Abstract
Mechanical ventilation (MV) is a therapeutic intervention widely used in the clinic to assist patients that have difficulty breathing due to lung edema, trauma, or general anesthesia. However, MV causes ventilator-induced lung injury (VILI), a condition characterized by increased permeability of the alveolar-capillary barrier that results in edema, hemorrhage, and neutrophil infiltration, leading to exacerbated lung inflammation and oxidative stress. This study explored the feasibility of using bixin, a canonical NRF2 inducer identified during the current study, to ameliorate lung damage in a murine VILI model. In vitro, bixin was found to activate the NRF2 signaling pathway through blockage of ubiquitylation and degradation of NRF2 in a KEAP1-C151 dependent manner; intraperitoneal (IP) injection of bixin led to pulmonary upregulation of the NRF2 response in vivo. Remarkably, IP administration of bixin restored normal lung morphology and attenuated inflammatory response and oxidative DNA damage following MV. This observed beneficial effect of bixin derived from induction of the NRF2 cytoprotective response since it was only observed in Nrf2+/+ but not in Nrf2−/− mice. This is the first study providing proof-of-concept that NRF2 activators can be developed into pharmacological agents for clinical use to prevent patients from lung injury during MV treatment.
Highlights
Against various types of stresses encountered subsequently
ventilation-induced lung injury (VILI) is a negative side effect of Mechanical ventilation (MV) that contributes to patient morbidity and mortality despite being the most effective therapy against respiratory deficiencies
In the pathology of VILI, two major events have been identified: volutrauma and biotrauma[44]
Summary
Against various types of stresses encountered subsequently. The use of natural compounds to activate NRF2 signaling has proven to be a feasible chemopreventive strategy, as demonstrated in various preclinical studies[18,19,20]. We identified bixin as a novel canonical NRF2 inducer, implying the previously defined antioxidant and anti-inflammatory properties of bixin may be derived from activation of the NRF2-mediated response, rather than acting as a direct ROS scavenger as previously reported. Bixin protects against VILI by suppression of inflammatory mediators, reduction in alveolar capillary leakage, and protection against DNA oxidative damage in an NRF2-dependant manner. These results suggest that pharmacological activation of NRF2 by bixin pretreatment may ameliorate the lung damage induced by MV, which could constitute the first clinical intervention to prevent VILI
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