Canagliflozin alleviates LPS-induced acute lung injury by modulating alveolar macrophage polarization

Background: Canagliflozin (CANA), a sodium-glucose cotransporter 2 inhibitor, is a novel therapeutic agent that exhibits multiple actions in type 2 diabetes. CANA can regulate intracellular glucose metabolism and exert anti-inflammatory effects in immune cells. Alveolar macrophage polarization balance is often associated with lower inflammation in acute lung injury (ALI). However, little is known about the anti-inflammatory effect of CANA on ALI. Methods: This study aimed to determine the effect of CANA on ALI as well as its potential ability to modulate alveolar macrophage polarization in ALI mouse models and bone marrow-derived macrophages (BMDMs). Results: The histopathological changes indicated that CANA alleviated lung injury in lipopolysaccharide-induced ALI mice models and exerted anti-inflammatory effects in the presence of lower levels of tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta in bronchoalveolar lavage fluid (BALF) and serum. Moreover, flow cytometry analysis of mouse BALF cells and BMDMs demonstrated that CANA can modulate and reconstitute M1 and M2 macrophage balance, inhibiting macrophages with the M1 phenotype while promoting macrophages to shift to the M2 phenotype. Immunohistochemistry and reverse transcription polymerase chain reaction were also performed. Conclusions: These findings indicate that CANA alleviates lung injury and exerts anti-inflammatory effects by modulating alveolar macrophage polarization balance, suggesting that CANA might act as a novel anti-inflammatory drug for treating ALI.