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Clinical Science (2007) 112, (265–280) (Printed in Great Britain)

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Review article

Liver fibrosis: cellular mechanisms of progression and resolution

Neil C. HENDERSON and John P. IREDALE

MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4TJ, U.K.

Key words: cirrhosis, collagen, fibrosis, hepatic stellate cell, inflammation, liver, myofibroblast.

Abbreviations: aa-M, alternatively activated macrophage; ANIT, a-naphthylisothiocyanate; BDL, bile-duct ligation; BEC, biliary epithelial cell; BM, bone marrow; CCl₄, carbon tetrachloride; DDC, 3,5-diethoxycarbonyl-1,4-dihydrocollidine; EMT, epithelial–mesenchymal transition; GdCl₃, gadolinium chloride; GFAP, glial fibrillary acidic protein; GFP, green fluorescent protein; EGFP, enhanced GFP; HCV, hepatitis C virus; HGF, hepatocyte growth factor; HSC, hepatic stellate cell; IFN, interferon; IL, interleukin; MIP-2, macrophage inflammatory protein-2; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; NASH, non-alcoholic steatohepatitis; NK, natural killer; PDGF, platelet-derived growth factor; poly I:C, polyinosinic-polycytidylic acid; RFP, red fluorescent protein; rIL-10, rat IL-10; a-SMA, a-smooth muscle actin; SCID, severe combined immunodeficiency; TAA, thioacetamide; TCR, T-cell receptor; TGF-b, transforming growth factor-b; T_h1, T-helper type 1; T_h2, T-helper type 2; TIMP, tissue inhibitor of metalloproteinases.

Correspondence: Professor John P. Iredale (email John.Iredale@ed.ac.uk).

Liver fibrosis represents a major worldwide health care burden. The last 15 years have seen a rapid growth in our understanding of the pathogenesis of this clinically relevant model of inflammation and repair. This work is likely to inform the design of effective antifibrotic therapies in the near future. In this review, we examine how the innate and adaptive immune response interacts with other key cell types in the liver, such as the myofibroblast, regulating the process of hepatic fibrosis and, where relevant, resolution of fibrosis with remodelling. Emphasis is placed on the increasing knowledge that has been generated by the use of transgenic animals and animals in which specific cell lines have been deleted. Additionally, we review the increasing evidence that, although significant numbers of wound-healing myofibroblasts are derived from the hepatic stellate cell, significant contributions may occur from other cell lineages, including those from distant sites such as bone marrow stem cells.

Received 30 August 2006/18 September 2006; accepted 2 October 2006

Published on the Internet 1 February 2007, doi:10.1042/CS20060242

©2007 The Biochemical Society