GTS-21 Alleviates Acute Lung Injury by Enhancing GLP-1 Secretion and Regulating Alveolar Surfactant Proteins via α7nAChR Activation

GTS-21, a selective α7-nicotinic acetylcholine receptor (α7nAChR) agonist, exhibits significant anti-inflammatory effects in acute lung injury (ALI), but its mechanisms remain incompletely understood. We hypothesize that its protective effects involve the regulation of Glucagon-like peptide-1 (GLP-1) and pulmonary surfactant protein (SP). P. aeruginosa-induced pneumonia (2.5 × 10⁵ CFU/mouse) and LPS-induced ALI (2.5 mg/kg) models via intratracheal instillation (IT) were used in WT, α7nAChR KO and GLP-1R KO mice. Lung injury was assessed via histopathology, cytokine quantification (IL-6, HMGB1), alveolar–capillary barrier injury, immune cell infiltration, circulating GLP-1, and SP expression in bronchoalveolar lavage fluid (BALF). GTS-21 significantly reduced mortality in WT mice with P. aeruginosa pneumonia, while α7nAChR KO mice showed increased mortality. GTS-21 also improved survival, attenuated lung injury, decreased leukocyte infiltration, and reduced HMGB1/protein concentration in BALF. In murine lipopolysaccharide (LPS)-induced ALI, GTS-21 improved histopathology and alveolar–capillary barrier integrity, lowered IL-6 and HMGB1, and enhanced GLP-1 elevation in WT mice but not α7nAChR KO mice. Furthermore, LPS suppressed SP-A and SP-D in BALF, which GTS-21 restored in WT mice. To confirm the role of GLP-1 in GTS-21-mediated lung protection, we examined inflammation in GLP-1R KO mice following LPS challenge. Anti-inflammatory effects of GTS-21 were blunted in these mice, suggesting a GLP-1-dependent mechanism. GTS-21 protects against bacterial pneumonia and ALI through α7nAChR activation, GLP-1 modulation, and SP regulation. These findings provide evidence that the protective effects of GTS-21 on ALI are mediated in part by GLP-1 and pulmonary surfactant.