The role of cytokine cascade in impaired liver regeneration and development of candidate pharmaceutical(s) to regulate this mechanism

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We conducted a study to investigate the mechanism of impaired liver regeneration induced by lipopolysaccharide (LPS) in mouse and obtained the following results.1. LPS induces tumor necrosis factor-α(TNF-α), thereby activating plasma kallikrein. Plasma kallikrein cleaves latent transforming growth factor-β, that is produced hepatic stellate cells. Cleaved (or activated) TGF-β strongly inhibits liver regeneration.2. The receptor responsible to this process is TNFR-1 but not TNFR-2 or Fas.3. TNF-α also recruits heat shock protein (HSP) to stimulate liver fibrosis, while the mode of action by HSP is dual.4. NIK-333, a candidate pharmaceutical under clinical development, reduces the emergence of TNF-α-positive oval cells and inhibits stellate cell activation. Thus, NIK-333 seems to be a promising compound to regulate the process as described above.The role of cytokine cascade in impaired liver regeneration was elucidated in a series of experiments, and a candidate compound to regulate this mechanism was also identified.