Molecular Regulation of Hepatic Fibrosis, an Integrated Cellular Response to Tissue Injury*

By S. Friedman. Journal of Biological Chemistry, 2000

2,166 citations recorded by the source corpus.

Background, Disease Context of Hepatic Fibrosis Chronic injury leading to fibrosis in liver occurs in response to a variety of insults, including viral hepatitis (especially hepatitis B and C), alcohol abuse, drugs, metabolic diseases due to overload of iron or copper, autoimmune attack of hepatocytes or bile duct epithelium, or congenital abnormalities (1). Typically, injury is present for months to years before significant scar accumulates, although the time course may be accelerated in congenital liver disease. Liver fibrosis is reversible, whereas cirrhosis, the endstage consequence of fibrosis, is generally irreversible. Thus, efforts to understand fibrosis focus primarily on events that lead to the early accumulation of scar in hopes of identifying therapeutic targets to slow its progression. Like other parenchyma, the normal liver contains an epithelial component (hepatocytes), an endothelial lining (which in liver is distinguished by fenestrae or pores), tissue macrophages (Kupffer cells), and a perivascular mesenchymal cell called the stellate cell (previously called Ito cell, lipocyte, perisinusoidal cell, or fat-storing cell) (Fig. 1); stellate cells are the key fibrogenic cell (see next section). The cellular elements of liver are organized within the sinusoid, or microvascular unit, with the subendothelial space of Disse separating the epithelium (hepatocytes) from the sinusoidal endothelium. In normal liver this space contains a basement membrane-like matrix, although it is not electron-dense like a typical basement membrane. The normal subendothelial extracellular matrix (ECM) is essential for maintaining the differentiated function of all resident liver cells. Establishing the importance of the normal ECM in liver has illuminated recent attempts to develop artificial liver support by recognizing that all cellular elements and supporting structures (not just the hepatocyte compartment) must be reconstituted to preserve differentiated function of liver ex vivo (2). As the liver becomes fibrotic, there are both quantitative and qualitative changes in composition of the hepatic ECM. The total content of collagens and noncollagenous components increases 3–5fold, accompanied by the shift in the type of ECM in subendothelial space from the normal low density basement membrane-like matrix to interstitial type matrix containing fibril-forming collagens.

Subfields: Epidemiology, Hepatology, Surgery

View Paper: https://www.semanticscholar.org/paper/45f24242658f00052739cc9748a638d62bf67ae5

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. S. Friedman
2. Robert F. Schwabe
3. Y. Saiman
4. J. Puche
5. J. Bonner
6. E. Seki
7. T. Donohue
8. N. Osna

In Hepatology

1. S. Friedman
2. Y. Saiman
3. J. Puche
4. J. Bonner
5. T. Donohue
6. N. Osna
7. K. Kharbanda
8. Ralf Weiskirchen

In Surgery

1. T. Donohue
2. Y. Saiman
3. N. Osna
4. J. Puche
5. K. Kharbanda
6. J. Bonner
7. H. Jaeschke
8. Ralf Weiskirchen

Citations in the corpus

• Roles of TGF-beta in hepatic fibrosis. (2002, background): “All four LTBP isoforms were identified in human liver (9,10) and in MFB (6).”
• Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle (2011, background): “It is well known that perivascular mesenchymal cells, called hepatic stellate cells, are the key fibrogenic cells in liver fibrosis (Friedman, 2000).”
• TLR4 enhances TGF-β signaling and hepatic fibrosis (2007, background): “TGF-β and platelet-derived growth factor (PDGF) have been characterized as key cytokines that mediate hepatic fibrogenesi”
• Hepatic Stellate Cells and Liver Fibrosis (2013, positive): “The framework for understanding stellate cell activation was established several years ago (63), and remains a practical and relevant template for characterizing the cell’s response to injury.”
• Regulation of PDGF and its receptors in fibrotic diseases. (2004, background): “Activated stellate cells respond to these paracrine signals through proliferation, chemotaxis, contractility, release of cytokines and chemokines, loss of retinoids, and deposition of extracellular matrix molecules[58].”
• Resolution of liver cirrhosis using vitamin A–coupled liposomes to deliver siRNA against a collagen-specific chaperone (2008, background): “When stimulated by reactive oxygen intermediates or cytokines, HS cells become activated and are transformed to proliferative, fibrogenic and contractile myofibroblast”
• Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation (2018, background): “However, overactivation or a failure to resolve their activation status (chronic activation from continued exposure to pro-inflammatory stimuli) can lead to the increased ECM deposition in the space of Disse that has a negative consequence for hepatocyte function and normal liver architecture, such ”
• Mechanisms of hepatotoxicity. (2002, background): “Hepatic stellate cells are central to the fibrotic response of the liver to injury, and ROS activate stellate cells (Friedman, 2000).”
• Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-β as major players and therapeutic targets (2006, background): “As outlined above, TGF-β is among other polypeptide mediators involved in hepatic fibrogenesis influencing the plasticity of HSC [23, 39].”
• Alcoholic Liver Disease: Pathogenesis and Current Management (2017, methodology): “SOURCE: Figure adapted from Friedman 2000. reside in the space of Disse as quiescent, lipid (retinyl-ester)-storing cells (figure 8).”