Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance
- PMID: 24718857
- PMCID: PMC4545252
- DOI: 10.1126/scitranslmed.3008182
Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance
Abstract
The incidence and prevalence of pathological fibrosis increase with advancing age, although mechanisms for this association are unclear. We assessed the capacity for repair of lung injury in young (2 months) and aged (18 months) mice. Whereas the severity of fibrosis was not different between these groups, aged mice demonstrated an impaired capacity for fibrosis resolution. Persistent fibrosis in lungs of aged mice was characterized by the accumulation of senescent and apoptosis-resistant myofibroblasts. These cellular phenotypes were sustained by alterations in cellular redox homeostasis resulting from elevated expression of the reactive oxygen species-generating enzyme Nox4 [NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase-4] and an impaired capacity to induce the Nrf2 (NFE2-related factor 2) antioxidant response. Lung tissues from human subjects with idiopathic pulmonary fibrosis (IPF), a progressive and fatal lung disease, also demonstrated this Nox4-Nrf2 imbalance. Nox4 mediated senescence and apoptosis resistance in IPF fibroblasts. Genetic and pharmacological targeting of Nox4 in aged mice with established fibrosis attenuated the senescent, antiapoptotic myofibroblast phenotype and led to a reversal of persistent fibrosis. These studies suggest that loss of cellular redox homeostasis promotes profibrotic myofibroblast phenotypes that result in persistent fibrosis associated with aging. Our studies suggest that restoration of Nox4-Nrf2 redox balance in myofibroblasts may be a therapeutic strategy in age-associated fibrotic disorders, potentially able to resolve persistent fibrosis or even reverse its progression.
Conflict of interest statement
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Comment in
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Lung disease: resetting the redox balance in lung fibrosis.Nat Rev Drug Discov. 2014 Jun;13(6):415. doi: 10.1038/nrd4344. Epub 2014 May 16. Nat Rev Drug Discov. 2014. PMID: 24833297 No abstract available.
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Putting the brakes on age-related idiopathic pulmonary fibrosis: can Nox4 inhibitors suppress IPF?Exp Gerontol. 2015 Mar;63:81-2. doi: 10.1016/j.exger.2015.02.002. Epub 2015 Feb 8. Exp Gerontol. 2015. PMID: 25668226 No abstract available.
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