scholarly journals HMGB1 recruits hepatic stellate cells and liver endothelial cells to sites of ethanol-induced parenchymal cell injury

2013 ◽  
Vol 305 (11) ◽  
pp. G838-G848 ◽  
Author(s):  
Yeon S. Seo ◽  
Jung H. Kwon ◽  
Usman Yaqoob ◽  
Liu Yang ◽  
Thiago M. De Assuncao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Liver Injury ◽  
Hepatic Stellate Cells ◽  
Hepg2 Cells ◽  
Cell Injury ◽  
Parenchymal Cell ◽  
Stellate Cells ◽  
Hmgb1 Protein ◽  
Liver Endothelial Cells ◽  
Stimulation Of

Hepatic stellate cells (HSC) and liver endothelial cells (LEC) migrate to sites of injury and perpetuate alcohol-induced liver injury. High-mobility group box 1 (HMGB1) is a protein released from the nucleus of injured cells that has been implicated as a proinflammatory mediator. We hypothesized that HMGB1 may be released from ethanol-stimulated liver parenchymal cells and contribute to HSC and LEC recruitment. Ethanol stimulation of rat hepatocytes and HepG2 cells resulted in translocation of HMGB1 from the nucleus as assessed by Western blot. HMGB1 protein levels were increased in the supernatant of ethanol-treated hepatocytes compared with vehicle-treated cells. Migration of both HSC and LEC was increased in response to conditioned medium for ethanol-stimulated hepatocytes (CMEtOH) compared with vehicle-stimulated hepatocytes (CMVEH) ( P < 0.05). However, the effect of CMEtOH on migration was almost entirely reversed by treatment with HMGB1-neutralizing antibody or when HepG2 cells were pretransfected with HMGB1-siRNA compared with control siRNA-transfected HepG2 cells ( P < 0.05). Recombinant HMGB1 (100 ng/ml) also stimulated migration of HSC and LEC compared with vehicle stimulation ( P < 0.05 for both HSC and LEC). HMGB1 stimulation of HSC increased the phosphorylation of Src and Erk and HMGB1-induced HSC migration was blocked by the Src inhibitor PP2 and the Erk inhibitor U0126. Hepatocytes release HMGB1 in response to ethanol with subsequent recruitment of HSC and LEC. This pathway has implications for HSC and LEC recruitment to sites of ethanol-induced liver injury.

Identification of Multi-Omics Cell Signatures of Early Liver Injury

2021 ◽  
Author(s):  
Maciej Migdał ◽  
Eugeniusz Tralle ◽  
Karim Abu Nahia ◽  
Łukasz Bugajski ◽  
Katarzyna Zofia Kędzierska ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Liver Injury ◽  
Hepatic Stellate Cells ◽  
Tissue Injury ◽  
Early Stage ◽  
Stellate Cells ◽  
Cell Types ◽  
Cell Type ◽  
Cell Type Specific ◽  
Liver Endothelial Cells

Abstract Background Liver fibrosis is a wound-healing response to tissue injury and inflammation hallmarked by the extracellular matrix (ECM) protein deposition in the liver parenchyma and tissue remodelling. Different cell types of the liver are known to play distinct roles in liver injury response. Hepatocytes and liver endothelial cells receive molecular signals indicating tissue injury and activate hepatic stellate cells which produce ECM proteins upon their activation. Despite the growing knowledge on the molecular mechanism underlying hepatic fibrosis in general, the cell-type-specific gene regulatory network associated with the initial response to hepatotoxic injury is still poorly characterized. Results In this study, we used thioacetamide (TAA) to induce hepatic injury in adult zebrafish. We isolated three major liver cell types - hepatocytes, endothelial cells and hepatic stellate cells - and identified cell-type-specific chromatin accessibility and transcriptional changes in an early stage of liver injury. We found that TAA induced transcriptional shifts in all three cell types hallmarked by significant alterations in the expression of genes related to fatty acid and carbohydrate metabolism, as well as immune response-associated and vascular-specific genes. Interestingly, liver endothelial cells exhibit the most pronounced response to liver injury at the transcriptome and chromatin level, hallmarked by the loss of their angiogenic phenotype. Conclusion Our results uncovered cell-type-specific transcriptome and epigenome responses to early stage liver injury, which provide valuable insights into understanding the molecular mechanism implicated in the early response of the liver to pro-fibrotic signals.

scholarly journals Multi-omics analyses of early liver injury reveals cell-type-specific transcriptional and epigenomic shift

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Maciej Migdał ◽  
Eugeniusz Tralle ◽  
Karim Abu Nahia ◽  
Łukasz Bugajski ◽  
Katarzyna Zofia Kędzierska ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Liver Injury ◽  
Hepatic Stellate Cells ◽  
Tissue Injury ◽  
Early Stage ◽  
Stellate Cells ◽  
Cell Types ◽  
Cell Type ◽  
Cell Type Specific ◽  
Liver Endothelial Cells

