Intermedin alleviates the inflammatory response and stabilizes the endothelial barrier in LPS-induced ARDS through the PI3K/Akt/eNOS signaling pathway

Abstract

Inflammatory storms and endothelial barrier dysfunction are the central pathophysiological features of acute respiratory distress syndrome (ARDS). Intermedin (IMD), a member of the calcitonin gene-related peptide (CGRP) family, has been reported to alleviate inflammation and protect endothelial cell (EC) integrity. However, the effects of IMD on ARDS have not been clearly elucidated. In the present study, clinical ARDS data were used to explore the relationship between serum IMD levels and disease severity and prognosis, and we then established a model to predict the possibility of hospital survival. Mouse models of ARDS and LPS-challenged endothelial cells were used to analyze the protective effect and underlying mechanism of IMD. We found that in patients with ARDS, increased serum IMD levels were associated with reduced disease severity and increased rates of hospital survival. IMD alleviated the LPS-induced inflammatory response by decreasing proinflammatory cytokines, NF-κB p65 expression and NF-κB p65 nuclear translocation. In addition, IMD stabilized the endothelial barrier by repairing adherens junctions (AJs), cytoskeleton and capillary leakage. IMD exerted protective effects against ARDS on pulmonary endothelial cells, at least partly, through PI3K/Akt/eNOS signaling, while IMD’s anti-inflammation effect was mediated through an eNOS-independent mechanism. Our study may provide new therapeutic insight for ARDS treatment.