Abstract
Cardiopulmonary bypass (CPB) provokes inflammation culminating in organ dysfunction and increased mortality. Recently, neutrophil extracellular traps (NETs) have been found to be involved in a variety of cardiovascular diseases promoting tissue and organ injury. Here, we aimed to elaborate the proinflammatory potential of circulating cell-free (cf)DNA in patients undergoing cardiac surgery with CPB. Plasma was collected pre- and postoperatively as well as at d1, d3, d5 and d8 after surgery. At d1, we found circulating cfDNA levels to be significantly increased in patients with prolonged CPB duration (>100 min) when compared to those with shorter CPB times (CPB < 100 min). Increased CPB duration yielded in higher levels of circulating mitochondrial (mt)DNA, soluble thrombomodulin (sCD141) and ICAM-1, reflecting endothelial damage. Positive correlation between cfDNA and sCD141 was demonstrated at all time points. Plasma and cfDNA from patients with CPB > 100 min induced NETs release by neutrophils from healthy donors which was not suppressed by inhibitors of intracellular toll-like receptor (TLR)9. DNA binding to neutrophils’ surface (s)TLR9 has been evidenced. Altogether, we demonstrate that elevated plasma cfDNA might be useful to assess CPB-mediated detrimental effects, including endothelial damage, in cardiac surgical patients with prolonged CPB duration. cfDNA-triggered NETosis is independent of classical TLR9 signaling.
Highlights
Cardiac surgery with cardiopulmonary bypass (CPB) support initiates a systemic inflammatory response (SIRS), presumably caused by contact of blood components with the artificial surface of the extracorporeal circuit, that is associated with postoperative morbidity and mortality[1]
Recent research has implicated mitochondrial DNA (mtDNA) as a damage-associated molecular pattern (DAMP) and marked increase in extracellular mtDNA was already found in different pathological disorders, e.g after cardiac surgery[18] and during sterile SIRS19. mtDNA fragments participate in different kinds of innate immune modulation by activating pattern recognition receptors, of which toll-like receptors (TLRs) are the most prominent one
Morbidity associated with Cardiopulmonary bypass (CPB) can be attributed to the generalized inflammatory response induced by blood-artificial surfaces interactions during extracorporeal circulation and the ischemia/reperfusion implications, including exacerbated inflammatory response resembling SIRS
Summary
Cardiac surgery with cardiopulmonary bypass (CPB) support initiates a systemic inflammatory response (SIRS), presumably caused by contact of blood components with the artificial surface of the extracorporeal circuit, that is associated with postoperative morbidity and mortality[1]. In this regard, many studies demonstrated increased inflammatory markers, such as TNF-α, IL-6, IL-8 after cardiac surgery with CPB2,3. The release of neutrophil extracellular traps (NETs)/cell-free DNA (cfDNA), by a process termed NETosis, and their potent proinflammatory and cytotoxic effects have gained much attention as risk factors for cardiovascular diseases as well as the development of postoperative complications[5,6,7]. We further sought to evaluate how cfDNA might amplify neutrophil-mediated inflammatory reactions and to further elucidate the significance of the classical DNA receptor TLR9 in this process
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