Anti-Inflammatory Effects of SGLT1 Synthetic Ligand in In Vitro and In Vivo Models of Lung Diseases

Abstract

Background. Several research findings suggest that sodium–glucose co-transporter 1 (SGLT1) is implicated in the progression and control of infections and inflammation processes at the pulmonary level. Moreover, our previous works indicate an engagement of SGLT1 in inhibiting the inflammatory response induced in intestinal epithelial cells by TLR agonists. In this study, we report the anti-inflammatory effects observed in the lung upon engagement of the transporter, and upon the use of glucose and BLF501, a synthetic SGLT1 ligand, for the treatment of animal models of lung inflammation, including a model of allergic asthma. Methods. In vitro experiments were carried out on human pneumocytes stimulated with LPS from Pseudomonas aeruginosa and co-treated with glucose or BLF501, and the production of IL-8 was determined. The anti-inflammatory effect associated with SGLT1 engagement was then assessed in in vivo models of LPS-induced lung injury, as well as in a murine model of ovalbumin (OVA)-induced asthma, treating mice with aerosolized LPS and the synthetic ligand. After the treatments, lung samples were collected and analyzed for morphological alterations by histological examination and immunohistochemical analysis; serum and BALF samples were collected for the determination of several pro- and anti-inflammatory markers. Results. In vitro experiments on human pneumocytes treated with LPS showed significant inhibition of IL-8 production. The results of two in vivo experimental models, mice exposed to aerosolized LPS and OVA-induced asthma, revealed that the engagement of glucose transport protein 1 (SGLT1) induced a significant anti-inflammatory effect in the lungs. In the first model, the acute respiratory distress induced in mice was abrogated by co-treatment with the ligand, with almost complete recovery of the lung morphology and physiology. Similar results were observed in the OVA-induced model of allergic asthma, both with aerosolized and oral BLF501, suggesting an engagement of SGLT1 expressed both in intestinal and alveolar cells. Conclusions. Our results confirmed the engagement of SGLT1 in lung inflammation processes and suggested that BLF501, a non-metabolizable synthetic ligand of the co-transporter, might represent a drug candidate for therapeutic intervention against lung inflammation states.