Abstract Background Liver fibrosis is a wound-healing response to tissue injury and inflammation hallmarked by the extracellular matrix (ECM) protein deposition in the liver parenchyma and tissue remodelling. Different cell types of the liver are known to play distinct roles in liver injury response. Hepatocytes and liver endothelial cells receive molecular signals indicating tissue injury and activate hepatic stellate cells which produce ECM proteins upon their activation. Despite the growing knowledge on the molecular mechanism underlying hepatic fibrosis in general, the cell-type-specific gene regulatory network associated with the initial response to hepatotoxic injury is still poorly characterized. Results In this study, we used thioacetamide (TAA) to induce hepatic injury in adult zebrafish. We isolated three major liver cell types - hepatocytes, endothelial cells and hepatic stellate cells - and identified cell-type-specific chromatin accessibility and transcriptional changes in an early stage of liver injury. We found that TAA induced transcriptional shifts in all three cell types hallmarked by significant alterations in the expression of genes related to fatty acid and carbohydrate metabolism, as well as immune response-associated and vascular-specific genes. Interestingly, liver endothelial cells exhibit the most pronounced response to liver injury at the transcriptome and chromatin level, hallmarked by the loss of their angiogenic phenotype. Conclusion Our results uncovered cell-type-specific transcriptome and epigenome responses to early stage liver injury, which provide valuable insights into understanding the molecular mechanism implicated in the early response of the liver to pro-fibrotic signals.

Neutrophil-induced liver cell injury in endotoxin shock is a CD11b/CD18-dependent mechanism

1991 ◽  
Vol 261 (6) ◽  
pp. G1051-G1056 ◽  
Author(s):  
H. Jaeschke ◽  
A. Farhood ◽  
C. W. Smith
Keyword(s):  
Liver Injury ◽  
Cell Injury ◽  
Tissue Injury ◽  
Oxidant Stress ◽  
Parenchymal Cell ◽  
Endotoxin Shock ◽  
Liver Cell Injury ◽  
Integrin Family ◽  
Dependent Mechanism

To investigate the role of neutrophils (PMNs) and PMN-dependent adhesion molecules in the pathogenesis of liver injury in a model of endotoxin shock, male ICR mice received a dose of 700 mg/kg galactosamine and 100 micrograms/kg Salmonella abortus equi endotoxin. PMNs accumulated continuously in the liver, reaching values of 446 +/- 71 PMNs/50 high-power fields at 9 h (basal value 18 +/- 7). Plasma alanine aminotransferase activities as index of parenchymal cell injury did not change up to 5 h posttreatment (basal value 35 +/- 5 U/l) but increased to 1,950 +/- 460 U/l at 9 h. The formation of glutathione disulfide (GSSG) in plasma as an index of an extracellular oxidant stress also increased only at 9 h. Pretreatment of animals with monoclonal antibodies against the CD11b and CD18 subunits of the CD11/CD18 integrin family on the surface of the PMN reduced the number of PMNs in the liver by 50% and significantly attenuated liver injury and GSSG formation. An anti-CD11a and a nonbinding control antibody were ineffective. It is concluded that PMNs are actively involved in the pathogenesis of galactosamine and endotoxin shock and that at least in part the accumulation of PMNs, the subsequent oxidant stress, and the tissue injury in this model of experimental hepatitis are CD11b/CD18 (Mac-1) dependent.

Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

2013 ◽  
Vol 305 (8) ◽  
pp. C789-C799 ◽  
Author(s):  
Ariane Mallat ◽  
Sophie Lotersztajn
Keyword(s):  
Liver Fibrosis ◽  
Liver Injury ◽  
Cell Injury ◽  
Parenchymal Cell ◽  
Chronic Liver ◽  
Special Focus ◽  
Chronic Liver Injury ◽  
Cellular Mechanisms ◽  
Extracellular Matrix Components ◽  
Liver Fibrogenesis

Liver fibrosis is the common scarring reaction associated with chronic liver injury that results from prolonged parenchymal cell injury and/or inflammation. The fibrogenic response is characterized by progressive accumulation of extracellular matrix components enriched in fibrillar collagens and a failure of matrix turnover. This process is driven by a heterogeneous population of hepatic myofibroblasts, which mainly derive from hepatic stellate cells and portal fibroblasts. Regression of fibrosis can be achieved by the successful control of chronic liver injury, owing to termination of the fibrogenic reaction following clearance of hepatic myofibroblasts and restoration of fibrolytic pathways. Understanding of the complex network underlying liver fibrogenesis has allowed the identification of a large number of antifibrotic targets, but no antifibrotic drug has as yet been approved. This review will highlight recent advances regarding the mechanisms that regulate liver fibrogenesis and fibrosis regression, with special focus on novel signaling pathways and the role of inflammatory cells. Translation of these findings to therapies will require continued efforts to develop multitarget therapeutic approaches that will improve the grim prognosis of liver cirrhosis.

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