Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces

Douglas A. Simonetto, Hui yin Yang, Meng Yin, Thiago M. de Assuncao, Jung Hee Kwon, Moira Hilscher, Shuchong Pan, Liu Yang, Yan Bi, Arthur Beyder, Sheng Cao, Robert D. Simari, Richard Ehman, Patrick S. Kamath, Vijay H. Shah

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)648-659
Number of pages12
Issue number2
StatePublished - Feb 1 2015

ASJC Scopus subject areas

  • Hepatology


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