Evolving therapies for liver fibrosis

Abstract

Fibrosis is an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. With protracted damage, fibrosis can progress toward excessive scarring and organ failure, as in liver cirrhosis. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development, with enormous potential but also high risks. Preclinical research has yielded numerous targets for antifibrotic agents, some of which have entered early-phase clinical studies, but progress has been hampered due to the relative lack of sensitive and specific biomarkers to measure fibrosis progression or reversal. Here we focus on antifibrotic approaches for liver that address specific cell types and functional units that orchestrate fibrotic wound healing responses and have a sound preclinical database or antifibrotic activity in early clinical trials. We also touch upon relevant clinical study endpoints, optimal study design, and developments in fibrosis imaging and biomarkers.

Mechanisms of Lung Fibrosis Resolution

“…Factors associated with inefficient fibrolysis in the liver include advanced vascular remodeling with architectural distortion, extensive cross-linking of ECM components hindering proteolytic removal, and the disappearance of cells that digest and degrade scar tissue. 6 Chronic infection with hepatitis C virus is a common cause of liver fibrosis, and the most compelling evidence that spontaneous resolution of fibrosis is possible in humans comes from studies examining the response to antiviral treatments. There is clear histological evidence from biopsy tissue of patients with mild-to-moderate fibrosis who are successfully treated for hepatitis C virus infection indicating resolution of the fibrosis seen in the index biopsy.…”

Docosahexaenoic acid attenuates Western diet-induced hepatic fibrosis in Ldlr mice by targeting the TGFβ-Smad3 pathway

“…Toll-like receptors (TLR2 and TLR4) have been linked to hepatic infl ammation and fi brosis (47)(48)(49)(50). We previously reported that feeding Ldlr Ϫ / Ϫ mice the WD increased plasma endotoxin ( 18 ), a gut-derived microbial factor that activates the TLR4 pathway ( 51 ).…”

Expression of mediators of purinergic signaling in human liver cell lines

“…Myofibroblasts derived from HSC are the primary effector cells in liver fibrosis [49][50][51], whereas hepatocytes and cholangiocytes work in coordinated fashion to secrete bile [52] and are primary targets of a variety of liver diseases [53,54] . Isolation of HSC, hepatocytes, and cholangiocytes is now technically straightforward [55], yet there are good reasons to use cell culture models of each of these cell types.…”