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The role of redox mechanisms in hepatic chronic wound healing and fibrogenesis.

Novo E, Parola M - Fibrogenesis Tissue Repair (2012)

Bottom Line: Under physiological conditions, intracellular and tissue levels of reactive oxygen species (ROS) are carefully controlled and employed as fine modulators of signal transduction, gene expression and cell functional responses (redox signaling).A significant derangement in redox homeostasis, resulting in sustained levels of oxidative stress and related mediators, plays a role in the pathogenesis of human diseases characterized by chronic inflammation, chronic activation of wound healing and tissue fibrogenesis, including chronic liver diseases.A major focus will be on redox-dependent mechanisms involved in the modulation of phenotypic responses of activated, myofibroblast-like, hepatic stellate cells (HSC/MFs), still considered as the most relevant pro-fibrogenic cells operating in chronic liver diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Experimental Medicine and Oncology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy ; Interuniversity Centre for Liver Pathophysiology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy.

ABSTRACT
Under physiological conditions, intracellular and tissue levels of reactive oxygen species (ROS) are carefully controlled and employed as fine modulators of signal transduction, gene expression and cell functional responses (redox signaling). A significant derangement in redox homeostasis, resulting in sustained levels of oxidative stress and related mediators, plays a role in the pathogenesis of human diseases characterized by chronic inflammation, chronic activation of wound healing and tissue fibrogenesis, including chronic liver diseases. In this chapter major concepts and mechanisms in redox signaling will be briefly recalled to introduce a number of selected examples of redox-related mechanisms that can actively contribute to critical events in the natural history of a chronic liver diseases, including induction of cell death, perpetuation of chronic inflammatory responses and fibrogenesis. A major focus will be on redox-dependent mechanisms involved in the modulation of phenotypic responses of activated, myofibroblast-like, hepatic stellate cells (HSC/MFs), still considered as the most relevant pro-fibrogenic cells operating in chronic liver diseases.

No MeSH data available.


Related in: MedlinePlus

ROS and related mediators as pro-fibrogenic stimuli for hepatic myofibroblasts. Activated hepatic stellate cells (HSC/MFs) and/or other populations of hepatic MFs may be envisaged as putative "target" cells that modify their behavior and phenotypic responses when exposed to the action of ROS and other oxidative stress - related reactive intermediates (for example, 4-hydroxynonenal or HNE, a major aldehydic end-product of lipid peroxidation elicited through different mechanisms). ROS and the other reactive intermediates can be formed following damage to hepatocytes, activation of either resident kupffer cells or macrophages recruited from peripheral circulation, release from damaged mitochondria, generation following activation of certain cytochrome P450 isoforms (as in chronic ethanol-mediated injury or in condition of NAFLD and NASH), to name just the most relevant options. More details can be found in the text.
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Figure 4: ROS and related mediators as pro-fibrogenic stimuli for hepatic myofibroblasts. Activated hepatic stellate cells (HSC/MFs) and/or other populations of hepatic MFs may be envisaged as putative "target" cells that modify their behavior and phenotypic responses when exposed to the action of ROS and other oxidative stress - related reactive intermediates (for example, 4-hydroxynonenal or HNE, a major aldehydic end-product of lipid peroxidation elicited through different mechanisms). ROS and the other reactive intermediates can be formed following damage to hepatocytes, activation of either resident kupffer cells or macrophages recruited from peripheral circulation, release from damaged mitochondria, generation following activation of certain cytochrome P450 isoforms (as in chronic ethanol-mediated injury or in condition of NAFLD and NASH), to name just the most relevant options. More details can be found in the text.

Mentions: Literature data of the last two decades have outlined that activated, MF-like, hepatic stellate cells (HSC/MFs) and, likely, MFs of different origin, are ideal pro-fibrogenic targets for ROS and HNE (Figure 4)[5,16-18]. Best characterized mechanisms and concepts are the following: a) antioxidant supplementation can prevent or reduce liver fibrosis in experimental models; b) ROS and HNE exert a direct, paracrine pro-fibrogenic action on human HSC/MFs by up-regulating pro-collagen type I expression, although through different signalling pathways [5], and the same event follows intracellular generation of ROS by TGFβ1 and leptin [34]; c) intracellular generation of ROS occurs in HSC/MFs and hepatic MFs in association to cytokine-receptor interactions and parallel activation of NADPH-oxidase [5,10,35], revealing a novel putative direct or indirect (as the case of losartan for AT-1 receptor) target for therapy in CLDs; d) increased intracellular levels of ROS, whatever the cause (cytokine-receptor interaction, entry from extracellular environment, increased mitochondrial release under hypoxic conditions, following iron overload or ER stress) is sufficient to stimulate oriented migration in target pro-fibrogenic cells through a biphasic mechanism [36-38]; e) intracellular generation of ROS is emerging as a common mechanism able to mediate the pro-angiogenic action of PDGF-BB and leptin on human HSC/MFs [39,40]; f) the specific mediator makes the difference, with ROS being able to up-modulate MFs proliferation [5] and chemotaxis [29] and HNE having no effect on migration or even able to inhibit PDGF-dependent proliferation by specifically targeting PDGF-βR tyrosine kinase [41].


