Combined Remote Ischemic Preconditioning and Erythropoietin Better Protect Against Lung Injury Induced by Skeletal Ischemia Reperfusion: Role of NLRP3 Inflammasome

Abstract ID 99282 Poster Board 213 Remote ischemic preconditioning (RIPC) diminishes multi-organ failure induced by skeletal muscle ischemia and reperfusion (S-I/R). The current study investigated whether skeletal RIPC protection against S-I/R-induced acute lung injury (ALI) could be facilitated following simultaneous exposure to the hormonal growth factor erythropoietin (EPO) in rats. The role of NLRP3 inflammasome and coupled apoptotic and miRNAs regulatory cascades in the interaction was also determined. S-I/R challenge was performed by 3-hr right hindlimb ischemia followed by 3-hr of reperfusion, whereas RIPC involved 3 brief consecutive I/R cycles of the contralateral hindlimb. The Lung injurious response to S-I/R was verified by: (i) decreases in minute respiratory volume (MRV), forced expiratory volume 1 (FEV1) and functional vital capacity (FVC), (ii) increases in respiratory rate (RR) and FEV1/FVC ratio, (iii) falls in lung surfactant protein-D (SP-D) and rises in of lung plasminogen activator inhibitor-1 (PAI-1) and intercellular adhesion molecule-1 (ICAM-1), and (iii) narrowed alveolar spaces, thickened inter-alveolar septum, and mononuclear cellular infiltration. These functional, biochemical, and structural lung blemishes were partially amended by RIPC and by EPO (500 or 5000 IU/kg) in a dose-related fashion. Further, the prior exposure to RIPC plus EPO-500 caused more prominent rectifications of ALI damages that surpassed the protection conferred by either intervention. Molecularly, the dual RIPC/EPO-500 regimen was also more effective in reversing the S-I/R-associated increments in pulmonary expressions of NLRP3 and related inflammatory (TLR4, MyD88, TRAF, NF-κB, TNF-α, IL-1β, and IL-18), apoptotic (ASC, procaspse-1, caspase-1), and microRNAs (increases in miR-21 and decreases miR-495). These findings suggest a pivotal role for the suppression of NLRP3 inflammasome and interconnected cellular offenses in the augmented therapeutic potential of the RIPC/EPO-500 regimen against S-I/R-induced ALI.