Mechanisms of liver fibrosis

Tsukada, Shigeki; Parsons, Christopher J.; Rippe, Richard A.

doi:10.1016/j.cca.2005.06.014

Cited by 326 publications

(254 citation statements)

References 362 publications

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“…121 Fibrogenesis-Collagen type I is the prototype constituent of the fibril-forming matrix in fibrotic liver, and its expression is regulated both transcriptionally and posttranscriptionally as described earlier and in several reviews. [122][123][124] TGFβ1, derived from both paracrine and autocrine sources, remains the classic fibrogenic cytokine (see Inagaki and Okazaki 124 and Breitkopf et al 125 for reviews). Signals downstream of TGFβ converge on Smad proteins, which fine-tune and enhance the effects of TGFβ during stellate cell activation; Smads 2 and 3 are stimulatory whereas Smad 7 is inhibitory 124,126,127 and is antagonized by Id1.…”

Section: Perpetuating Pathwaysmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, posttranscriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.The field of hepatic fibrosis is flourishing thanks to continued experimental advances complemented by exciting progress in the treatment of chronic liver disease. 1 Control of chronic hepatitis B and C by antiviral therapies has established that advanced fibrosis can regress in association with improved clinical outcomes, 2-4 thereby intensifying enthusiasm to uncover the mechanistic basis for hepatic fibrogenesis and its attenuation. At the same time, simple paradigms defining the cellular sources of extracellular matrix (ECM), and the roles of cytokines and paracrine interactions among resident liver cells and inflammatory cells have yielded a more nuanced understanding of how the liver responds to injury. These advances have had a collateral benefit towards understanding fibrosis in other organs, particularly the pancreas. 5 Thus, a review of the mechanisms underlying hepatic fibrosis is not only timely, but is more clinically relevant than ever. This article focuses on recent advances in the field, building on established principles from earlier reviews 6,7 while weaving in their clinical relevance, but also emphasizing the molecular subtleties that have emerged through continued progress in the field. General PrinciplesFibrosis, or scarring of the liver, is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although even acute injury will activate mechanisms of fibrogenesis, the sustained signals associated with chronic liver disease caused by infection, Cirrhosis, the most advanced stage ...

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Section: Perpetuating Pathwaysmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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“…Hepatic fibrosis is characterized by excess deposition of fibrillar collagen and other extracellular matrix components in the liver [10]. Central to this process is the activation of hepatic stellate cells (HSC) from a quiescent, retinoid-storing state to a myofibroblastic phenotype characterized by increased production of collagen and other extracellular matrix components, elevated proliferative rate, expression of a-smooth muscle actin (SMA), and increased responsiveness to cytokines [11,12]. Normally, HSC activation is an early event in the healing process after liver injury, and upon removal of the injurious stimulus there is a reduction of activated HSC, either through apoptosis or through a return to the quiescent state.…”

Section: Insl3mentioning

confidence: 99%

Relaxin receptors in hepatic stellate cells and cirrhotic liver

Bennett

Dalton

Mahan

et al. 2007

Biochemical Pharmacology

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“…The ability of LC cells to respond to profibrotic triggers such as mechanical stress and transforming growth factor-β (TGF-β) resulting in enhanced ECM synthesis, implicates LC as an important pro-fibrotic tissue that could lead to loss of structural integrity resulting in collapse of LC and associated neuronal loss in gluacoma (Hernandez 2000 and. Endothelin-1 has been increasingly recognized for its role as a pro-fibrotic factor resulting in enhanced ECM synthesis and has been widely implicated in the pathology of various connective tissue disorders (Eng and Friedman 2000;Eddy 2000;Wakatsuki et al, 2004;Clozel and Salloukh 2005;Tsukada et al, 2006;Khan ZA 2006). We were therefore interested in studying the role ET-1 in regulation of collagens type I and VI in LC cells.…”

Section: Discussionmentioning

confidence: 99%

“…Intravitreal administration of ET-1 in various animal models results in loss of retinal ganglion cells by apoptosis, blockade of axonal transport, activation of optic nerve head astrocytes contributing to optic neuropathy similar to that observed in glaucoma (Stokely et al, 2002;Chauhan et al, 2004;Lau et al, 2006). ET-1 is also recognized as an important pro-fibrotic factor in initiating and maintaining fibrosis of various tissues, by enhancing collagen synthesis and deposition in several cell types including fibroblasts, cardiac myocytes, and smooth muscle cells (Eng and Friedman 2000;Eddy 2000;Wakatsuki et al, 2004;Clozel and Salloukh 2005;Tsukada et al, 2006;Khan ZA 2006). The role of ET-1 in the regulation of ECM collagens at the level of optic nerve head remains to be studied.…”

Section: Introductionmentioning

confidence: 99%

Endothelin-1 mediated regulation of extracellular matrix collagens in cells of human lamina cribrosa

Rao

Krishnamoorthy

Yorio

2008

Experimental Eye Research

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Endothelin-1(ET-1), a potent vaso-active peptide, mediates extracellular matrix regulation resulting in an increase in collagen deposition in various cell types and tissues and has been proposed to play a key role in glaucoma pathology. The role of ET-1 in the regulation of extracellular matrix collagens at the level of optic nerve head is not known. In this study we have examined the role of ET-1 in extracellular matrix collagen regulation in primary cultures of human lamina cribrosa cells. Our hypothesis is that ET-1 increases remodeling of the ECM of cells of the lamina cribrosa. Such actions could contribute to the development of optic neuropathy. QPCR analysis revealed that ET-1 mediated an increase in mRNA levels of collagen type I alpha 1 and collagen type VI alpha 1 chains at all doses of ET-1 with a significant increase at 1nM and 10nM concentration in LC cells. A dose dependent increase in collagen type I and type VI protein deposition and secretion was also observed by Western blot in response to ET-1 and was significant at 10nM and 100nM concentrations of ET-1. ET-1 increased the [ 3 H] proline uptake in LC cells suggesting that ET-1 contributed to an increase in total collagen synthesis in LC cells. ET-1 -mediated increase in collagen type I, type VI and total collagen synthesis was significantly blocked by the ET A receptor antagonist, BQ610, as well as with the ET B receptor antagonist, BQ788, suggesting the involvement of both receptor subtypes in ET-1 mediated collagen synthesis in LC cells. These results suggest that ET-1 regulates extra cellular matrix-collagen synthesis in LC cells and may contribute to ECM remodeling at the level of LC of POAG subjects who have elevated plasma and aqueous humor levels of endothelin-1.

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Mechanisms of liver fibrosis

Cited by 326 publications

References 362 publications

Mechanisms of Hepatic Fibrogenesis

Mechanisms of Hepatic Fibrogenesis

Relaxin receptors in hepatic stellate cells and cirrhotic liver

Endothelin-1 mediated regulation of extracellular matrix collagens in cells of human lamina cribrosa

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