Fasudil prevents liver fibrosis via activating natural killer cells and suppressing hepatic stellate cells

ARTICLE HIGHLIGHTS

Research background

Rho kinase inhibition reportedly improves liver fibrosis. Fasudil, as a RhoA kinase inhibitor, is used to improve brain microcirculation and promote nerve regeneration clinically. The viability of Fasudil in liver fibrosis is still unknown.

Research motivation

Repositioning existing drugs e.g., Fasudil might be an effective strategy for obtaining therapeutics against liver fibrosis.

Research objectives

To evaluate the anti-fibrotic effects of Fasudil in vitro and in a mouse model of thioacetamide (TAA)-induced liver fibrosis.

Research methods

The anti-fibrotic effect of Fasudil was investigated in a TAA-induced mouse model. At 1 wk after induction with TAA, Fasudil was intraperitoneally injected once a day for 3 wk, hepatic pathological changes, liver fibrosis and immune cell activation were determined using hematoxylin and eosin staining, sirius red staining, western blotting and quantitative polymerase chain reaction and fluorescence-activated cell sorting. Furthermore, the effect of Fasudil on hepatic stellate cell (HSC) and natural killer (NK) cells was assayed in vitro.

Research results

Treatment with Fasudil alleviated hepatic pathological changes and reversed hepatic fibrosis in the TAA-chronic models with decreased deposition of collagen fibers, reduced expression of HSC activation marker (alpha smooth muscle actin), and reduced secretion of transforming growth factor beta 1 (TGF-β1), matrix metalloproteinase 2 (MMP-2), and MMP-9. Fasudil treatment increased NK cell activation and cytotoxicity by activating the extracellular signal-related kinase and nuclear factor kappa B signaling pathways. Fasudil directly promoted the apoptosis and inhibited the proliferation of HSC by decreasing α-SMA and TGF-β1.

Research conclusions

Fasudil inhibited liver fibrosis by activating NK cells and blocking HSC activation.

Research perspectives

Fasudil treatment prevents liver fibrosis via activating NK cells but suppressing HSCs. As a drug used clinically, these results provide a feasible solution for the clinical treatment of liver fibrosis.