Evolving therapies for liver fibrosis
Detlef Schuppan, Yong Ook Kim
Detlef Schuppan, Yong Ook Kim
Published May 1, 2013
Citation Information: J Clin Invest. 2013;123(5):1887-1901. https://doi.org/10.1172/JCI66028.
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Review Series

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.

Authors

Detlef Schuppan, Yong Ook Kim

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Figure 1

Myofibroblasts and their fibrogenic activation.

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Myofibroblasts and their fibrogenic activation. Cells and major factors ...
Cells and major factors upstream of quiescent portal fibroblasts and hepatic stellate cells that induce transformation to fibrogenic myofibroblasts. This schematic highlights several major targets to treat liver fibrosis. Notably, the ECM itself can serve as modulator of fibrogenesis and fibrolysis. Thus collagen fibrils become crosslinked by LOXL2, which contributes to the reduced reversibility of advanced fibrosis, and collagen-binding ECM receptors (especially the integrins α1β1, α2β1, and α11β1) confer signals of stress or stress relaxation that either maintain fibrogenic activation or induce fibrolytic activity of the myofibroblasts. Additional minor contributors to fibrogenic activation are not shown here (see text for details). A2AR, adenosine 2A receptor; AT1R, angiotensin 1 receptor; CBR1, cannabinoid receptor 1; ET-1, endothelin-1; ETAR, endothelin A receptor; FXR, farnesoid X receptor; Hh(R), hedgehog (receptor); Int, integrin; LPA1R, lysophosphatidic acid receptor 1; NGFR, nerve growth factor receptor; PTX2, pentraxin 2; TRAILR, TNF-related apoptosis-inducing ligand receptor; YB-1, Y-box binding protein.