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

Abstract

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.

Exosome Adherence and Internalization by Hepatic Stellate Cells Triggers Sphingosine 1-Phosphate-dependent Migration

“…Western Blot Analysis-HSCs or liver tissue were lysed and prepared for WB analysis as described previously (26,27). Immunoblot analysis was performed according to the protocol recommended for individual antibodies as listed in supplemental Table 1.…”

“…CCl 4 was administered for 3 weeks rather than 4 weeks to minimize the toxicity of JTE-013 observed in pilot studies. In a different experiment, mice were subjected to bile duct ligation (BDL) or sham operation for 3 weeks to induce fibrosis, as described previously (27,31). Blood and liver were harvested to evaluate liver fibrosis.…”

Timing of transjugular intrahepatic portosystemic shunt for Budd-Chiari syndrome: An Italian hepatologist’s perspective

“…However, definition for response to therapy was not stated [1][2][3][4]7,[14][15][16] and a proposal of such a definition needs validation [18] . Moreover, such proposal suggests arbitrary clinical criteria that are at the same way debatable and not easily usable in clinical practice (Figure 1).…”

“…The biggest criticism of AASLD indication for the management of BCS is that they are based on the assumption that further treatment should be done for BCS only when hemodynamic consequences on portal hypertension become clinically evident, such as giving no consideration to the chronic ischemic liver damage effects on hepatic function and to the possibility of preventing liver failure by relieving impaired hepatic veins outflow [3,5,[12][13][14] . Moreover, patients receiving only medical therapy often have a bad outcome.…”

“…In fact, a substantial rate of patients with BCS (numerically different in the cohorts of patients with BCS published) finally develops liver cirrhosis, in the absence of known causative factors but chronic liver ischemia [13] . This theory was not evidence-based, required validation and only pretended to serve as a basis for future research [14] . However, some confirmation was reported.…”