Academic Unit of Health Sciences, Federal University of Jatai, Jatai, Goias, Brazil.
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
Am J Physiol Regul Integr Comp Physiol. 2023 Apr 1;324(4):R435-R445. doi: 10.1152/ajpregu.00154.2022. Epub 2023 Feb 3.
Coronavirus disease 2019 (COVID-19) infection has a negative impact on the cytokine profile of pregnant women. Increased levels of proinflammatory cytokines seem to be correlated with the severity of the disease, in addition to predisposing to miscarriage or premature birth. Proinflammatory cytokines increase the generation of reactive oxygen species (ROS). It is unclear how interleukin-6 (IL-6) found in the circulation of patients with severe COVID-19 might affect gestational health, particularly concerning umbilical cord function. This study tested the hypothesis that IL-6 present in the circulation of women with severe COVID-19 causes umbilical cord artery dysfunction by increasing ROS generation and activating redox-sensitive proteins. Umbilical cord arteries were incubated with serum from healthy women and women with severe COVID-19. Vascular function was assessed using concentration-effect curves to serotonin in the presence or absence of pharmacological agents, such as tocilizumab (antibody against the IL-6 receptor), tiron (ROS scavenger), ML171 (Nox1 inhibitor), and Y27632 (Rho kinase inhibitor). ROS generation was assessed by the dihydroethidine probe and Rho kinase activity by an enzymatic assay. Umbilical arteries exposed to serum from women with severe COVID-19 were hyperreactive to serotonin. This effect was abolished in the presence of tocilizumab, tiron, ML171, and Y27632. In addition, serum from women with severe COVID-19 increased Nox1-dependent ROS generation and Rho kinase activity. Increased Rho kinase activity was abolished by tocilizumab and tiron. Serum cytokines in women with severe COVID-19 promote umbilical artery dysfunction. IL-6 is key to Nox-linked vascular oxidative stress and activation of the Rho kinase pathway.
新型冠状病毒疾病 2019（COVID-19）感染对孕妇的细胞因子谱有负面影响。促炎细胞因子水平升高似乎与疾病的严重程度相关，此外还会导致流产或早产。促炎细胞因子会增加活性氧（ROS）的产生。目前尚不清楚循环中发现的白细胞介素 6（IL-6）如何影响妊娠健康，特别是脐带功能。本研究检验了一个假设，即循环中存在的严重 COVID-19 患者的 IL-6 通过增加 ROS 的生成并激活氧化还原敏感蛋白，从而导致脐带动脉功能障碍。用来自健康妇女和严重 COVID-19 妇女的血清孵育脐带动脉。在存在或不存在药物（如托珠单抗（IL-6 受体抗体）、tiron（ROS 清除剂）、ML171（Nox1 抑制剂）和 Y27632（Rho 激酶抑制剂））的情况下，通过 5-羟色胺在浓度-效应曲线上评估血管功能。通过二氢乙啶探针评估 ROS 生成，通过酶促测定评估 Rho 激酶活性。暴露于来自严重 COVID-19 妇女血清的脐带动脉对 5-羟色胺反应过度。这种作用在存在托珠单抗、tiron、ML171 和 Y27632 的情况下被消除。此外，来自严重 COVID-19 妇女的血清增加了 Nox1 依赖性 ROS 生成和 Rho 激酶活性。Rho 激酶活性的增加被托珠单抗和 tiron 所消除。严重 COVID-19 妇女的血清细胞因子促进脐带动脉功能障碍。IL-6 是 Nox 相关血管氧化应激和 Rho 激酶途径激活的关键。
