Reversal of Persistent Fibrosis in Aging by Targeting Nox4-Nrf2 Redox Imbalance

Fibrosis resolution is impaired by aging and is mediated by altered cellular redox homeostasis because of a Nox4-Nrf2 imbalance that promotes an apoptosis-resistant myofibroblast phenotype. Scarred for Life? Fibrosis or “scarring” of vital internal organs is an increasing cause of debilitation and death worldwide. The risk of organ fibrosis increases with age, accounting for a growing “epidemic” of fibrotic disorders in aging populations such as in the United States. A study by Hecker et al. provides new insights into how the aging process may lead to a predisposition to fibrosis. In a mouse model of injury-induced lung fibrosis, these investigators found that the ability to resolve fibrosis was impaired in aged mice compared to young cohorts. Resolution of fibrosis is normally dependent on a process known as “apoptosis” (or programmed cell death) of myofibroblasts in injured tissues; this normal wound-healing response was found to be less efficient in aged mice. Myofibroblasts from aged mice acquired a prolonged senescent and apoptosis-resistant phenotype, which was attributed to an imbalance between the oxidant-generating enzyme Nox4 [reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-4] and the antioxidant response factor Nrf2 (NFE2-related factor 2). Genetic or pharmacologic approaches to suppress the expression or activation of Nox4 in aged mice with persistent fibrosis enhanced the capacity for fibrosis resolution. There was evidence for Nox4-Nrf2 imbalance and apoptosis-resistant behavior of myofibroblasts in the lungs of human subjects with the progressive and fatal fibrotic disorder idiopathic pulmonary fibrosis. The results of these studies improve our understanding of how and why elderly patients become susceptible to progressive fibrotic disorders, such as idiopathic pulmonary fibrosis. Additionally, this study uncovers new approaches for treating fibrotic disorders by targeting the “stubborn” and apoptosis-resistant myofibroblast. 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.