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Mechanisms of pulmonary fibrosis: role of activated myofibroblasts and NADPH oxidase.

Thannickal VJ - Fibrogenesis Tissue Repair (2012)

Bottom Line: A common feature of pathological fibrosis involving the lung and other organs is the persistent activation of myofibroblasts in injured tissues.Recent evidence supports the role of a member of the NADPH oxidase (NOX) gene family, NOX4, in myofibroblast differentiation, matrix synthesis and contractility.Therapeutic targeting of NOX4 is likely to be effective in progressive cases of fibrosis involving multiple organs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, 1530 3rd Avenue South, THT 422, Birmingham, AL 35294-0006, USA.

ABSTRACT
A common feature of pathological fibrosis involving the lung and other organs is the persistent activation of myofibroblasts in injured tissues. Recent evidence supports the role of a member of the NADPH oxidase (NOX) gene family, NOX4, in myofibroblast differentiation, matrix synthesis and contractility. Additionally, NOX4 may contribute directly or indirectly to alveolar epithelial cell death, while myofibroblasts themselves acquire an apoptosis-resistant phenotype. Thus, NOX4 may be responsible for the cardinal features of progressive fibrosis - myofibroblast activation and epithelial cell dysrepair. Therapeutic targeting of NOX4 is likely to be effective in progressive cases of fibrosis involving multiple organs.

No MeSH data available.


Related in: MedlinePlus

Hypothetical model of a central role of NADPH oxidase-4 (NOX4) in pathological fibrosis: Aging, environmental and genetic/epigenetic factors influence the persistent expression/activation of NADPH oxidase 4 (NOX4) in fibrotic tissues. This may be due to aberrations in injury repair responses or in maintenance regeneration, resulting in a failure to maintain cellular homeostasis in fibrotic tissues. Loss of tissue homeostasis is characterized by myofibroblast activation and epithelial cell dysrepair, with their attendant cellular phenotypes, that promotes pathological tissue fibrosis.
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Figure 1: Hypothetical model of a central role of NADPH oxidase-4 (NOX4) in pathological fibrosis: Aging, environmental and genetic/epigenetic factors influence the persistent expression/activation of NADPH oxidase 4 (NOX4) in fibrotic tissues. This may be due to aberrations in injury repair responses or in maintenance regeneration, resulting in a failure to maintain cellular homeostasis in fibrotic tissues. Loss of tissue homeostasis is characterized by myofibroblast activation and epithelial cell dysrepair, with their attendant cellular phenotypes, that promotes pathological tissue fibrosis.

Mentions: Pulmonary fibrosis results from a large number of known causes (e.g. organic and inorganic dust exposures); however, a specific etiological agent in IPF has not been identified [3]. A number of risk factors have been identified; these include inhalational exposures, including cigarette smoking, gastroesophageal reflux, diabetes mellitus, and advanced age. Given the natural course of the disease and the epidemiologcal data supporting the concept that IPF is an age-associated disease [4], one possibility is that this results from a failure of "maintenance regeneration" due to a combination of chronic, subclinical insults in a subset of genetically-susceptible, elderly patients (Figure 1). Indeed, telomerase mutations have been identified in familial IPF [5,6], and shortened telomeres appear to be a risk factor for sporadic IPF [7]. Fibrosis associated with "injury-provoked regeneration" which may be easier to recognize clinically due to the relative acuteness of disease onset and progression, as in diseases such as hypersensitivity pneumonitis.


Mechanisms of pulmonary fibrosis: role of activated myofibroblasts and NADPH oxidase.

Thannickal VJ - Fibrogenesis Tissue Repair (2012)

Hypothetical model of a central role of NADPH oxidase-4 (NOX4) in pathological fibrosis: Aging, environmental and genetic/epigenetic factors influence the persistent expression/activation of NADPH oxidase 4 (NOX4) in fibrotic tissues. This may be due to aberrations in injury repair responses or in maintenance regeneration, resulting in a failure to maintain cellular homeostasis in fibrotic tissues. Loss of tissue homeostasis is characterized by myofibroblast activation and epithelial cell dysrepair, with their attendant cellular phenotypes, that promotes pathological tissue fibrosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368794&req=5

Figure 1: Hypothetical model of a central role of NADPH oxidase-4 (NOX4) in pathological fibrosis: Aging, environmental and genetic/epigenetic factors influence the persistent expression/activation of NADPH oxidase 4 (NOX4) in fibrotic tissues. This may be due to aberrations in injury repair responses or in maintenance regeneration, resulting in a failure to maintain cellular homeostasis in fibrotic tissues. Loss of tissue homeostasis is characterized by myofibroblast activation and epithelial cell dysrepair, with their attendant cellular phenotypes, that promotes pathological tissue fibrosis.
Mentions: Pulmonary fibrosis results from a large number of known causes (e.g. organic and inorganic dust exposures); however, a specific etiological agent in IPF has not been identified [3]. A number of risk factors have been identified; these include inhalational exposures, including cigarette smoking, gastroesophageal reflux, diabetes mellitus, and advanced age. Given the natural course of the disease and the epidemiologcal data supporting the concept that IPF is an age-associated disease [4], one possibility is that this results from a failure of "maintenance regeneration" due to a combination of chronic, subclinical insults in a subset of genetically-susceptible, elderly patients (Figure 1). Indeed, telomerase mutations have been identified in familial IPF [5,6], and shortened telomeres appear to be a risk factor for sporadic IPF [7]. Fibrosis associated with "injury-provoked regeneration" which may be easier to recognize clinically due to the relative acuteness of disease onset and progression, as in diseases such as hypersensitivity pneumonitis.

Bottom Line: A common feature of pathological fibrosis involving the lung and other organs is the persistent activation of myofibroblasts in injured tissues.Recent evidence supports the role of a member of the NADPH oxidase (NOX) gene family, NOX4, in myofibroblast differentiation, matrix synthesis and contractility.Therapeutic targeting of NOX4 is likely to be effective in progressive cases of fibrosis involving multiple organs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, 1530 3rd Avenue South, THT 422, Birmingham, AL 35294-0006, USA.

ABSTRACT
A common feature of pathological fibrosis involving the lung and other organs is the persistent activation of myofibroblasts in injured tissues. Recent evidence supports the role of a member of the NADPH oxidase (NOX) gene family, NOX4, in myofibroblast differentiation, matrix synthesis and contractility. Additionally, NOX4 may contribute directly or indirectly to alveolar epithelial cell death, while myofibroblasts themselves acquire an apoptosis-resistant phenotype. Thus, NOX4 may be responsible for the cardinal features of progressive fibrosis - myofibroblast activation and epithelial cell dysrepair. Therapeutic targeting of NOX4 is likely to be effective in progressive cases of fibrosis involving multiple organs.

No MeSH data available.


Related in: MedlinePlus