Department of Medical Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
Therapeutic and Protective Protein Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg EL-Arab, Alexandria, Egypt.
Eur J Pharmacol. 2023 Jul 5;950:175701. doi: 10.1016/j.ejphar.2023.175701. Epub 2023 Apr 11.
Empagliflozin, a selective inhibitor of Na-glucose cotransporter-2, has been reported to exert anti-inflammatory and anti-fibrotic effects in addition to autophagy modulation. Addressing the role of autophagy in allergic asthma revealed controversial results. The potential effect of empagliflozin treatment on airway inflammation and remodelling as well as autophagy modulation in a murine model of allergic asthma was investigated. Over a 7-week period, male BALB/c mice were sensitized and challenged by intraperitoneal injection and inhalation of ovalbumin, respectively. Animals were treated with empagliflozin (10 mg/kg; orally) and/or rapamycin (an autophagy inducer; 4 mg/kg; intraperitoneally) before every challenge. Methacholine-induced airway hyperresponsiveness was evaluated one day after the last challenge. After euthanasia, serum, bronchoalveolar lavage fluid, and lung tissues were collected for biochemical, histopathological, and immunohistochemical assessment. Results revealed that empagliflozin decreased airway hyperresponsiveness, serum ovalbumin-specific immunoglobulin E, and bronchoalveolar lavage total and differential leukocytic counts. Levels of inflammatory and profibrotic cytokines (IL-4, IL-5, IL-13, IL-17, and transforming growth factor-β1) were all inhibited. Moreover, empagliflozin preserved pulmonary microscopic architecture and alleviated bronchiolar epithelial thickening, goblet cell hyperplasia, fibrosis and smooth muscle hypertrophy. These effects were associated with inhibition of ovalbumin-activated autophagic flux, as demonstrated by decreased LC3B expression and LC3BII/I ratio, as well as increased P62 expression. However, the therapeutic potential of empagliflozin was inhibited when rapamycin was co-administered. In conclusion, this study demonstrates that empagliflozin has immunomodulatory, anti-inflammatory, and anti-remodelling properties in ovalbumin-induced allergic asthma and suggests that autophagic flux inhibition may play a role in empagliflozin's anti-asthmatic effects.
恩格列净是一种选择性钠-葡萄糖共转运蛋白 2 抑制剂，除了能调节自噬外，还具有抗炎和抗纤维化作用。自噬在过敏性哮喘中的作用的研究结果存在争议。本研究旨在探讨恩格列净治疗对卵清蛋白诱导的过敏性哮喘小鼠模型气道炎症和重塑以及自噬调节的潜在作用。在 7 周的时间内，雄性 BALB/c 小鼠通过腹腔注射和吸入卵清蛋白分别进行致敏和激发。在每次激发前，动物分别用恩格列净（10mg/kg；口服）和/或雷帕霉素（自噬诱导剂；4mg/kg；腹腔注射）治疗。在最后一次激发后一天，评估乙酰甲胆碱诱导的气道高反应性。安乐死后收集血清、支气管肺泡灌洗液和肺组织，进行生化、组织病理学和免疫组织化学评估。结果显示，恩格列净降低了气道高反应性、血清卵清蛋白特异性免疫球蛋白 E 以及支气管肺泡灌洗液总白细胞和分类白细胞计数。炎症和促纤维化细胞因子（IL-4、IL-5、IL-13、IL-17 和转化生长因子-β1）水平均受到抑制。此外，恩格列净还保留了肺的微观结构，减轻了细支气管上皮增厚、杯状细胞增生、纤维化和平滑肌肥大。这些作用与抑制卵清蛋白激活的自噬流有关，表现为 LC3B 表达和 LC3BII/I 比值降低，以及 P62 表达增加。然而，当联合使用雷帕霉素时，恩格列净的治疗潜力受到抑制。综上所述，本研究表明，恩格列净在卵清蛋白诱导的过敏性哮喘中具有免疫调节、抗炎和抗重塑作用，并提示自噬流抑制可能在恩格列净的抗哮喘作用中发挥作用。
