Dipeptidyl Peptidase-4 (DPP-4) Inhibitor Saxagliptin Alleviates Lipopolysaccharide-Induced Acute Lung Injury via Regulating the Nrf-2/HO-1 and NF-κB Pathways

Abstract

Purpose We aimed at investigating the effects of Dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin (Saxa) on mouse acute lung injury (ALI)-induced by lipopolysaccharide (LPS) and the potential mechanisms. Materials/methods Animals were divided into four groups: control, Saxa, LPS, and LPS + Saxa. Histopathology changes of lung tissues were assessed by hematoxylin and eosin staining and periodic acid-Schiff staining. The degree of edema was determined by wet/dry ratio. The levels of oxidative stress markers and inflammatory cytokines in lung homogenate and bronchoalveolar lavage fluid were detected using kits. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to test apoptosis and Western blotting was applied to measure the expression of apoptosis-associated proteins. The expression of nuclear factor erythroid 2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1) and nuclear factor-kappa B (NF-κB) pathways were detected by Western blotting. Results The results revealed that Saxa attenuated LPS-induced pathological injury and edema. Saxa decreased the levels of reactive oxygen species (ROS), malondialdehyde (MDA), myeloperoxidase (MPO) and increased the levels of superoxide dismutase (SOD) and catalase (CAT). The contents of inflammatory cytokines were reduced in the Saxa intervention group. Saxa attenuated apoptosis accompanied by alterations in the expression of apoptosis-associated proteins. Furthermore, the expression of Nrf-2 and HO-1 were upregulated whereas phospho (p)-NF-κB p65 and phospho-inhibitory subunit of NF-κB alpha (p-IκB-α) were downregulated after Saxa treatment. Conclusion These findings concluded that Saxa alleviates oxidative stress, inflammation and apoptosis in ALI induced by LPS via modulating the Nrf-2/HO-1 and NF-κB pathways, which provides evidence for employing Saxa in ALI treatment.

Keywords

• acute lung injury
• saxagliptin
• lipopolysaccharide
• inflammation
• apoptosis