59
Date
08/22/2014Pubmed ID
25142214Pubmed Central ID
PMC4303520DOI
10.1002/hep.27387Scopus ID
2-s2.0-84921483405 (requires institutional sign-in at Scopus site) 135 CitationsAbstract
UNLABELLED: Chronic passive hepatic congestion (congestive hepatopathy) leads to hepatic fibrosis; however, the mechanisms involved in this process are not well understood. We developed a murine experimental model of congestive hepatopathy through partial ligation of the inferior vena cava (pIVCL). C57BL/6 and transgenic mice overexpressing tissue factor pathway inhibitor (SM22α-TFPI) were subjected to pIVCL or sham. Liver and blood samples were collected and analyzed in immunohistochemical, morphometric, real-time polymerase chain reaction, and western blot assays. Hepatic fibrosis and portal pressure were significantly increased after pIVCL concurrent with hepatic stellate cell (HSC) activation. Liver stiffness, as assessed by magnetic resonance elastography, correlated with portal pressure and preceded fibrosis in our model. Hepatic sinusoidal thrombosis as evidenced by fibrin deposition was demonstrated both in mice after pIVCL as well as in humans with congestive hepatopathy. Warfarin treatment and TFPI overexpression both had a protective effect on fibrosis development and HSC activation after pIVCL. In vitro studies show that congestion stimulates HSC fibronectin (FN) fibril assembly through direct effects of thrombi as well as by virtue of mechanical strain. Pretreatment with either Mab13 or Cytochalasin-D, to inhibit β-integrin or actin polymerization, respectively, significantly reduced fibrin and stretch-induced FN fibril assembly.
CONCLUSION: Chronic hepatic congestion leads to sinusoidal thrombosis and strain, which in turn promote hepatic fibrosis. These studies mechanistically link congestive hepatopathy to hepatic fibrosis.
Author List
Simonetto DA, Yang HY, Yin M, de Assuncao TM, Kwon JH, Hilscher M, Pan S, Yang L, Bi Y, Beyder A, Cao S, Simari RD, Ehman R, Kamath PS, Shah VHAuthor
Thiago Milech De Assuncao Research Scientist II in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ActinsAdult
Aged
Animals
Anticoagulants
Case-Control Studies
Cells, Cultured
Disease Models, Animal
Female
Fibrin
Fibronectins
Hepatic Stellate Cells
Humans
Hyperemia
Ligation
Liver Circulation
Liver Cirrhosis
Male
Mice, Inbred C57BL
Mice, Transgenic
Middle Aged
Thrombosis
Vena Cava, Inferior
Young Adult
