Preconditioning the immature lung with enhanced Nrf2 activity protects against oxidant-induced hypoalveolarization in mice

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic disease of preterm babies with poor clinical outcomes. Nrf2 transcription factor is crucial for cytoprotective response, whereas Keap1—an endogenous inhibitor of Nrf2 signaling—dampens these protective responses. Nrf2-sufficient (wild type) newborn mice exposed to hyperoxia develop hypoalveolarization, which phenocopies human BPD, and Nrf2 deficiency worsens it. In this study, we used PND1 pups bearing bearing hypomorphic Keap1 floxed alleles (Keap1f/f) with increased levels of Nrf2 to test the hypothesis that constitutive levels of Nrf2 in the premature lung are insufficient to mitigate hyperoxia-induced hypoalveolarization. Both wildtype and Keap1f/f pups at PND1 were exposed to hyperoxia for 72 h and then allowed to recover at room air for two weeks (at PND18), sacrificed, and lung hypoalveolarization and inflammation assessed. Hyperoxia-induced lung hypoalveolarization was remarkably lower in Keap1f/f pups than in wildtype counterparts (28.9% vs 2.4%, wildtype vs Keap1f/f). Likewise, Keap1f/f pups were protected against prolonged (96 h) hyperoxia-induced hypoalveolarization. However, there were no differences in hyperoxia-induced lung inflammatory response immediately after exposure or at PND18. Lack of hypoalveolarization in Keap1f/f pups was accompanied by increased levels of expression of antioxidant genes and GSH as assessed immediately following hyperoxia. Keap1 knockdown resulted in upregulation of lung cell proliferation postnatally but had opposing effects following hyperoxia. Collectively, our study demonstrates that augmenting endogenous Nrf2 activation by targeting Keap1 may provide a physiological way to prevent hypoalveolarization associated with prematurity.

Oxygen Toxicity to the Immature Lung—Part I: Pathomechanistic Understanding and Preclinical Perspectives

“…Several approaches have tested the potential of augmenting Nrf2 activity, including preconditioning of the lung by targeting Keap1 and treatment with rapamycin, which resulted in increased baseline Nrf2 levels and antioxidant capacity. While the inflammatory response to hyperoxia was not altered in Nrf2-augmented mice, hypoalveolarization was markedly reduced [4,55]. In recent years, it has become clear that miRNA regulations constitute key events in the pathogenesis of BPD in hyperoxic injury models, and comparable changes have been documented in infants with BPD [56].…”

Echinatin mitigates H2O2-induced oxidative damage and apoptosis in lens epithelial cells via the Nrf2/HO-1 pathway

“…Nrf2 is dissociated from Keap1 and transferred to the nucleus under the stimulation of oxidative stress, phosphorylation or electrophiles. 50 HO-1 and NQO1 are the key downstream factors of Nrf2 signal transduction, which are very important in protecting cells from the oxidative damage. 51,52 Recent studies have shown that trimetazidine can delay the formation of age-related cataracts by regulating the expression of Nrf2 and reducing the production of ROS.…”

Auranofin-Mediated NRF2 Induction Attenuates Interleukin 1 Beta Expression in Alveolar Macrophages

“…AREs are found in many antioxidant genes and are responsible for upregulating cellular defenses (NRF2 pathway reviewed in [23]). Enhancement of the NRF2 activity has demonstrated protective effects in several models of lung injury [24][25][26][27][28]. As a result, modulation of NRF2 has become an attractive drug target for inflammatory diseases (reviewed in [27]).…”