Plasma exosomal miR-223 regulated IL-6 and inflammasome during cardiopulmonary bypass surgery

• Main Authors: Shih-Sheng Chang, 張詩聖
• Other Authors: Chi-Yuan Li
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/678g3j

博士 === 中國醫藥大學 === 臨床醫學研究所博士班 === 106 === BACKGROUND Cardiopulmonary bypass had been widely used in cardiac surgery. In addition to surgical injury, CPB also leads to inflammatory responses, which could lead to systemic inflammatory response and subsequent clinical morbidities and even mortalities. There were several possible mechanisms reported for CPB related inflammation, included ischemia-reperfusion injury, endotoxin and complement activation. Some clinical studies noticed the inflammatory mediators peaked early in the CPB process and declined thereafter, which wasn’t observed in patients received cardiac surgery without CPB. We hypothesized certain protective endogenous homeostasis existed and should be important for preventing excessive hazardous systemic inflammation during CPB. Inflammasome is a multi-meric protein complex and plays pivotal roles in inflammatory response. Among them, NLRP3 had been extensively studied for its important facilitation in formation of caspase and IL-1. IL-6 and IL-8 are secreted by macrophages and are key mediators during inflammation in terms of their enhancement of development and chemotaxis of leukocytes into the target sites. Recently, cell-cell communication with exosomes and microRNA had been reported. It had been shown that some microRNAs play pivotal roles in inflammatory response and cardiovascular disease. Some studies indicated the temporal change of circulating microRNA during CPB surgery. By using bioinformatics and literature review, we choose microRNA-223 as our study target. We assessed whether plasma exosomal microRNAs in patients undergoing cardiac surgery with CPB are involved in the regulation of inflammatory responses. METHODS & RESULTS We enrolled patients underwent cardiac surgery with CPB. Patients with autoimmunity disease, asthma, COPD, cancer and use of NSAIDs or steroids were excluded. Plasma samples were isolated from CPB patients (n = 21) at 5 specified time points: pre-surgery, pre-CPB and 2 hours (h), 4 h and 24 h after CPB began. Plasma TNF-α expression was increased after CPB began compared to that in the pre-surgery samples. Plasma IL-8 and IL-6 expression peaked at 4 h after CPB began but was downregulated at 24 h. The number of plasma exosomes collected at 2 h (55.1 ± 8.3%), 4 h (63.8 ± 10.1%) and 24 h (83.5 ± 3.72%) after CPB began was significantly increased compared to that in the pre-CPB samples (42.8 ± 0.11%). These exosomes had a predominantly parental cellular origin from RBCs and platelets. Additionally, the plasma exosomal miR-223 levels were significantly increased after CPB began compared to those in the pre-CPB samples. Further, exosomal miR-223 from plasma collected after CPB began downregulated IL-6 and NLRP3 expression in the monocytes. CONCLUSIONS Cardiopulmonary bypass (CPB) evokes a broad range of inflammatory responses during the intra- and post-operative periods. Here, we show the important role of exosomes and exosomal miRNA in cell-cell communication and their regulatory role in inflammatory responses during cardiac surgery with CPB. RBCs and platelets released predominant exosomes into circulation, and exosomal miR-223 that was significantly overexpressed after CPB began downregulated NLRP3 and IL-6 expression in monocytes. Our novel findings might provide a clue for using exosomal microRNA as a biomarker and even therapeutic target in the systemic inflammatory response in patients underwent CPB.