Investigation of injury and pharmacological modulation of biliary epithelial cells in ductopenic disease

Abstract

Senescence and its associated secretory phenotype have been investigated in several vanishing bile duct syndromes. The current study evaluated the presence of senescent biliary epithelial cells (BEC) in acute cellular rejection of human liver allografts to ascertain whether senescent cells contribute to human disease progression in liver transplantation. There was a significant correlation between senescent BEC and grade of rejection. Furthermore there was a significant correlation between grade of rejection and BEC undergoing epithelial to mesenchymal transition (EMT). There was never any overlap between senescence and EMT markers in BEC. Further investigation of the association between senescence and EMT in vitro using both primary and immortalised human BEC exposed to oxidative stress showed, for the first time, that TGF-­b2 is part of the Senescence Associated Secretory Phenotype (SASP) in liver disease. Blockade of TGF-­b signalling by inhibition of the TGFbR, prevented any of the oxidative stress-­induced changes in BEC. Blockade of integrin aVb6 integrin also showed a variable ability to prevent TGF-­b mediated changes in BEC. HGF and its mimetic, 1K1, were able to prevent oxidative stress induced EMT in BEC. Furthermore 1K1 showed a smaller induction of autophagy than HGF and was able to prevent up regulation of senescence markers. The paradigm of oxidative stress-­induced senescence leading to EMT was assessed in the current study, with identification of powerful therapeutic agents able to prevent these changes. This suggests that premature cellular ageing (senescence) in acute liver disease could be pharmacologically prevented from occurring. Inhibition of senescence prevents disease promotion by the effects of the SASP, blocking the progression to chronic disease; this may well apply to all organ systems