title: Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner.
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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Shasha
authors.initials: S
authors.lastname: Tao
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Rojo de la Vega
authors.affiliation: Arizona Respiratory Center and Department of Medicine, University of Arizona, Tucson, AZ 85721.
authors.forename: Hector
authors.initials: H
authors.lastname: Quijada
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.|Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Georg T
authors.initials: GT
authors.lastname: Wondrak
authors.affiliation: Arizona Respiratory Center and Department of Medicine, University of Arizona, Tucson, AZ 85721.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Arizona Respiratory Center and Department of Medicine, University of Arizona, Tucson, AZ 85721.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.|Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724, USA.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002338:Carotenoids / Q000494:pharmacology*; D004249:DNA Damage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D020011:Protective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D054875:Ubiquitination; D055397:Ventilator-Induced Lung Injury / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D020011:Protective Agents; D002338:Carotenoids; C004588:bixin