Functions of the fibrinolytic system in human ito cells and its control by basic fibroblast and platelet-derived growth factor

Fibbi, Gabriella; Pucci, Marco; Grappone, Cecilia; Pellegrini, G.; Salzano, R.; Casini, Alessandro; Milani, Stefano; Rosso, Mario Del

doi:10.1002/hep.510290343

Cited by 51 publications

(46 citation statements)

References 63 publications

(100 reference statements)

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“…181 Stellate cells express uroplasminogen activator receptor and its inhibitor, as well as other components of the plasmin system. [182][183][184] Collectively, these findings suggest that stellate cells contain most, if not all, of the molecules necessary to either activate or inhibit metalloproteinases.…”

Section: Matrix Degradation and Resolution Of Fibrosismentioning

confidence: 90%

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: Matrix Degradation and Resolution Of Fibrosismentioning

confidence: 90%

Mechanisms of Hepatic Fibrogenesis

2008

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“…29,39 Multiple cytokines have been implicated in HSC activation 29 including FGF1 and FGF2. 22,40 FGF1 is present in perisinusoidal HSCs in regenerating liver. 41 FGF2 elicits mitogenesis, chemotaxis, and chemoinvasion of HSCs in culture.…”

Section: Discussionmentioning

confidence: 99%

“…41 FGF2 elicits mitogenesis, chemotaxis, and chemoinvasion of HSCs in culture. 22,40 During acute CCl 4 intoxication before formation of fibrotic lesions, FGF2 was observed in centrilobular clusters of mononuclear phagocytes that were surrounded by many FGF2-negative HSCs. 42 Thus, it was suggested that phagocytederived FGF2 may participate in the recruitment and activation of HSCs at the acute stage of CCl 4 intoxication.…”

Section: Discussionmentioning

confidence: 99%

Role of Fibroblast Growth Factor Type 1 and 2 in Carbon Tetrachloride-Induced Hepatic Injury and Fibrogenesis

Wang

Jin

et al. 2003

The American Journal of Pathology

150

126

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Genomic ablation of hepatocyte-specific fibroblast growth factor receptor (FGFR)4 in mice revealed a role of FGF signaling in cholesterol and bile acid metabolism and hepatolobular restoration in response to injury without effect on liver development or hepatocyte proliferation. Although the potential role of all 23 FGF polypeptides in the liver is still unclear, the most widely studied prototypes, FGF1 and FGF2, are present and have been implicated in liver cell growth and function in vitro. To determine whether FGF1 and FGF2 play a role in response to injury and fibrosis, we examined the impact of both acute and chronic exposure to carbon tetrachloride (CCl 4 ) in the livers of FGF1-and FGF2-deficient mice. After acute CCl 4 exposure, FGF1(؊/؊)FGF2(؊/؊) mice exhibited an accelerated release of serum alanine aminotransferase similar to FGFR4 deficiency, but no effect on overall hepatolobular restoration or bile acid metabolism. The fibroblast growth factors (FGFs) comprise a family of 23 reported members that have varying affinities for variants of four different FGF receptor kinases (FGFR1 to FGFR4). 1-3 FGF1 and FGF2, the first two cloned members of the FGF family, 4,5 have received the most study, are widely expressed, and thus, predicted to be involved in tissue-specific functions and associated pathologies at their site of expression. 6,7 In vitro FGF1 affects cells of multiple origin whereas activity of FGF2 appears more limited to cells derived from mesenchyme and neuroectoderm. 8 FGF1 and FGF2 have been implicated in derivation of the liver from foregut endoderm. 9 However, mice lacking FGF1, FGF2, or both FGF1 and FGF2 are viable, fertile, and grossly indistinguishable from wild type (WT) except for modest defects in cardiovascular tissue, healing of skin wounds, and neuronal tissue. 3,10,11 This suggests that FGF1 and FGF2 alone are not essential for embryonic development or are compensated by other members of the extensive FGF ligand family. Consequently, FGF1-and FGF2-deficient animals are available for study of the role of the two factors in adult tissue homeostasis. Despite their ubiquity, little has emerged except for the modest effects of ablation of FGF1 and FGF2 in the cardiovascular, skin, and nervous systems.Although the levels of mRNA transcripts are low, longlived FGF1 and FGF2 polypeptides are present in the resting liver at significant levels. 12 This suggests that a significant reservoir of both ligands is present in the resting liver in an inactive state before activation and

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“…Six to nine photographic fields from three plates were scanned for each point. mRNA levels of uPAR, uPA and PAI-1 were determined by an internal-based semiquantitative RT-PCR, using procedures previously described [26]. The primers' sequences, the size of products and cycling profile are reported in Table 1.…”

Section: In Vitro Capillary Morphogenesis Assaymentioning

confidence: 99%

“…The primers' sequences, the size of products and cycling profile are reported in Table 1. The reaction products were analyzed by electrophoresis in 1% agarose gel containing ethidium bromide, followed by photography under ultraviolet illumination using Polaroid positive/negative instant films, and quantified as reported [26].…”

Section: In Vitro Capillary Morphogenesis Assaymentioning

confidence: 99%

TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis

Serratì

Margheri

Pucci

et al. 2009

Biochemical Pharmacology

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The role of transforming growth factor-beta (TGF) in tumor promotion and in angiogenesis is context-dependent. While TGF prevents tumor growth and angiogenesis in early phases of tumor development, evidence is accumulating about its pro-angiogenic and tumor promotion activities in late stages of tumor progression. Here we have studied, in an experimental context previously reported to disclose the pro-

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Functions of the fibrinolytic system in human ito cells and its control by basic fibroblast and platelet-derived growth factor

Cited by 51 publications

References 63 publications

Mechanisms of Hepatic Fibrogenesis

Mechanisms of Hepatic Fibrogenesis

Role of Fibroblast Growth Factor Type 1 and 2 in Carbon Tetrachloride-Induced Hepatic Injury and Fibrogenesis

TGFβ1 antagonistic peptides inhibit TGFβ1-dependent angiogenesis

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