Medeiros Matheus L, Oliveira Akila L, Antunes Edson
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Alexander Fleming St., Campinas 13083-881, SP, Brazil.
Int J Mol Sci. 2025 Jun 16;26(12):5753. doi: 10.3390/ijms26125753.
Asthma is a chronic inflammatory airway disease that can be aggravated by metabolic comorbidities such as type 2 diabetes mellitus (DM2) and obesity. Elevated levels of methylglyoxal (MGO), a reactive glycolysis byproduct, have been associated with exacerbation of allergic airway disease. SGLT2 inhibitors have been successfully employed in DM2 treatment. Here, we hypothesized that elimination of MGO might be a potential anti-inflammatory mechanism of SGLT2 inhibitors. This study aimed to evaluate the effects of empagliflozin on ovalbumin (OVA)-induced airway inflammation in mice chronically exposed to MGO. Male C57BL/6 mice sensitized with OVA were exposed to 0.5% MGO for 12 weeks and treated with empagliflozin (10 mg/kg, gavage, two weeks). MGO exposure significantly enhanced airway eosinophil infiltration, mucus production and collagen deposition, as well as levels of IL-4, IL-5, eotaxin and TNF-α. Empagliflozin treatment significantly reduced OVA-induced airway disease, which was accompanied by reductions in IgE, IL-4, IL-5, eotaxin, and TNF-α levels. Empagliflozin significantly reduced the MGO levels in serum, and immunohistochemical staining, and protein expression of MGO-hydroimidazolone (MG-H1), while increasing IL-10 levels and glyoxylase-1 (GLO 1) activity in lungs. In conclusion, empagliflozin efficiently removes MGO from circulation, while increasing the MGO detoxification by GLO 1, thereby mitigating the OVA-induced inflammation in MGO-exposed mice.
哮喘是一种慢性炎症性气道疾病，可因2型糖尿病（DM2）和肥胖等代谢合并症而加重。甲基乙二醛（MGO）是一种活性糖酵解副产物，其水平升高与过敏性气道疾病的加重有关。钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂已成功用于DM2治疗。在此，我们假设消除MGO可能是SGLT2抑制剂的一种潜在抗炎机制。本研究旨在评估恩格列净对长期暴露于MGO的小鼠卵清蛋白（OVA）诱导的气道炎症的影响。用OVA致敏的雄性C57BL/6小鼠暴露于0.5% MGO 12周，并用恩格列净（10 mg/kg，灌胃，两周）治疗。暴露于MGO显著增强了气道嗜酸性粒细胞浸润、黏液分泌和胶原蛋白沉积，以及白细胞介素-4（IL-4）、白细胞介素-5（IL-5）、嗜酸性粒细胞趋化因子和肿瘤坏死因子-α（TNF-α）的水平。恩格列净治疗显著减轻了OVA诱导的气道疾病，同时伴有免疫球蛋白E（IgE）、IL-4、IL-5、嗜酸性粒细胞趋化因子和TNF-α水平的降低。恩格列净显著降低了血清中MGO的水平，以及MGO-氢咪唑酮（MG-H1）的免疫组化染色和蛋白表达，同时增加了肺中白细胞介素-10（IL-10）的水平和乙二醛酶-1（GLO 1）的活性。总之，恩格列净有效地从循环中清除MGO，同时通过GLO 1增加MGO的解毒作用，从而减轻MGO暴露小鼠中OVA诱导的炎症。
