Interplay of Matrix Stiffness and c-SRC in Hepatic Fibrosis

Advanced oxidation protein products induce hepatocyte epithelial–mesenchymal transition via a ROS‐dependent, TGF‐β/Smad signaling pathway

“…Liver fibrosis was traditionally believed to be caused by excessive extracellular matrix (ECM) production of hepatic stellate cells (HSCs) (Fang et al, 2014;Gortzen et al, 2015;Hong et al, 2015). However, a recent study has shown that the occurrence of EMT in hepatocytes also contributed to liver fibrosis (Kong et al, 2015).…”

Rho‐kinase inhibition is beneficial in fibrosis

“…Moreover, RhoA expression is downregulated in hepatocytes cultured on stiff polyacrylamide gels, as was recently shown by our group. (2) Regarding how the RhoA/ROCK pathway is tightly linked to stiffness, (3) the present work does not elucidate whether ROCK is up-regulated or downregulated in hepatocytes. Taking into account that RhoA is down-regulated in hepatocytes, it remains unclear whether further inhibition of RhoA/ROCK may help preserve hepatocyte function.…”

“…(1) Previously published evidence supports this hypothesis, showing that c-SRC is up-regulated and activated in hepatocytes cultured on stiff gels, which leads to RhoA downregulation and consecutively ROCK down-regulation. (2) Even though Desai et al provided strong in vitro evidence using atomic force microscopy and gels with a tunable shear modulus, the study did not sufficiently address the gradient of matrix stiffness across the different zones between portal vein and hepatic vein, as well as the polarity of the hepatocytes. Finally, hepatic stellate cells cultured on stiff polyacrylamide gels induce RhoA expression, (2) and RhoA and/or Rho-kinase inhibition may ameliorate fibrosis and portal hypertension in experimental and human cirrhosis, especially as the overall expression of RhoA/ Rho-kinase expression and activity is up-regulated in cirrhosis.…”

“…(2) Even though Desai et al provided strong in vitro evidence using atomic force microscopy and gels with a tunable shear modulus, the study did not sufficiently address the gradient of matrix stiffness across the different zones between portal vein and hepatic vein, as well as the polarity of the hepatocytes. Finally, hepatic stellate cells cultured on stiff polyacrylamide gels induce RhoA expression, (2) and RhoA and/or Rho-kinase inhibition may ameliorate fibrosis and portal hypertension in experimental and human cirrhosis, especially as the overall expression of RhoA/ Rho-kinase expression and activity is up-regulated in cirrhosis. (5) Therefore, the inhibition of Rho-kinase might be beneficial 2-fold, as an antifibrotic mechanism and by preserving hepatocyte function; and it should be explored further in the human setting.…”

“…Concerning the issue of the dose-response or nonlinear association between each component of metabolic syndrome with cardiovascular events and death, it would be less of a concern in our study. This is because all the components of metabolic syndrome were ana-lyzed as binary categorical covariates, according to the modified National Cholesterol Education Program Adult Treatment Panel III criteria, (2) in the multivariable analysis. On the other hand, we acknowledge that our use of a single measurement may dilute the relationship between metabolic syndrome components and the studied outcomes.…”