The role of redox mechanisms in hepatic chronic wound healing and fibrogenesis.

Novo E, Parola M - Fibrogenesis Tissue Repair (2012)

ROS and related mediators as pro-fibrogenic stimuli for hepatic myofibroblasts. Activated hepatic stellate cells (HSC/MFs) and/or other populations of hepatic MFs may be envisaged as putative "target" cells that modify their behavior and phenotypic responses when exposed to the action of ROS and other oxidative stress - related reactive intermediates (for example, 4-hydroxynonenal or HNE, a major aldehydic end-product of lipid peroxidation elicited through different mechanisms). ROS and the other reactive intermediates can be formed following damage to hepatocytes, activation of either resident kupffer cells or macrophages recruited from peripheral circulation, release from damaged mitochondria, generation following activation of certain cytochrome P450 isoforms (as in chronic ethanol-mediated injury or in condition of NAFLD and NASH), to name just the most relevant options. More details can be found in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368756&req=5

Figure 4: ROS and related mediators as pro-fibrogenic stimuli for hepatic myofibroblasts. Activated hepatic stellate cells (HSC/MFs) and/or other populations of hepatic MFs may be envisaged as putative "target" cells that modify their behavior and phenotypic responses when exposed to the action of ROS and other oxidative stress - related reactive intermediates (for example, 4-hydroxynonenal or HNE, a major aldehydic end-product of lipid peroxidation elicited through different mechanisms). ROS and the other reactive intermediates can be formed following damage to hepatocytes, activation of either resident kupffer cells or macrophages recruited from peripheral circulation, release from damaged mitochondria, generation following activation of certain cytochrome P450 isoforms (as in chronic ethanol-mediated injury or in condition of NAFLD and NASH), to name just the most relevant options. More details can be found in the text.
Mentions: Literature data of the last two decades have outlined that activated, MF-like, hepatic stellate cells (HSC/MFs) and, likely, MFs of different origin, are ideal pro-fibrogenic targets for ROS and HNE (Figure 4)[5,16-18]. Best characterized mechanisms and concepts are the following: a) antioxidant supplementation can prevent or reduce liver fibrosis in experimental models; b) ROS and HNE exert a direct, paracrine pro-fibrogenic action on human HSC/MFs by up-regulating pro-collagen type I expression, although through different signalling pathways [5], and the same event follows intracellular generation of ROS by TGFβ1 and leptin [34]; c) intracellular generation of ROS occurs in HSC/MFs and hepatic MFs in association to cytokine-receptor interactions and parallel activation of NADPH-oxidase [5,10,35], revealing a novel putative direct or indirect (as the case of losartan for AT-1 receptor) target for therapy in CLDs; d) increased intracellular levels of ROS, whatever the cause (cytokine-receptor interaction, entry from extracellular environment, increased mitochondrial release under hypoxic conditions, following iron overload or ER stress) is sufficient to stimulate oriented migration in target pro-fibrogenic cells through a biphasic mechanism [36-38]; e) intracellular generation of ROS is emerging as a common mechanism able to mediate the pro-angiogenic action of PDGF-BB and leptin on human HSC/MFs [39,40]; f) the specific mediator makes the difference, with ROS being able to up-modulate MFs proliferation [5] and chemotaxis [29] and HNE having no effect on migration or even able to inhibit PDGF-dependent proliferation by specifically targeting PDGF-βR tyrosine kinase [41].

Bottom Line: Under physiological conditions, intracellular and tissue levels of reactive oxygen species (ROS) are carefully controlled and employed as fine modulators of signal transduction, gene expression and cell functional responses (redox signaling).A significant derangement in redox homeostasis, resulting in sustained levels of oxidative stress and related mediators, plays a role in the pathogenesis of human diseases characterized by chronic inflammation, chronic activation of wound healing and tissue fibrogenesis, including chronic liver diseases.A major focus will be on redox-dependent mechanisms involved in the modulation of phenotypic responses of activated, myofibroblast-like, hepatic stellate cells (HSC/MFs), still considered as the most relevant pro-fibrogenic cells operating in chronic liver diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Experimental Medicine and Oncology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy ; Interuniversity Centre for Liver Pathophysiology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy.

ABSTRACT
Under physiological conditions, intracellular and tissue levels of reactive oxygen species (ROS) are carefully controlled and employed as fine modulators of signal transduction, gene expression and cell functional responses (redox signaling). A significant derangement in redox homeostasis, resulting in sustained levels of oxidative stress and related mediators, plays a role in the pathogenesis of human diseases characterized by chronic inflammation, chronic activation of wound healing and tissue fibrogenesis, including chronic liver diseases. In this chapter major concepts and mechanisms in redox signaling will be briefly recalled to introduce a number of selected examples of redox-related mechanisms that can actively contribute to critical events in the natural history of a chronic liver diseases, including induction of cell death, perpetuation of chronic inflammatory responses and fibrogenesis. A major focus will be on redox-dependent mechanisms involved in the modulation of phenotypic responses of activated, myofibroblast-like, hepatic stellate cells (HSC/MFs), still considered as the most relevant pro-fibrogenic cells operating in chronic liver diseases.

No MeSH data available.


Related in: MedlinePlus