Authors: Heymann, Felix; Trautwein, Christian; Tacke, Frank

Source: Inflammation & Allergy - Drug Targets, Volume 8, Number 4, September 2009 , pp. 307-318(12)

Publisher: Bentham Science Publishers

Abstract:

Although chronic liver disease has many etiologies, including chronic viral hepatitis, alcohol abuse, metabolic syndrome, and autoimmune disorders, the cellular and pathological mechanisms leading to hepatic fibrosis and - as an end-stage - cirrhosis are relatively common and uniform. Liver fibrosis is characterized by an accumulation of extracellular matrix proteins, and activated hepatic stellate cells (HSC), portal fibroblasts and myofibroblasts have been identified as major collagen-producing cells in the injured liver. Experimental models of liver fibrosis highlight the importance of hepatic macrophages, so-called Kupffer cells, for perpetuating an inflammatory phase resulting in the massive release of proinflammatory cytokines and chemokines as well as activation of HSC. Recent studies demonstrate that these actions are only partially conducted by liver-resident macrophages, but largely depend on recruitment of monocytes into the liver, namely of the inflammatory Gr1+ (Ly6C+) monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 participate in regulating monocyte subset infiltration. Macrophages, on the other hand, display a remarkable plasticity and can differentiate into functionally diverse subtypes, e.g. `classically activated' M1 and `alternatively activated' M2 macrophages. Experimental animal models indicate that monocytes/macrophages are not only critical for fibrosis progression, but also for fibrosis regression, because macrophages can also degrade extracellular matrix proteins and exert anti-inflammatory actions. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in liver fibrosis.

Keywords: Monocyte; liver fibrosis; macrophage; Kupffer cell; chemokines; CCR2; TGF-β; liver cirrhosis

Document Type: Research article

DOI: http://dx.doi.org/10.2174/187152809789352230

Publication date: 2009-09-01

More about this publication?

• Inflammation & Allergy - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in inflammation and allergy e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in inflammation and allergy. As the discovery, identification, characterization and validation of novel human drug targets for anti-inflammation and allergy drug discovery continues to grow, this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.

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