Tissue injury disrupts the mechanical homeostasis that underlies normal tissue architecture and function. The failure to resolve injury and restore homeostasis gives rise to progressive fibrosis that is accompanied by persistent alterations in the mechanical environment as a consequence of pathological matrix deposition and stiffening. This Review focuses on our rapidly growing understanding of the molecular mechanisms linking the altered mechanical environment in injury, repair, and fibrosis to cellular activation. In particular, our focus is on the mechanisms by which cells transduce mechanical signals, leading to transcriptional and epigenetic responses that underlie both transient and persistent alterations in cell state that contribute to fibrosis. Translation of these mechanobiological insights may enable new approaches to promote tissue repair and arrest or reverse fibrotic tissue remodeling.
Background & Aims Metabolic stress during liver injury enhances autophagy and provokes stellate cell activation, with secretion of scar matrix. Conditions that augment protein synthesis increase demands on the endoplasmic reticulum (ER) folding capacity and trigger the unfolded protein response (UPR) to cope with resulting ER stress. Generation of reactive oxygen species (ROS) is a common feature of hepatic fibrogenesis, and crosstalk between oxidative stress and ER stress has been proposed. The aim of our study was to determine the impact of oxidant and ER stress on stellate cell activation. Methods Oxidant stress was induced in hepatic stellate cells using H2O2 in culture or by ethanol feeding in vivo, and the UPR response was analyzed. Because the branch of the UPR mainly affected was IREα, we blocked this pathway in stellate cells and analyzed the fibrogenic response, together with autophagy and downstream MAPK signaling. The Nrf2 antioxidant response was also evaluated in stellate cells under oxidant stress conditions. Results H2O2 treatment in culture or ethanol feeding in vivo increased the UPR response based on splicing of XBP1 mRNA, which triggered autophagy. The Nrf2-mediated antioxidant response, as measured by qRT-PCR of its target genes was also induced under ER stress conditions. Conversely, blockade of the IRE1 pathway in stellate cells significantly decreased both their activation and autophagic activity in a p38 MAPK dependent manner, leading to a reduced fibrogenic response. Conclusions These data implicate mechanisms underlying protein folding quality control in regulating the fibrogenic response in hepatic stellate cells.
Background & Aims: Mechanical forces contribute to portal hypertension (PHTN) and fibrogenesis. We investigated the mechanisms by which forces are transduced by liver sinusoidal endothelial cells (LSECs) into pressure and matrix changes. Methods: We isolated primary LSECs from mice and induced mechanical stretch with a Flexcell device, to recapitulate the pulsatile forces induced by congestion, and performed microarray and RNA-sequencing analyses to identify gene expression patterns associated with stretch. We also performed studies with C57BL/6 mice (controls), mice with deletion of neutrophil elastase (NE-/-) or PAD4 (Pad4-/-) (enzymes that formation of neutrophil extracellular traps [NETs]), and mice with LSEC-specific deletion of Notch1 (Notch1 iΔEC). We performed partial ligation of the suprahepatic inferior vena cava (pIVCL) to simulate congestive hepatopathy-induced portal hypertension in mice; some mice were given subcutaneous injections of sivelestat or underwent bile-duct ligation. Portal pressure was measured using a digital blood pressure analyzer and we performed intravital imaging of livers of mice.
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.
This study demonstrates that HBCa surveillance significantly improves outcomes, including survival, in patients with PSC. (Hepatology 2018;67:2338-2351).
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The physiological consequences of the Fontan circulation impose risk for hepatic dysfunction and may culminate in hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Consensus regarding appropriate surveillance modalities to diagnose liver disease in Fontan patients is lacking, in part due to the relative lack of strong evidence and prospective studies in this patient population. The goal of this paper is to critically review the current evidence and provide recommendations for the surveillance of hepatic complications in the post-Fontan patient population.
Neutrophil extracellular traps, or NETs, are heterogenous, filamentous structures which consist of extracellular DNA, granular proteins, and histones. NETs are extruded by a neutrophil in response to various stimuli. Although NETs were initially implicated in immune defense, subsequent studies have implicated NETs in a spectrum of disease processes, including autoimmune disease, thrombosis, and cancer. NETs also contribute to the pathogenesis of several common liver diseases, including alcohol-associated liver disease and portal hypertension. Although there is much interest in the therapeutic potential of NET inhibition, future clinical applications must be balanced against potential increased risk of infection.
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