Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner.

TitleBixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner.
Publication TypeJournal Article
Year of Publication2016
AuthorsTao S, de la Vega MRojo, Quijada H, Wondrak GT, Wang T, Garcia JGN, Zhang DD
JournalSci Rep
Volume6
Pagination18760
Date Published2016 Jan 05
ISSN Number2045-2322
KeywordsAnimals, Anti-Inflammatory Agents, Antioxidants, Carotenoids, Disease Models, Animal, DNA Damage, Dose-Response Relationship, Drug, Female, Kelch-Like ECH-Associated Protein 1, Lung, Mice, Mice, Knockout, NF-E2-Related Factor 2, NF-kappa B, Oxidative Stress, Phosphorylation, Protective Agents, Signal Transduction, Ubiquitination, Ventilator-Induced Lung Injury
Abstract

<p>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.</p>

DOI10.1038/srep18760
Alternate JournalSci Rep
PubMed ID26729554
PubMed Central IDPMC4700431
Grant List2R01 ES015010 / ES / NIEHS NIH HHS / United States
R03 CA167580 / CA / NCI NIH HHS / United States
P30ES006694 / ES / NIEHS NIH HHS / United States
P30 ES006694 / ES / NIEHS NIH HHS / United States
HL91899 / HL / NHLBI NIH HHS / United States
1R03CA167580 / CA / NCI NIH HHS / United States
R01 CA154377 / CA / NCI NIH HHS / United States
P01 HL126609 / HL / NHLBI NIH HHS / United States
HL58064 / HL / NHLBI NIH HHS / United States
P01 HL058064 / HL / NHLBI NIH HHS / United States
R01 ES015010 / ES / NIEHS NIH HHS / United States
R01 HL091889 / HL / NHLBI NIH HHS / United States