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Cell injury/death leads to Activation, Stellate cells
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
Damaged hepatocytes can lead to activation of hepatic stellate cells (HSCs) through the release of ROS, cytokines and chemokines. Engulfment of apoptotic bodies from hepatocytes results in HSC activation and induces NOX (NADPH oxidases) expression in HSCs. DNA from apoptotic hepatocytes induces toll-like receptor 9 (TLR9)-dependent changes of HSCs that are consistent with late stages of HSC differentiation (activation), with up-regulation of collagen production and inhibition of platelet derived growth factor (PDGF)-mediated chemotaxis to retain HSCs at sites of cellular apoptosis. The release of latent TGF-beta complex into the micro-environment by damaged hepatocytes is likely to be one of the first signals for adjacent HSCs leading to their activation.
Damaged hepatocytes also influence liver sinusoidal endothelial cell (LSECs), which make an integral part of the hepatic reticulo-endothelial system and have a role in HSC activation. LSECs are morphologically identified by their fenestrations, which are transcytoplasmic canals arranged in sieve plates. In healthy liver, hepatocytes and HSCs maintain this phenotype of LSECs through release of vascular endothelial growth factor (VEGF). Differentiated (i.e. fenestrated) LSECs prevent HSC activation and promote reversal of activated HSC to quiescence, but LSEC lose this effect when they are de-differentiated due to liver injury. Preclinical studies have demonstrated that LSECs undergo defenestration as an early event that not only precedes liver fibrosis, but may also be permissive for it. Changes in LSEC differentiation might be an integral part of the development of fibrosis. Furthermore, in fibrosis LSECs become highly pro-inflammatory and secrete an array of cytokines and chemokines     
This relationship is classified as indirect as HSCs activation is partly mediated by TGF-β1 and LSECs.
Evidence Supporting this KER
Uncertainties and Inconsistencies
There are no inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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