Ghrelin Protects Against Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome Through the Phosphatidylinositol 3-Kinase/AKT Pathway

Pulmonary endothelial barrier dysfunction is a major pathophysiology observed in acute respiratory distress syndrome (ARDS). Ghrelin, a key regulator of metabolism, has been shown to play protective roles in the respiratory system. However, its effects on lipopolysaccharide (LPS)-induced pulmonary endothelial barrier injury are unknown. In this study, the effects of Ghrelin on LPS-induced ARDS and endothelial cell injury were evaluated in vivo and in vitro. Our results showed that Ghrelin had protective effects on LPS-induced ARDS and endothelial barrier disruption by inhibiting apoptosis, promoting cell migration and tube formation, and activating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. Furthermore, Ghrelin stabilized LPS-induced endothelial barrier function by decreasing endothelial permeability and increasing the expression of the intercellular junction protein VE-cadherin (vascular endothelial cadherin). LY294002, a specific inhibitor of the PI3K pathway, reversed the protective effects of Ghrelin on the endothelial cell barrier. In conclusion, our findings indicated that Ghrelin protected against LPS-induced ARDS by impairing the pulmonary endothelial barrier partly through activating the PI3K/AKT pathway. Thus, Ghrelin may be a valuable therapeutic strategy for the prevention or treatment of ARDS. Funding Statement: This work was supported by the National Natural Science Foundation of China (Grant 81670066, 81772302); the Science and Technology Planning Project of Guangdong Province (Grant 2019A1515011198/2016A020216009); the Science and Technology Program of Guangzhou City (Grant 2014Y2-00136 /201803010122). Declaration of Interests: The authors have nothing to disclose. Ethics Approval Statement: All animal experiments were conducted following prevailing laws and institutional guidelines on the humane care and use of laboratory animals and were approved by the Institutional Animal Care and the Medical Ethical Committee of the First Affiliated Hospital of Sun Yat-sen University ([2019]254).