Shear stress associated with cardiopulmonary bypass induces expression of inflammatory cytokines and necroptosis in monocytes

Abstract

Cardiopulmonary bypass (CPB) is required during most cardiac surgeries. CBP drives systemic inflammation and multi-organ dysfunction that is especially severe in neonatal patients. Limited understanding of molecular mechanisms underlying CPB-associated inflammation presents a significant barrier to improve clinical outcomes. To better understand these clinical issues, we performed the first mRNA-sequencing on total circulating leukocytes from neonatal patients undergoing CPB. Our data identified myeloid cells, particularly monocytes, as the major cell type driving transcriptional responses to CPB. Furthermore, interleukin-8 (IL8) and tumor necrosis factor-α (TNFα) were inflammatory cytokines robustly upregulated in leukocytes from both patients and piglets exposed to CPB. To delineate the molecular mechanism, we exposed THP-1 human monocytic cells to CPB-like conditions including artificial surfaces, high shear stress, and cooling/rewarming. Shear stress was found to drive cytokine upregulation via calciumdependent signaling pathways. We also observed that a subpopulation of THP-1 cells died via TNFα-mediated necroptosis, which we hypothesize contributes to post-CPB inflammation. Together, our study identifies a shear-stress modulated molecular mechanism that drives systemic inflammation in pediatric CPB patients. These are also the first data to demonstrate that shear-stress causes necroptosis. Finally, we observe that calcium and TNFα signaling are novel targets to ameliorate post-CPB inflammation.

microRNA Expression Levels Change in Neonatal Patients During and After Exposure to Cardiopulmonary Bypass

“…We also eliminated all mRNAs that were not present in our ancillary mRNA analysis. 4 This filtering ensured that only the highest quality relationships were validated.…”

“…In a previous study using a separate population, we identified 2, 688 genes which exhibited temporal dysregulation after CPB, which were categorized into 5 distinct groups. 4 We expanded on this analysis to investigate relationships between these differentially expressed genes (DEGs) and the miRNA target genes identified in this analysis. 1,046 of these 2,688 DEGs (38.9%) were reported targets of differentially expressed miRNAs, as shown in Table 2 and Figure 1C.…”

“…Some of the miRNA target genes included regulatory kinases of differentially expressed mRNAs found in our corresponding mRNA-seq data (Figure 3). 4…”

“…the number of mRNA targets for each individual miRNA are presented in supplemental table 2. (D) Overlapping and distinct target genes within each cluster that were previously associated with CPB 4.…”

Synthetic Material Abdominal Swabs Reduce Activation of Platelets and Leukocytes Compared to Cotton Materials

“…In most surgeries, where heavy bleeding is expected, such as hip replacement, openheart, or aorta surgeries, blood is aspirated using a vacuum blood sucker and retransfusion of the aspirated blood is routinely performed to avoid allogeneic blood transfusions [4]. The coagulation, fibrinolysis, and inflammation in the sucked blood are strongly activated [5,6]. Furthermore, cells are exposed to shear stress, which can lead to their destruction [7].…”