Department of Respiratory Medicine, Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover Medical School, 30625 Hannover, Germany.
ExcellGene SA, 1970 Monthey, Switzerland.
Int J Mol Sci. 2021 Jul 26;22(15):7941. doi: 10.3390/ijms22157941.
For the treatment of severe COVID-19, supplementation with human plasma-purified α-1 antitrypsin (AAT) to patients is currently considered. AAT inhibits host proteases that facilitate viral entry and possesses broad anti-inflammatory and immunomodulatory activities. Researchers have demonstrated that an interaction between SARS-CoV-2 spike protein (S) and lipopolysaccharides (LPS) enhances pro-inflammatory responses in vitro and in vivo. Hence, we wanted to understand the potential anti-inflammatory activities of plasma-derived and recombinant AAT (recAAT) in a model of human total peripheral blood mononuclear cells (PBMCs) exposed to a combination of CHO expressed trimeric spike protein and LPS, ex vivo. We confirmed that cytokine production was enhanced in PBMCs within six hours when low levels of LPS were combined with purified spike proteins ("spike"). In the presence of 0.5 mg/mL recAAT, however, LPS/spike-induced TNF-α and IL-1β mRNA expression and protein release were significantly inhibited (by about 46-50%) relative to LPS/spike alone. Although without statistical significance, recAAT also reduced production of IL-6 and IL-8. Notably, under the same experimental conditions, the plasma-derived AAT preparation Respreeza (used in native and oxidized forms) did not show significant effects. Our findings imply that an early pro-inflammatory activation of human PBMCs is better controlled by the recombinant version of AAT than the human plasma-derived AAT used here. Considering the increasing clinical interest in AAT therapy as useful to ameliorate the hyper-inflammation seen during COVID-19 infection, different AAT preparations require careful evaluation.
对于严重 COVID-19 的治疗，目前考虑向患者补充人血浆纯化的α-1 抗胰蛋白酶（AAT）。AAT 抑制有助于病毒进入的宿主蛋白酶，并具有广泛的抗炎和免疫调节作用。研究人员已经证明，SARS-CoV-2 刺突蛋白（S）和脂多糖（LPS）之间的相互作用增强了体外和体内的促炎反应。因此，我们希望了解在暴露于 CHO 表达的三聚体刺突蛋白和 LPS 的组合的人总外周血单核细胞（PBMC）模型中，血浆衍生的和重组的 AAT（recAAT）的潜在抗炎活性。我们证实，当低水平的 LPS 与纯化的刺突蛋白“刺突”结合时，PBMC 中的细胞因子产生在六小时内增强。然而，在存在 0.5 mg/mL recAAT 的情况下，LPS/刺突诱导的 TNF-α和 IL-1β mRNA 表达和蛋白释放与 LPS/刺突单独相比显著抑制（约 46-50%）。尽管没有统计学意义，但 recAAT 还减少了 IL-6 和 IL-8 的产生。值得注意的是，在相同的实验条件下，血浆衍生的 AAT 制剂 Respreeza（以天然和氧化形式使用）没有显示出显著的效果。我们的发现表明，与这里使用的人血浆衍生的 AAT 相比，重组版本的 AAT 更好地控制了人类 PBMC 的早期促炎激活。考虑到 AAT 治疗作为改善 COVID-19 感染期间过度炎症的有用方法的临床兴趣日益增加，不同的 AAT 制剂需要仔细评估。
