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.