Empagliflozin inhibits autophagy and mitigates airway inflammation and remodelling in mice with ovalbumin-induced allergic asthma

Abstract

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.

Keywords: Airway hyperresponsiveness; Bronchial asthma; Inflammatory cytokines; LC3B; P62; Rapamycin.