Role of Nrf2/HO-1 signaling pathway in bone marrow mesenchymal stem cells-induced reduction of endotoxin-induced acute lung injury in rats

Objective To evaluate the role of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in bone marrow mesenchymal stem cells (MSCs)-induced reduction of endotoxin-induced acute lung injury (ALI) in rats. Methods Thirty-two clean-grade healthy male Sprague-Dawley rats, weighing 180-250 g, were divided into 4 groups (n=8 each) using a random number table method: control group (group C), ALI group, MSCs group and brusatol plus MSCs group (group B+ MSCs). Lipopolysaccharide 20 mg/kg was intravenously infused to establish the model of acute lung injury. Phosphate buffered saline(PBS)1 ml was intravenously infused at 1 h after establishing the model in group ALI. The equal volume of sterile saline and PBS was given instead in group C. PBS (1 ml) containing MSCs 1×106 cells was intravenously infused at 1 h after establishing the model in group MSCs. Brusatol 0.4 mg/kg was intraperitoneally injected every other day during 10 days before establishing the model, and MSCs were given at 1 h after establishing the model in group B+ MSCs. Bronchoalveolar lavage fluid (BALF) was collected and lung tissues were removed at 6 h after establishing the model. The protein concentration and neutrophil count in BALF were determined, and the wet/dry weight ratio (W/D ratio) were calculated. The pathological changes of lung tissues were observed by hematoxylin-eosin staining. The expression of Nrf2 and HO-1 by Western blot, activities of myeloperoxidase (MPO) and superoxide dismutase (SOD) and content of malondialdehyde (MDA) were determined . Results Compared with group C, the W/D ratio and total cell count and protein concentration in BALF were significantly increased, the MPO activity was enhanced, the MDA content was increased, the SOD activity was weakened, and the expression of Nrf2 was up-regulated (P<0.05), and the pathological changes were accentuated in group ALI. Compared with group ALI, the W/D ratio and total cell count and protein concentration in BALF were significantly decreased, the MPO activity was weakened, the MDA content was decreased, the SOD activity was enhanced, and the expression of Nrf2 and HO-1 was up-regulated (P<0.05), and the pathological changes were significantly attenuated in group MSCs. Compared with group MSCs, the total cell count was significantly increased, the MPO activity was enhanced, the MDA content was increased, the expression of Nrf2 and HO-1 was down-regulated (P<0.05), and the pathological changes were accentuated in group B+ MSCs. Conclusion Nrf2/HO-1 signaling pathway is involved in bone marrow MSCs-induced reduction of endotoxin-induced acute lung injury in rats. Key words: NF-E2 related factor 2; Heme oxygenase-1; Mesenchymal stromal cells; Acute lung injury; Endotoxemia