Ning Wenjuan, Xu Xiaoxiao, Zhou Shican, Wu Xiao, Wu Hang, Zhang Yijie, Han Jichang, Wang Junpeng
Infection and Immunity Institute and Translational Medical Center of Huaihe Hospital, Henan University, Kaifeng, China.
Front Nutr. 2022 Oct 11;9:998662. doi: 10.3389/fnut.2022.998662. eCollection 2022.
This study explored the profibrotic impact of high glucose in the lung and potential mechanisms using latent TGF-β1-induced human epithelial cell pulmonary fibrosis and bleomycin (BLM)-induced pulmonary fibrosis models. Results demonstrated that high glucose administration induced epithelial-mesenchymal transition (EMT) in human epithelial cells in a dose-dependent manner activating latent TGF-β1, followed by increased expression of mesenchymal-related proteins and decreased expression of epithelial marker protein E-cadherin. Further mechanism analysis showed that administration of high glucose dose-dependently promoted total and mitochondrial reactive oxygen species (ROS) accumulation in human epithelial cells, which promoted latent TGF-β1 activation. However, -acetyl-L-cysteine, a ROS eliminator, inhibited such effects. An feed study found that mice given a high-glucose diet had more seriously pathological characteristics of pulmonary fibrosis in BLM-treated mice, including increasing infiltrated inflammatory cells, collagen I deposition, and the expression of mesenchymal-related proteins while decreasing the expression of the epithelial marker E-cadherin. In addition, high glucose intake further increased TGF-β1 concentration and upregulated p-Smad2/3 and snail in lung tissues from BLM-treated mice when compared to BLM-treated mice. Finally, supplementation with high glucose further increased the production of lipid peroxidation metabolite malondialdehyde and decreased superoxide dismutase activity in BLM-treated mice. Collectively, these findings illustrate that high glucose supplementation activates a form of latent TGF-β1 by promoting ROS accumulation and ultimately exacerbates the development of pulmonary fibrosis.
本研究利用潜伏性转化生长因子-β1（TGF-β1）诱导的人上皮细胞肺纤维化模型和博来霉素（BLM）诱导的肺纤维化模型，探讨了高糖在肺中的促纤维化作用及其潜在机制。结果表明，高糖给药以剂量依赖的方式诱导人上皮细胞发生上皮-间质转化（EMT），激活潜伏性TGF-β1，随后间充质相关蛋白表达增加，上皮标志物蛋白E-钙黏蛋白表达降低。进一步的机制分析表明，高糖给药剂量依赖性地促进人上皮细胞中总活性氧（ROS）和线粒体ROS的积累，从而促进潜伏性TGF-β1的激活。然而，ROS清除剂N-乙酰半胱氨酸可抑制这种作用。一项喂养研究发现，给予高糖饮食的小鼠在BLM处理后具有更严重的肺纤维化病理特征，包括浸润性炎症细胞增加、I型胶原沉积以及间充质相关蛋白表达增加，而上皮标志物E-钙黏蛋白表达降低。此外，与BLM处理的小鼠相比，高糖摄入进一步增加了BLM处理小鼠肺组织中TGF-β1的浓度，并上调了p-Smad2/3和Snail的表达。最后，补充高糖进一步增加了BLM处理小鼠脂质过氧化代谢产物丙二醛的产生，并降低了超氧化物歧化酶的活性。总的来说，这些发现表明，补充高糖通过促进ROS积累激活了一种形式的潜伏性TGF-β1，最终加剧了肺纤维化的发展。
