Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta 31511, Egypt.
Department of Biochemistry, College of Medicine, Ha'il University, Hail 81411, Saudi Arabia.
Int J Mol Sci. 2023 May 30;24(11):9481. doi: 10.3390/ijms24119481.
Pulmonary fibrosis (PF) is a life-threatening disorder that severely disrupts normal lung architecture and function, resulting in severe respiratory failure and death. It has no definite treatment. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has protective potential in PF. However, the mechanisms underlying these effects require further elucidation. Therefore, this study aimed to evaluate the ameliorative effect of EMPA against bleomycin (BLM)-induced PF and the potential mechanisms. Twenty-four male Wister rats were randomly divided into four groups: control, BLM treated, EMPA treated, and EMPA+BLM treated. EMPA significantly improved the histopathological injuries illustrated by both hematoxylin and eosin and Masson's trichrome-stained lung tissue sections, as confirmed by electron microscopic examination. It significantly reduced the lung index, hydroxyproline content, and transforming growth factor β1 levels in the BLM rat model. It had an anti-inflammatory effect, as evidenced by a decrease in the inflammatory cytokines' tumor necrosis factor alpha and high mobility group box 1, inflammatory cell infiltration into the bronchoalveolar lavage fluid, and the CD68 immunoreaction. Furthermore, EMPA mitigated oxidative stress, DNA fragmentation, ferroptosis, and endoplasmic reticulum stress, as evidenced by the up-regulation of nuclear factor erythroid 2-related factor expression, heme oxygenase-1 activity, glutathione peroxidase 4 levels, and a decrease in C/EBP homologous protein levels. This protective potential could be explained on the basis of autophagy induction via up-regulating lung expression and the LC3 II immunoreaction observed in this study. Our findings indicated that EMPA protected against BLM-induced PF-associated cellular stress by enhancing autophagy and modulating sestrin2/adenosine monophosphate-activated protein kinase/nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signaling.
肺纤维化（PF）是一种危及生命的疾病，严重破坏正常的肺结构和功能，导致严重的呼吸衰竭和死亡。目前尚无明确的治疗方法。钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂恩格列净（EMPA）在 PF 中有保护作用。然而，这些作用的机制尚需进一步阐明。因此，本研究旨在评估 EMPA 对博来霉素（BLM）诱导的 PF 的改善作用及其潜在机制。24 只雄性 Wister 大鼠随机分为四组：对照组、BLM 处理组、EMPA 处理组和 EMPA+BLM 处理组。EMPA 显著改善了苏木精和伊红以及 Masson 三色染色的肺组织切片所示的组织病理学损伤，电镜检查也证实了这一点。它显著降低了 BLM 大鼠模型的肺指数、羟脯氨酸含量和转化生长因子 β1 水平。它具有抗炎作用，表现在肿瘤坏死因子 α和高迁移率族蛋白 1 等炎症细胞因子减少，炎症细胞浸润到支气管肺泡灌洗液，以及 CD68 免疫反应减少。此外，EMPA 减轻了氧化应激、DNA 片段化、铁死亡和内质网应激，这表现在核因子红细胞 2 相关因子表达上调、血红素加氧酶-1 活性、谷胱甘肽过氧化物酶 4 水平升高和 C/EBP 同源蛋白水平降低。本研究通过上调肺组织表达和观察到的 LC3 II 免疫反应，诱导自噬，发现这种保护作用可能解释了 EMPA 对 BLM 诱导的 PF 相关细胞应激的保护作用。我们的研究结果表明，EMPA 通过增强自噬和调节 sestrin2/腺苷单磷酸激活蛋白激酶/核因子红细胞 2 相关因子 2/血红素加氧酶 1 信号通路，对 BLM 诱导的 PF 相关细胞应激具有保护作用。
