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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.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.

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

Major events involved in the fibrogenic progression of chronic liver diseases. CLDs may involve different aetiological agents or conditions able to cause persisting (i.e., chronic) parenchymal liver injury and then hepatocyte cell death (either necrosis or apoptosis). As a result of chronic liver injury, a persistent inflammatory reaction can occur which may significantly affect the progression of the disease by either contributing to the perpetuation of parenchymal injury or by generating a microenvironment pressure in terms of growth factor, cytokine and other mediators that can efficiently favour tissue repair and the activation of pro-fibrogenic cells. This is the scenario that will lead to the persistent activation of myofibroblast-like cells from different precursors. Activated MFs will contribute either to perpetuation of inflammation by releasing pro-inflammatory mediators or to the excess synthesis and accumulation of fibrillar (rich in collagen type I and III) extracellular matrix (ECM) components. If the aetiological agent or causal condition persists, the CLD can undergo a fibrosclerotic progression to cirrhosis and liver failure. Since cirrhosis is characterized by formation of regenerative nodules of parenchyma surrounded and separated by fibrotic septa, this scenario is intrinsically associated with significant changes in hepatic angio-architecture. Fibrosis itself as well as the development of hypoxic areas have been reported to further contribute to perpetuation of liver injury.
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Figure 3: Major events involved in the fibrogenic progression of chronic liver diseases. CLDs may involve different aetiological agents or conditions able to cause persisting (i.e., chronic) parenchymal liver injury and then hepatocyte cell death (either necrosis or apoptosis). As a result of chronic liver injury, a persistent inflammatory reaction can occur which may significantly affect the progression of the disease by either contributing to the perpetuation of parenchymal injury or by generating a microenvironment pressure in terms of growth factor, cytokine and other mediators that can efficiently favour tissue repair and the activation of pro-fibrogenic cells. This is the scenario that will lead to the persistent activation of myofibroblast-like cells from different precursors. Activated MFs will contribute either to perpetuation of inflammation by releasing pro-inflammatory mediators or to the excess synthesis and accumulation of fibrillar (rich in collagen type I and III) extracellular matrix (ECM) components. If the aetiological agent or causal condition persists, the CLD can undergo a fibrosclerotic progression to cirrhosis and liver failure. Since cirrhosis is characterized by formation of regenerative nodules of parenchyma surrounded and separated by fibrotic septa, this scenario is intrinsically associated with significant changes in hepatic angio-architecture. Fibrosis itself as well as the development of hypoxic areas have been reported to further contribute to perpetuation of liver injury.

Mentions: A redox sensor is a redox-sensitive specialized protein, that is able to "sense" intracellular levels of ROS by a redox-based mechanism affecting one or more residues/domains within its three-dimensional structure, then transforming the redox change into a specific "signal" able to positively affect signalling pathways (particularly those elicited by interaction of growth factors, cytokines, chemokines and other peptides with their respective receptors) and transcription of redox-sensitive genes. In conditions of chronic liver diseases (see major events in Figure 3) the following mechanisms and concepts are likely to have a major role (for more details see ref. [2-5,9,10]).


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

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

Major events involved in the fibrogenic progression of chronic liver diseases. CLDs may involve different aetiological agents or conditions able to cause persisting (i.e., chronic) parenchymal liver injury and then hepatocyte cell death (either necrosis or apoptosis). As a result of chronic liver injury, a persistent inflammatory reaction can occur which may significantly affect the progression of the disease by either contributing to the perpetuation of parenchymal injury or by generating a microenvironment pressure in terms of growth factor, cytokine and other mediators that can efficiently favour tissue repair and the activation of pro-fibrogenic cells. This is the scenario that will lead to the persistent activation of myofibroblast-like cells from different precursors. Activated MFs will contribute either to perpetuation of inflammation by releasing pro-inflammatory mediators or to the excess synthesis and accumulation of fibrillar (rich in collagen type I and III) extracellular matrix (ECM) components. If the aetiological agent or causal condition persists, the CLD can undergo a fibrosclerotic progression to cirrhosis and liver failure. Since cirrhosis is characterized by formation of regenerative nodules of parenchyma surrounded and separated by fibrotic septa, this scenario is intrinsically associated with significant changes in hepatic angio-architecture. Fibrosis itself as well as the development of hypoxic areas have been reported to further contribute to perpetuation of liver injury.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Major events involved in the fibrogenic progression of chronic liver diseases. CLDs may involve different aetiological agents or conditions able to cause persisting (i.e., chronic) parenchymal liver injury and then hepatocyte cell death (either necrosis or apoptosis). As a result of chronic liver injury, a persistent inflammatory reaction can occur which may significantly affect the progression of the disease by either contributing to the perpetuation of parenchymal injury or by generating a microenvironment pressure in terms of growth factor, cytokine and other mediators that can efficiently favour tissue repair and the activation of pro-fibrogenic cells. This is the scenario that will lead to the persistent activation of myofibroblast-like cells from different precursors. Activated MFs will contribute either to perpetuation of inflammation by releasing pro-inflammatory mediators or to the excess synthesis and accumulation of fibrillar (rich in collagen type I and III) extracellular matrix (ECM) components. If the aetiological agent or causal condition persists, the CLD can undergo a fibrosclerotic progression to cirrhosis and liver failure. Since cirrhosis is characterized by formation of regenerative nodules of parenchyma surrounded and separated by fibrotic septa, this scenario is intrinsically associated with significant changes in hepatic angio-architecture. Fibrosis itself as well as the development of hypoxic areas have been reported to further contribute to perpetuation of liver injury.
Mentions: A redox sensor is a redox-sensitive specialized protein, that is able to "sense" intracellular levels of ROS by a redox-based mechanism affecting one or more residues/domains within its three-dimensional structure, then transforming the redox change into a specific "signal" able to positively affect signalling pathways (particularly those elicited by interaction of growth factors, cytokines, chemokines and other peptides with their respective receptors) and transcription of redox-sensitive genes. In conditions of chronic liver diseases (see major events in Figure 3) the following mechanisms and concepts are likely to have a major role (for more details see ref. [2-5,9,10]).

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.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.

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