*2.2. Anti-Inflammatory Response*

An inflammatory response to autocrine or paracrine stimulation prompts HSC activation and proliferation. HSC activation consists of two stages: initiation and perpetuation [25,27]. Early changes in gene expression and phenotype represent the initiation stage. Initiation is mainly induced by cytokines, or other stimuli from cells around HSCs and act as paracrine pathways [27]. Reactive oxygen species (ROS) released from Kupffer cells can directly stimulate and activate HSCs [45]. By cascade amplification of inflammatory response, a large number of inflammatory cells infiltrate the damaged sites, and secrete inflammatory cytokines, leading to HSC activation and proliferation [46]. Continuous stimulation can induce HSCs into myofibroblast cells, inducing the perpetuation stage. The activated HSCs subsequently release chemokines, further aggravating the inflammatory response. In this stage, HSC promotes inflammation, fibrosis, and cell proliferation in the autocrine and/or paracrine pathway. Therefore, the inflammation response plays an important role in liver fibrosis. Anti-inflammatory drugs such as corticosteroids [47], colchicine [48], and ursodeoxycholic acid [49] have been used to treat liver fibrosis. Another anti-inflammatory strategy involves the application of specific receptor antagonists to

neutralize inflammatory cytokines. In one study, the antifibrotic and anti-inflammatory effects of IL-10 were observed in patients infected with hepatitis C [50]. Moreover, hepatic macrophages participate in the pathogenesis of liver fibrosis by the secretion of inflammatory factors. Targeting hepatic macrophages is also an effective anti-inflammatory technique for the treatment of liver fibrosis [51].
