Abstract
Hepatic fibrosis, a progressive chronic disease mainly caused by hepatitis viral infections, alcohol abuse or metabolic syndrome leading to liver dysfunction and is the growing cause of mortality worldwide. Tyrosine kinase inhibitor BIBF1120 (Nintedanib) has been evaluated in clinical trials for idiopathic pulmonary fibrosis and advanced Hepatocellular carcinoma, but has not been explored for liver fibrosis yet. In this study, we aimed to investigate the therapeutic effects and mechanism of BIBF1120 in liver fibrogenesis. The effects of BIBF1120 were evaluated in TGFβ-activated mouse 3T3 fibroblasts, LX2 cells, primary human hepatic stellate cells (HSCs) and CCl4-induced liver fibrogenesis mouse model. Fibroblasts-conditioned medium studies were performed to assess the paracrine effects on macrophages and endothelial cells. In-vitro in TGFβ-activated fibroblasts, BIBF1120 significantly inhibited expression of major fibrotic parameters, wound-healing and contractility. In vivo in CCl4-induced acute liver injury model, post-disease BIBF1120 administration significantly attenuated collagen accumulation and HSC activation. Interestingly, BIBF1120 drastically inhibited intrahepatic inflammation and angiogenesis. To further elucidate the mechanism of action, 3T3-conditioned medium studies demonstrated increased 3T3-mediated macrophage chemotaxis and endothelial cells tube formation and activation, which was significantly decreased by BIBF1120. These results suggests that BIBF1120 can be a potential therapeutic approach for the treatment of liver fibrosis.
Highlights
Produce pro-fibrotic mediators and chemokines that directly activate and recruit fibroblasts and inflammatory cells and control extracellular matrix (ECM) turnover by regulating the balance of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs)[7,8]
BIBF1120 led to the inhibition of TGFβ-stimulated fibroblasts activation as depicted by attenuation of mRNA expression levels of α-SMA; PDGFβR (Platelet derived growth factor beta receptor) and tissue inhibitor of metalloproteinases 1 (TIMP1) (Tissue inhibitor of matrix metalloproteases 1) (Fig. 1D–F)
We assessed the effects on the fibronectin receptor, Integrin alpha 5 (ITGA5) since it has been shown that α5β1 is highly expressed in fibroblasts and promotes fibroblast motility and survival[25,26]
Summary
Produce pro-fibrotic mediators and chemokines that directly activate and recruit fibroblasts and inflammatory cells and control ECM turnover by regulating the balance of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs)[7,8]. HSCs activated in response to hypoxia, play a key role in angiogenesis through interactions with endothelial cells via PGDF and VEGF signaling[16]. These data suggests the multidimensional role of HSCs i.e. exaggerating inflammation and angiogenesis in liver fibrosis[6,16]. Liver sinusoidal endothelial cells (LSECs) has shown to play a critical role in liver fibrosis[17,18]. Receptors for vascular endothelial growth factors (VEGF) and fibroblast growth factor (FGF) are shown to be induced during HSC activation that contribute to angiogenesis and fibroblasts activation respectively[16]. We further investigated the antagonistic effects of BIBF1120 on fibroblasts resulting in inhibitory paracrine effects on macrophages and endothelial cells
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