Idiopathic pulmonary fibrosis (IPF) is a fatal disease, characterized by progressive scar tissue formation leading to respiratory failure. The incidence and prevalence of IPF increase with age, with a mean age of 66 years at the time of diagnosis. However, the mechanism(s) for this age-associated predilection are not known. Aged (18m) C57BL6 mice were subjected to bleomycin-induced lung fibrosis.  We evaluated the efficacy of genetic and pharmacologic strategies to inhibit Nox4 in aged mice with established persistent fibrosis.   Fibrosis was assessed at 6 weeks post-injury by whole tissue morphology, immunohistochemistry, and biochemical assays. Body weights and survival were monitored throughout the study.  Our studies indicate that Nox4 expression remains elevated in fibrogenic regions of aged mice with persistent lung fibrosis; Genetic or pharmacologic inhibition of Nox4 in these mice led to recovery to baseline body weights, whereas vehicle-treated mice remained below baseline levels throughout the observation period.  Further, inhibition of Nox4 led to decreased myofibroblast accumulation with decreased expression of senescence markers p21 and p16.  Importantly, Nox4 inhibition led to a reversal of age-associated persistent fibrosis and improved survival.  These studies indicate that upregulation of the ROS-generating enzyme, Nox4, results in sustained and persistent senescence of myofibroblasts that confer an apoptosis-resistant phenotype to these reparative cells.  While we have shown previously that targeting Nox4 at the time of injury ameliorates the development of injury-induced lung fibrosis in young mice, these studies demonstrate for the first time that targeting Nox4 in aged mice with established lung fibrosis promotes resolution.  These studies demonstrate proof-of-concept for therapeutic targeting of Nox4 which may represent an effective therapeutic strategy for age-associated fibrotic lung disease.   Finally, these target validation studies are the basis of novel a high throughput screening strategy to identify novel compounds that are highly selective for Nox4.<br/> <br/> <br/> <br/>

Therapeutic targeting of Nox4 leads to reversal of age-associated persistent fibrosis

249th National Meeting (2015)

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