EXPLORING TARGETED AND NON-TARGETED APPROACHES IN THE DEVELOPMENT OF ANTI-FIBROTIC THERAPY FOR LIVER FIBROSIS

Abstract

In liver fibrosis, prolonged injury and chronic inflammation results in excessive accumulation of ECM proteins, contributing to the formation of a permanent fibrotic scar, leading to cirrhosis and liver failure. During liver fibrosis, HSCs, the primary cell responsible for producing ECM proteins, become activated via a series of signaling cascades leading to the induction of gene expression of fibrogenic proteins. Evidence suggests the role of tyrosine kinase receptors, in contributing to HSC fibrosis and propagation. Using our targeted approach, we demonstrated tyrosine kinase inhibition may aid in reversal of liver fibrosis via inhibition of TGF-1 induced stimulation of LX-2 cells, as seen in the reduction of fibrotic markers, and promotion of fibrolysis, via reduction of TIMP expression and increased MMP expression. Using our non-targeted approach, we showed effectiveness of MSC-exosomes in reducing fibrotic marker expression at a protein level but no evidence so far at the transcript level.