Mesenchymal Stem Cells Attenuate Diabetic Lung Fibrosis via Adjusting Sirt3-Mediated Stress Responses in Rats
Mesenchymal Stem Cells Attenuate Diabetic Lung Fibrosis via Adjusting Sirt3-Mediated Stress Responses in Rats
复制标题
间充质干细胞通过调节 Sirt3 介导的大鼠应激反应来减轻糖尿病肺纤维化
DOI：
10.1155/2020/8076105
复制
发表时间：
2020-02-04
影响因子：
--
通讯作者：
Lu, Yanrong
中科院分区：
文献类型：
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作者：
Chen, Yang;Zhang, Fuping;Lu, Yanrong
糖尿病影响多种器官，如肾脏、眼睛和肝脏，越来越多的证据表明，肺也是糖尿病的靶器官之一，Sirt 3介导的应激反应如炎症、氧化应激、细胞凋亡、自噬和ER应激的失衡可能导致糖尿病肺纤维化。虽然已有研究报道间充质干细胞（mesenchymal stem cells，MSCs）对糖尿病并发症有一定的治疗作用，但MSCs对糖尿病肺损伤的作用及机制尚不清楚。本研究通过建立STZ诱导的糖尿病大鼠模型，探讨骨髓间充质干细胞对糖尿病肺纤维化的影响及其可能机制。结果显示，在糖尿病大鼠中成功地诱导了肺纤维化改变，而MSC显著抑制甚至逆转了该改变。具体而言，MSC上调Sirt 3和SOD 2的表达水平，然后激活Nrf 2/ARE信号通路，从而控制肺组织中MDA、GSH含量以及iNOS和NADPH氧化酶亚基p22 phox表达水平。同时，MSCs诱导的高水平Sirt 3和SOD 2通过抑制NF-κB/HMGB 1/NLRP 3/caspase-1信号通路降低IL-1β、TNF-α、ICAM-1和MMP-9的表达水平，并通过上调P-Akt表达水平调节切割型caspase-3、Bax和Bcl-2的表达水平，从而抑制肺组织的凋亡。此外，MSC还调节LC 3、P62、BiP、Chop和PERK的表达水平，从而增强自噬和减轻内质网应激。综上所述，我们的研究结果表明，MSC通过调节Sirt 3介导的反应，包括炎症，氧化应激，凋亡，自噬和内质网应激，有效地减轻糖尿病肺纤维化，为进一步探索基于MSC的糖尿病治疗提供了理论基础。
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 lung 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 are not clear. In this study, the STZ-induced diabetes model was constructed in rats, and the effect and potential mechanisms of bone marrow MSCs on diabetic lung 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 upregulated the expression levels of Sirt3 and SOD2 and then activated the Nrf2/ARE signaling pathway, thereby controlling MDA, GSH content, and iNOS and 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/caspase-1 signaling pathway, as well as regulating the expression levels of cleaved caspasese-3, Bax, and Bcl2 by upregulating 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. Taken together, our results suggest that MSCs effectively attenuate diabetic lung fibrosis via adjusting Sirt3-mediated responses, including inflammation, oxidative stress, apoptosis, autophagy, and endoplasmic reticulum stress, providing a theoretical foundation for further exploration of MSC-based diabetic therapeutics.