Regulating NLRP3 Inflammasome-Induced Pyroptosis via Nrf2: TBHQ Limits Hyperoxia-Induced Lung Injury in a Mouse Model of Bronchopulmonary Dysplasia

Abstract

Abstract Background Nuclear factor e2-related factor 2 (Nrf2) plays a key role in cellular resistance to oxidative stress injury. Oxidative stress injury caused by Nrf2 imbalance leads to cellular abnormalities, such as increased pyroptosis, DNA damage, and inflammatory activation, which may lead to the arrest of alveolar development and bronchopulmonary dysplasia (BPD) in premature infants under hyperoxic conditions. Methods We established a BPD mouse model to investigate the effects of tert-butylhydroquinone (TBHQ), an Nrf2 activator, on oxidative stress injury, pyroptosis, NLRP3 inflammasome activation, and alveolar development. Results TBHQ reduced abnormal cell death in the lung tissue of BPD mice and restored the number and normal structure of alveoli. TBHQ administration activated the Nrf2/haem oxygenase-1 (HO-1) signalling pathway, resulting in the decrease of the following: reactive oxygen species (ROS), activation of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, and expression and activation of IL-18 and IL-1β, as well as inhibition of pyroptosis. In contrast, after Nrf2 gene knockout in BPD mice, the degree of oxidative stress injury and cell death in the lungs was more severe, and the development of alveoli was significantly blocked. Conclusions We demonstrate that TBHQ may promote alveolar development by enhancing the level of Nrf2-induced antioxidation in the lung tissue of BPD mice, and that the decrease in the NLRP3 inflammasome and pyroptosis caused by Nrf2 activation may be the main mechanism at play. These results suggest that TBHQ is a promising treatment for lung injury in premature infants with hyperoxia.