Exercise Hormone Irisin Mitigates Endothelial Barrier Dysfunction and Experimental Lung Injury

Background: Increased microvascular leakage is a cardinal feature of many critical diseases. Regular exercise is associated with improved endothelial function and reduced risk of cardiorespiratory disease. Irisin, secreted during exercise, contributes to many health benefits of exercise. However, the effects of irisin on endothelial function in the context of lung injury remain unknown. Methods: The direct effect of irisin on endothelial barrier function was studied in human microvascular endothelial cells (HMVECs) and human umbilical vein endothelial cells (HUVECs). The therapeutic effect of irisin was evaluated in 4 preclinical models of acute lung injuey (ALI). Serum irisin levels were measured and associated with disease severity in 60 ARDS patients. Findings: In this study, we found that irisin remarkably strengthened endothelial junctions and barrier function via binding to integrin αVβ5 receptor in LPS-treated endothelial cells. The beneficial effect of irisin was associated with suppression of the Src-MLCK-β-catenin pathway, activation of the AMPK-Cdc42/Rac1 pathway and improvement of mitochondrial function. In preclinical models of ALI, exogenous irisin improved pulmonary function, decreased lung edema and injury, suppressed inflammation, and increased survival. In ARDS patients, serum irisin levels were decreased and inversely correlated with disease severity and mortality. Interpretation: Irisin enhances endothelial barrier function and mitigates microvascular leakage related lung injury. Irisin may assist with the urgent medical need for preventing or minimizing ARDS and other microvascular leakage related diseases. Funding Statement: National Nature Science Foundation of China (No. 81770491) and the Ministry of Education Innovation Team Development Program of China (No. IRT16R57). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: The study was approved by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University. All study participants provided informed consent in accordance with the Declaration of Helsinki.