Semaglutide ameliorates lipopolysaccharide-induced acute lung injury through inhibiting HDAC5-mediated activation of NF-κB signaling pathway

Abstract

Background As a life-threatening respiratory syndrome, acute lung injury (ALI) is characterized by uncontrollable inflammatory activities. Semaglutide (SEM) has been identified as an effective anti-inflammatory drug in a variety of diseases. This study intended to explore the functional effect and potential mechanisms of SEM in ALI. Methods Lipopolysaccharide (LPS) was used to construct an in vivo ALI model based on Sprague-Dawley (SD) rats and an in vitro ALI model based on human pulmonary artery endothelial cells (HPAECs). Hematoxylin & eosin (H&E) staining and ELISA were applied to evaluate the histopathological changes in pulmonary tissues and detect TNF-α and IL-6 levels. RT-qPCR and Western blotting were used to measure gene and protein expressions in pulmonary tissues and cells. HPAEC viability and apoptosis were evaluated by CCK-8 method and flow cytometry methods. Results Semaglutide pretreatment significantly mitigated pulmonary injury, reduced TNF-α and IL-6 production, and led to a decrease in cleaved caspase-3 level and an increase in Bcl-2 level, suggesting SEM could ameliorate LPS-induced ALI in rats. In vitro, SEM increased the proliferative capability and mitigated inflammation and apoptosis in LPS-stimulated HPAECs. In addition, SEM inhibited HDAC5-mediated NF-κB signaling pathway in HPAECs. HDAC5 overexpression or NF-κB signaling activation could partly impair SEM-mediated protective effects against LPS-induced damage to HPAECs. Conclusion Semaglutide restrains LPS-induced ALI by inhibiting HDAC5/NF-κB signaling pathway.

Zinc-Dependent Histone Deacetylases in Lung Endothelial Pathobiology

“…Consistently, HDAC5 impairs angiogenesis in scleroderma ECs [145]. Recent data indicated that HDAC5 may be involved in LPS-induced inflammatory responses in human pulmonary artery ECs (HPAECs) [146].…”

Effect of Semaglutide and Empagliflozin on Pulmonary Structure and Proteomics in Obese Mice

“…40 Semaglutide attenuates acute lung injury via blocking the HDAC5/NF-κB pathway. 41 Recent research has suggested that semaglutide possesses both anti-inflammatory and anti-apoptotic properties. 42 Empagliflozin, an SGLT2 inhibitor, not only reduces mortality rates but also impedes the advancement of experimental pulmonary hypertension.…”

Anti-inflammatory benefits of semaglutide: State of the art

“…In a study using male Swiss albino mice, semaglutide reduced levels of TNF-α, IL-6, and IL-1β in brain tissues during endotoxemia and polymicrobial sepsis, leading to improved cognitive abilities [72] . Additionally, semaglutide reduced lung injury in a rat model of lipopolysaccharide (LPS)-induced acute lung injury by suppressing TNF-α, IL-6, and Nf-κB activities [73] .…”

“… Effects Model Treatment Ref. Reduced the TNF-α, IL-6 and Nf-κB signalings LPS-induced lung injury in rats Semaglutide [73] Blocked the NLRP3 activity PTT-induced seizure in C57/BL6J mouse Semaglutide [70] Reduced the TNF-α, IL-6, and IL-1β levels in brain tissues Endo-toxemia in male Swiss albino mice Semaglutide [72] Reduced p38 MAPK, c-Jun- NF-κB p65 inflammation signaling pathway in brain tissues Animal model of seizure Semaglutide [71] Reduced intramuscular fat and improved muscle function by lowering the, TNF-α, IL-6, IL-1β levels Male C57BL/6 mice Semaglutide [78] Declined TNF-α, and IL-6 serum and heart tissues Obese mouse Semaglutide [62] Decreased vascular inflammation and micro-calcifications Obese rabbit Semaglutide [79] Attenuated inflammatory markers and improved cardiac function Obese mice Semaglutide [80] …”