Inhibition of endotoxin-induced acute lung injury in rats by bone marrow-derived mesenchymal stem cells: Role of Nrf2/HO-1 signal axis in inhibition of NLRP3 activation.

Both the Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway and Nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) pathway are considered essential for the development of acute lung injury (ALI)/ARDS induced by sepsis. Our aim was to study the role of Nrf2/HO-1 pathway on activation of the NLRP3 in the protective effect of marrow mesenchymal stem cells (BMSCs) on LPS-induced ALI. We found that BMSCs ameliorated ALI as evidenced by 1) decreased histopathological injury, wet/dry ratio, and protein permeability index in lung; 2) decreased reactive oxygen species (ROS), malondialdehyde (MDA), and protein carbonyl content and restored the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in lung tissue; 3) reduced LPS-induced increase in inflammatory cell count and promotion of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels in bronchoalveolar lavage fluid (BALF); 4) improvement in the four-day survival rate of animals; and 5) enhanced expression of Nrf2 and HO-1 and decreased expression of NOD-like receptor protein 3(NLRP3) and caspase-1 (p20) in lung tissue. Of note, Nrf2 transcription factor inhibitor brusatol and HO-1 inhibitor tin protoporphyrin IX (SnppIX) reversed BMSCs induced down-expression of NLRP3 and caspase-1 (p20), and inhibited the protective effects of BMSCs. These findings demonstrated that the Nrf2-mediated HO-1 signaling pathway plays a critical role in the protective effects of BMSCs on LPS-induced ALI. BMSCs may play an anti-inflammatory effect partly through the Nrf2/HO-1-dependent NLRP3 pathway.

Lei L ，Guo Y ，Lin J ，Lin X ，He S ，Qin Z ，Lin Q ... -  《-》

6-Gingerol attenuates sepsis-induced acute lung injury by suppressing NLRP3 inflammasome through Nrf2 activation.

Pan Q ，Liu P ，Wan M 《-》

Bakuchiol regulates TLR4/MyD88/NF-κB and Keap1/Nrf2/HO-1 pathways to protect against LPS-induced acute lung injury in vitro and in vivo.

Bakuchiol (Bak) possesses a protective effect in acute lung injury (ALI). Nonetheless, the molecular processes that regulate the protective activity of Bak in ALI remain elusive. Lipopolysaccharide (LPS)-treated rats and RLE-6TN cells were used as the ALI models in vivo and in vitro to investigate the function and mechanism of Bak. Rats were divided into four groups: control, LPS, LPS + Bak (30 mg/kg), and LPS + Bak (60 mg/kg). RLE-6TN cells were assigned into four groups: control, LPS, LPS + Bak (10 µM), and LPS + Bak (20 µM). Myeloperoxidase (MPO) and 4-hydroxy-2-nonenal (4-HNE) levels were detected by immunohistochemistry (IHC). The levels of TNF-α, IL-6, and IL-1β were quantified by ELISA. Apoptosis was analyzed by TdT-mediated dUTP nick-end labeling (TUNEL) staining and flow cytometry. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and reactive oxygen species (ROS) were assayed to evaluate oxidative stress. In LPS-induced rats, Bak attenuated pathological injury, lung wet/dry weight ratio, MPO expression, and protein concentration and cell number in bronchial alveolar lavage fluid (BALF). Bak decreased the secretion of TNF-α, IL-6, and IL-1β in BALF. Bak reduced MDA content and 4-HNE expression, and increased SOD and GSH-Px activities in lung tissues. Bak also repressed pulmonary apoptosis by decreasing Bax expression and enhancing Bcl-2 expression. In LPS-treated RLE-6TN cells, Bak downregulated the mRNA levels of TNF-α, IL-6, and IL-1β and inhibited the protein expression of iNOS and COX2. Bak decreased MDA level and ROS production and increased SOD and GSH-Px activities. Bak also suppressed cell apoptosis, reduced Bax expression, and increased Bcl-2 expression. Moreover, Bak decreased the expression of TLR4, MyD88, p-IκBα, and p-p65. Additionally, Bak inhibited Keap1 expression and increased Nrf2 and HO-1 levels. Bak protects against LPS-induced inflammation, oxidative stress, and apoptosis in ALI by regulating TLR4/MyD88/NF-κB and Keap1/Nrf2/HO-1 pathways.

Zhao L ，Zhang Z ，Li P ，Gao Y ，Shi Y ... -  《-》

Orientin relieves lipopolysaccharide-induced acute lung injury in mice: The involvement of its anti-inflammatory and anti-oxidant properties.

Oxidative stress and inflammatory responses are nearly involved in the pathogenesis of various diseases, including acute lung injury (ALI). Orientin (Ori), a flavonoid component extracted from natural plants, displayed anti-inflammatory and antioxidant properties in our previous studies. In the current study, we aimed to investigate the amelioration effect of Ori on lipopolysaccharide (LPS)-induced ALI, and we further explored the potential molecular mechanisms. The present results indicated that Ori effectively alleviated LPS-induced ALI by improving the histological changes of lung; decreasing the lung W/D ratio and protein levels, the release of inflammatory cells and cytokines into the bronchoalveolar lavage fluid (BALF); inhibiting nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and high mobility group box 1 (HMGB1) protein expression; reducing malondialdehyde (MDA) formation and reactive oxygen species (ROS) generation; and increasing the content of glutathione (GSH) and superoxide dismutase (SOD) contents. Moreover, Ori treatment not only significantly suppressed the LPS-induced nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, and nuclear factor-kappa B (NF-κB) signaling pathway activation, but also obviously restored the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD (P) H: quinone oxidoreductase (NQO1), glutamate-cysteine ligase catalytic (GCLC), and heme oxygenase 1 (HO-1) expression in the lung; all of which are reduced by LPS. Taken together, these data suggested that Ori plays an important role in the protection against ALI by suppressing inflammation and oxidative stress which may be strongly related to the suppression of NLRP3 inflammasome and NF-κB activation, as well as the upregulation of the Nrf2 signaling pathway.

Xiao Q ，Cui Y ，Zhao Y ，Liu L ，Wang H ，Yang L ... -  《-》

Oridonin protects LPS-induced acute lung injury by modulating Nrf2-mediated oxidative stress and Nrf2-independent NLRP3 and NF-κB pathways.

Yang H ，Lv H ，Li H ，Ci X ，Peng L ... -  《Cell Communication and Signaling》