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

本实验研究了脂多糖（lipopolysaccharide，LPS）诱导小鼠肝再生障碍的机制，取得了以下结果. LPS诱导肿瘤坏死因子-α（TNF-α），从而激活血浆激肽释放酶。血浆激肽释放酶裂解肝星状细胞产生的潜在转化生长因子-β。切割（或活化）的TGF-β强烈抑制肝脏再生。负责这一过程的受体是TNFR-1，而不是TNFR-2或Fas。TNF-α还可募集热休克蛋白（HSP）刺激肝纤维化，而HSP的作用方式是双重的. NIK-333是一种正在临床开发的候选药物，可减少TNF-α阳性卵圆细胞的出现并抑制星状细胞活化。因此，NIK-333似乎是一个很有前途的化合物，以调节上述过程。细胞因子级联在受损的肝再生中的作用在一系列实验中得到阐明，并确定了一个候选化合物，以调节这一机制。

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.