α7nAChR Activation Combined with Endothelial Progenitor Cell Transplantation Attenuates Lung Injury in Diabetic Rats with Sepsis through the NF-κB and JAK2/STAT3 Pathways

Abstract

Background: Chronic diabetes mellitus compromises the vascular system, which causes organ injury, including in the lung. Due to the strong compensatory ability of the lung, it always shows subclinical symptoms. Once sepsis occurs, the degree of lung injury is more severe under hyperglycaemia. α7nAChRs play an important role in regulating inflammation and metabolism. Our previous study demonstrated that PNU282987, an α7nAChR agonist, could improve endothelial progenitor cell functions. In this study, we examined the role of diabetes mellitus during sepsis and whether α7nAChR activation combined with endothelial progenitor cell transplantation can protect the lung from septic and diabetic impairments. Methods: Type 2 diabetic model rats were induced by a high-fat diet and streptozotocin. Then, these rats were exposed to lipopolysaccharide in a two-hit manner to cause sepsis. The oxygenation index, wet-to-dry ratio and histopathological score of the lungs were tested after PNU282987 treatment and EPC transplantation. IL-6, IL-8, TNF-α and IL-10 levels were measured by ELISA. Caspase-3, Bax, Bcl-2, NF-κB, phosphorylated JAK2 and phosphorylated STAT3 levels were measured by western blotting to investigate apoptosis and the underlying mechanism. Results:Sepsis caused obvious lung injury, which was exacerbated by diabetic conditions. α7nAChR activation and endothelial progenitor cell injection reduced injury in diabetic rats with sepsis, alleviating inflammation and decreasing apoptosis. This treatment was more effective when PNU282987 and endothelial progenitor cells were administered together. The JAK2/STAT3 signalling pathway was activated during this process, and the phosphorylation of NF-κB was inhibited. Conclusion: Activating α7nAChRs and endothelial progenitor cell transplantation alleviated the lung injury in diabetic rats with sepsis. Combining PNU282987 with endothelial progenitor cell transplantation showed better results than either treatment alone. During this process, the JAK2/STAT3 signalling pathway was activated, and NF-κB was inhibited.