THE PROTECTIVE EFFECT AND MECHANISM OF MESENCHYMAL STEM CELLS ON DIABETIC PULMONARY FIBROSIS IN RATS

Abstract

Background and Objective: Diabetes affects a variety of organs such as the kidneys, eyes, and liver, and there is increasing evidence that the lung is also one of the target organs of diabetes and imbalance of Sirt3-mediated stress responses such as inflammation, oxidative stress, apoptosis, autophagy, and ER stress may contribute to diabetic pulmonary fibrosis. Although previous studies have reported that mesenchymal stem cells (MSCs) have beneficial effects on various diabetic complications, the effect and mechanisms of MSCs on diabetes-induced lung injury is not clear. Therefore, the present study aims to investigate the protective effect and possible mechanisms of MSCs against diabetic pulmonary fibrosis in rats. Methods and Results: In this study, the STZ-induced diabetes model was constructed in rats, and the effect and potential mechanisms of bone marrow MSCs on diabetic pulmonary fibrosis were investigated. The results revealed that fibrotic changes in the lung were successfully induced in the diabetic rats, while MSCs significantly inhibited or even reversed the changes. Specifically, MSCs up-regulated the expression levels of Sirt3 and SOD2 and then activated the Nrf2/ARE signaling pathway, thereby controlling MDA, GSH content and iNOS, NADPH oxidase subunit p22phox expression levels in the lung tissue. Meanwhile, high levels of Sirt3 and SOD2 induced by MSCs reduced the expression levels of IL-1β, TNF-α, ICAM-1 and MMP9 by suppressing the NF-κB/HMGB1/NLRP3/Caspase1 signaling pathway, as well as regulated the expression levels of cleaved caspasese3, Bax and Bcl2 by up-regulating the expression level of P-Akt, thereby inhibiting the apoptosis of the lung tissue. In addition, MSCs also regulated the expression levels of LC3, P62, BiP, Chop, and PERK, thereby enhancing autophagy and attenuating endoplasmic reticulum stress. Conclusions: In conclusion, our study demonstrates that MSCs effectively ameliorate diabetic pulmonary fibrosis via regulating Sirt3-mediated stress responses, including enhancement of autophagy and inhibition of oxidative stress, inflammation, apoptosis, and endoplasmic reticulum stress. These results not only shed new light on the pathogenesis of diabetic lung injury but also provide a theoretical foundation for further exploration of diabetic pulmonary fibrosis therapeutics. Keywords: Mesenchymal stem cells, diabetic pulmonary fibrosis, Sirt3, stress response This work was supported by the National Natural Science Foundation of China (grant numbers 81870609, 31571474, 81802210).