Keratinocyte growth factor inhibits hepatic inflammation and fibrosis in murine models of hepatic injury

Keratinocyte growth factor (KGF) plays a pivotal role in regulating cell proliferation, migration, differentiation and survival, in response to injury and tissue repair. The activation of hepatic stellate cells (HSCs) is the key event of hepatic fibrosis, and we have previously shown that KGF expression is upregulated during the activation of HSCs. However, no data exist on the expression and function of KGF in chronic liver disease.

This aim of this study was characterize the role of KGF in liver fibrosis.

Methods and Results: KGF-deficient (KGF-ko) and wildtype (wt) control mice were subjected to two models of hepatic fibrosis, namely (i) application of thioacetamide (TAA) in the drinking water and (ii) feeding a methionine-choline deficient diet (MCD) inducing non-alcoholic steatohepatitis. In both models KGF-ko mice exhibited significantly elevated serum transaminases, histological inflammation and hepatic TNF and IL-1 expression compared to wt-mice. Further, KGF-ko showed advanced HSC activation, profibrogenic gene expression (Collagen I and TGF-beta) and fibrosis as assessed by measurement of hydroxyproline and histology. Application of recombinant KGF to KGF-ko mice ameliorated the enhanced inflammation and fibrosis compared to wt-mice in the MCD-model.

Summary and conclusion: Recombinant KGF therapy is already approved in the US and Europe for decreasing the incidence and duration of oral mucositis, and has been shown to be safe. Furthermore, we have previously shown that FGFR2IIIb, which is the exclusive receptor for KGF, acts as a tumor-suppressor in hepatocellular carcinoma. Thus, KGF appears as promising novel anti-fibrogenic drug for the treatment of hepatic fibrosis in patients with chronic liver disease.