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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 multiorgan 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 mRNA sequencing on total circulating leukocytes from neonatal patients undergoing CPB. Our data identify myeloid cells, particularly monocytes, as the major cell type driving transcriptional responses to CPB. Furthermore, IL-8 and TNF-α 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 calcium-dependent signaling pathways. We also observed that a subpopulation of THP-1 cells died via TNF-α-mediated necroptosis, which we hypothesize contributes to post-CPB inflammation. Our study identifies a shear stress-modulated molecular mechanism that drives systemic inflammation in pediatric CPB patients. These are also the first data to our knowledge to demonstrate that shear stress causes necroptosis. Finally, we observe that calcium and TNF-α signaling are potentially novel targets to ameliorate post-CPB inflammation.

SUBMITTER: Tu LN

PROVIDER: S-EPMC7821587 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cardiopulmonary bypass (CPB), the mechanical support required during the majority of cardiac surgeries, causes significant systemic inflammation and multi-organ dysfunction that is especially severe in neonatal patients. Currently, the limited understanding of the molecular mechanisms that underlie CPB-associated inflammation presents a significant barrier to the development of therapeutic interventions. To address this knowledge gap, we performed mRNA sequencing of total circulating leukocytes from neonatal patients undergoing CPB. The transcriptional signatures across 7 time points ranging from pre-CPB, during CPB, to 24 hours post-CPB were found to be dominated by myeloid cells, particularly monocytes. INTERLEUKIN-8 (IL8) and TUMOR NECROSIS FACTOR-α (TNFα) were two inflammatory cytokines specifically and robustly upregulated in the leukocytes from both CPB patients and piglets exposed to CPB. To delineate the mechanism how CPB activates cytokine production, we exposed THP-1 cells, a human monocyte cell line, in vitro to CPB-like conditions including artificial surfaces, high shear stress and cooling/rewarming. The in vitro CPB data recapitulated the in vivo CPB condition in that IL8 and TNFα were strongly upregulated. Shear stress was the major driver of cytokine expression as compared to the temperature or plastic exposure. Extracellular calcium influx was found essential for the shear-stress mediated upregulation of cytokines via the MEK/ERK/AP-1 and Calcineurin/NFAT pathways. After being exposed to CPB conditions, a subpopulation of THP-1 cells died by apoptosis and TNFα-mediated necroptosis, the latter form of which potentially contribute to the post-CPB tissue injuries. Together, our study is the first to elucidate the shear-stress modulated molecular mechanisms leading to systemic inflammation in pediatric CPB and the link between inflammation and organ damage. Calcium signaling pathways and TNFα signaling are novel targets for therapeutic development to improve clinical outcomes. To our knowledge, these are also the first data to implicate necroptosis in CPB and show that shear stress can activate necroptosis.

Project description:IntroductionInduction of an inflammatory response is thought to have a significant role in the complications that follow cardiopulmonary bypass (CPB). The statin drugs are increasingly being recognized as having potent anti-inflammatory effects and hence have potential to influence an important mechanism of injury in CPB, although there is no current confirmation that this is indeed the case. Our objective was to systematically review if pre-operative prophylactic statin therapy, compared with placebo or standard of care, can decrease the inflammatory response in people undergoing heart surgery with CPB.MethodsWe performed a systematic and comprehensive literature search for all randomized controlled trials (RCTs) of open heart surgery with CPB in adults or children who received prophylactic statin treatment prior to CPB, with reported outcomes which included markers of inflammation. Two authors independently identified eligible studies, extracted data, and assessed study quality using standardized instruments. Weighted mean difference (WMD) was the primary summary statistic with data pooled using a random effects model. Descriptive analysis was used when data could not be pooled.ResultsEight RCTs were included in the review, with the number of trials for each inflammatory outcome being even more limited. Pooled data demonstrated benefit with the use of statin to attenuate the post-CPB increase in interleukins 6 and 8 (IL-6, IL-8), peak high sensitivity C-reactive protein (hsCRP), and tumor necrosis factor-alpha (TNF-alpha) post-CPB (WMD [95% confidence interval (CI)] -23.5 pg/ml [-36.6 to -10.5]; -23.4 pg/ml [-35.8 to -11.0]; -15.3 mg/L [CI -26.9 to -3.7]; -2.10 pg/ml [-3.83 to -0.37] respectively). Very limited RCT evidence suggests that prophylactic statin therapy may also decrease adhesion molecules following CPB including neutrophil CD11b and soluble P (sP)-selectin.ConclusionsAlthough the RCT evidence may suggest a reduction in post-CPB inflammation by statin therapy, the evidence is not definitive due to significant limitations. Several of the trials were not methodologically rigorous and statin intervention was highly variable in this small number of studies. This systematic review demonstrates that there is a significant gap that exists in the current literature in regards to the potential anti-inflammatory effect of statin therapy prior to CPB.

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

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