Shear stress associated with cardiopulmonary bypass induces expression of inflammatory cytokines and necroptosis in monocytes.
Shear stress associated with cardiopulmonary bypass induces expression of inflammatory cytokines and necroptosis in monocytes.
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与体外循环相关的剪切应力诱导单核细胞炎症细胞因子的表达和坏死性凋亡。
DOI：
10.1172/jci.insight.141341
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发表时间：
2021
期刊：
影响因子：
8
通讯作者：
Bittel
中科院分区：
文献类型：
--
作者：
Tu,LanN;Hsieh,Lance;Kajimoto,Masaki;Charette,Kevin;Kibiryeva,Nataliya;Forero,Adriana;Hampson,Sarah;Marshall,JenniferA;O'Brien,James;Scatena,Marta;Portman,MichaelA;Savan,Ram;Benner,Chris;Aliseda,Alberto;Nuri,Muhammad;Bittel
体外循环（CPB）在大多数心脏手术中是必需的。CBP引起全身炎症和多器官功能障碍，在新生儿患者中尤为严重。对cpb相关炎症的分子机制的有限理解是改善临床结果的重大障碍。为了更好地理解这些临床问题，我们对新生儿CPB患者的总循环白细胞进行了mRNA测序。我们的数据确定骨髓细胞，特别是单核细胞，是驱动CPB转录反应的主要细胞类型。此外，暴露于CPB的患者和仔猪的白细胞中IL-8和TNF-α是炎症细胞因子的显著上调。为了描述分子机制，我们将THP-1人类单核细胞暴露于cpb样条件下，包括人工表面、高剪切应力和冷却/再加热。发现剪切应力通过钙依赖的信号通路驱动细胞因子上调。我们还观察到THP-1细胞亚群通过TNF-α介导的坏死下垂死亡，我们假设这有助于cpb后炎症。我们的研究确定了一种剪切应力调节的分子机制，驱动小儿CPB患者的全身性炎症。这也是我们所知的第一个证明剪切应力导致坏死下垂的数据。最后，我们观察到钙和TNF-α信号是改善cpb后炎症的潜在新靶点。
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.