Sodium Propionate Enhances Nrf2-Mediated Protective Defense Against Oxidative Stress and Inflammation in Lipopolysaccharide-Induced Neonatal Mice

Abstract

Background Alveolar arrest and the impaired angiogenesis caused by chronic inflammation and oxidative stress are two main factors in bronchopulmonary dysplasia (BPD). Short-chain fatty acids (SCFAs), especially propionate, possess anti-oxidant and anti-inflammatory effects. The present study was designed to examine the roles of sodium propionate (SP) on lipopolysaccharide (LPS)-challenged BPD and its potential mechanisms. Methods WT, Nrf2 -/- mice and pulmonary microvascular endothelial cells (HPMECs) were used in this study. LPS was performed to mimic BPD model both in vivo and vitro. Lung histopathology, inflammation and oxidative stress-related mRNA expressions in lungs involved in BPD pathogenesis were investigated. In addition, cell viability and angiogenesis were also tested. Results The increased nuclear factor erythroid 2-related factor (Nrf2) and decreased Kelch-like ECH-associated protein-1 (Keap-1) expressions were observed after SP treatment in the LPS-induced neonatal mouse model of BPD. In LPS-induced wild-type but not Nrf2 -/- neonatal mice, SP reduced pulmonary inflammation and oxidative stress and exhibited obvious pathological alterations of the alveoli. Moreover, in LPS-evoked HPMECs, SP accelerated Nrf2 nuclear translocation presented and exhibited cytoprotective and pro-angiogenesis effects. In addition, SP diminished the LPS-induced inflammatory response by blocking the activation of nuclear factor-kappa B pathway. Moreover, pretreatment with ML385, an Nrf2 specific inhibitor, offsets the beneficial effects of SP on inflammation, oxidative stress and angiogenesis in LPS-evoked HPMECs. Conclusion SP protects against LPS-induced lung alveolar simplification and abnormal angiogenesis in neonatal mice and HPMECs in an Nrf2-dependent manner.

Maternal propionate supplementation ameliorates glucose and lipid metabolic disturbance in hypoxia-induced fetal growth restriction

“…For experiments with the SP treatment, maternal mice were administered SP (200 mmol L −1 , Sigma-Aldrich, USA) in the drinking water ad libitum at the termination of hypoxia exposure until 14 d postpartum while the control and IUGR dams still drank normally (n = 3 per group). 25,26 After 14 d postpartum, all dams drank normally until the end of lactation. Male offspring from dams were selected after postnatal day 21 (PN 21) and housed on a 12 h light/dark cycle in a temperature-controlled room with standard chow and tap water ad libitum.…”

“…23,24 In our previous studies, we have discovered an anti-inflammatory effect of SP against LPS-induced lung injury 25 and the protective role of propionate against LPSinduced bronchopulmonary dysplasia. 26 There is accumulating clinical and experimental evidence that IUGR is a major risk factor for bronchopulmonary dysplasia. 6 In an isocyclic gestational protein restriction-induced IUGR model, propionate concentration was decreased by IUGR before weaning, whereas the concentrations of other SCFAs were decreased at day 40.…”

Yinchen Linggui Zhugan decoction ameliorates high fat diet-induced nonalcoholic fatty liver disease by modulation of SIRT1/Nrf2 signaling pathway and gut microbiota

“…Multiple evidences suggested that SIRT1 was activated by SCFAs directly or indirectly ( Jiao et al, 2020 ). In addition, specific SCFAs (such as BA and PA) are activators of the Keap1-Nrf2 defense pathway, which can activate cellular antioxidant mechanisms and downregulate the expression of pro-inflammatory factors ( Guo et al, 2020 ; Chen et al, 2021 ; González-Bosch et al, 2021 ). It is evident that SCFAs could link the microbiota with the maintenance of host redox homeostasis via SIRT1/Nrf2 signaling.…”

Health Benefits and Side Effects of Short-Chain Fatty Acids

“…Additionally, the evidence showed that acetate effectively resolved neutrophilic inflammation via inducing caspase-dependent apoptosis of neutrophils, decreasing the activity of nuclear factor-kappa B (NF-κB) and enhancing the production of anti-inflammatory mediators, such as IL-10, transforming growth factor-β (TGF-β), and annexin A1 [ 22 ]. In the LPS-treated neonatal mice model, pulmonary inflammation and oxidative stress were reduced by sodium propionate; in the LPS-treated human pulmonary microvascular endothelial cells (HPMECs) model, sodium propionate not only accelerated Nrf2 nuclear translocation, protected cells, and promoted angiogenesis, but also reduced inflammatory response via the NF-κB pathway [ 23 ]. Moreover, one in vivo study showed that propionate interfered with the production and migration of inflammatory mediators [ 24 ].…”