Neutrophil-mediated oxidative stress and albumin structural damage predict COVID-19-associated mortality.
Neutrophil-mediated oxidative stress and albumin structural damage predict COVID-19-associated mortality.
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作者：
Badawy MA;Yasseen BA;El-Messiery RM;Abdel-Rahman EA;Elkhodiry AA;Kamel AG;El-Sayed H;Shedra AM;Hamdy R;Zidan M;Al-Raawi D;Hammad M;Elsharkawy N;El Ansary M;Al-Halfawy A;Elhadad A;Hatem A;Abouelnaga S;Dugan LL;Ali SS
人血清白蛋白（HSA）是血液中的前线抗氧化蛋白，具有抗炎和抗凝功能。在这里，我们报告说，COVID-19 诱导的氧化应激会对 HSA 造成结构损伤，并与危重患者的死亡率相关。我们招募了 39 名患者，随访时间中位数为 12.5 天（1-35 天），其中 23 人死亡。通过分析患者和健康个体 (n=11) 的血液样本，我们提供的证据表明，中性粒细胞是血液中氧化应激的主要来源，并且过氧化氢在非幸存者的血浆中大量积累。然后，我们分析了对照、幸存者和非幸存者受试者 (n=10-11) 全血中与 HSA 结合的自旋标记脂肪酸 (SLFA) 的电子顺磁共振谱。非幸存者的 HSA 显示出显着降低的蛋白质堆积顺序参数、更快的 SLFA 相关旋转时间和更小的 S/W 比（HSA 内的强结合/弱结合位点），所有这些都反映了非常流体的蛋白质微环境。在装载/卸载 16-DSA 后，我们发现重症患者的 HSA 转运功能可能会受损。按平均值分层，Kaplan-Meier 生存分析表明，较低的 S/W 比值和血浆中累积的 H2O2 显着预测院内死亡率（S/W≤0.15, 81.8% (18/22) vs. S/W>0.15, 18.2% (4/22), p=0.023；血浆 [H2O2]>8.6 μM, 65.2% (15/23) 对比 34.8% (8/23)，p=0.043）。当我们将这两个参数组合为比率 ((S/W)/[H2O2]) 来得出风险评分时，所得风险评分低于高保真度预测死亡率的平均值 (<0.019)（95.5% (21/22) vs. 4.5% (1/22)，对数秩 χ2=12.1，p=4.9×10−4）。导出的参数可以提供替代标记来评估针对 HSA 替代和/或氧化应激的 COVID-19 治疗的新候选药物。
Human serum albumin (HSA) is the frontline antioxidant protein in blood with established anti-inflammatory and anticoagulation functions. Here, we report that COVID-19-induced oxidative stress inflicts structural damages to HSA and is linked with mortality outcome in critically ill patients. We recruited 39 patients who were followed up for a median of 12.5 days (1–35 days), among them 23 had died. Analyzing blood samples from patients and healthy individuals (n=11), we provide evidence that neutrophils are major sources of oxidative stress in blood and that hydrogen peroxide is highly accumulated in plasmas of non-survivors. We then analyzed electron paramagnetic resonance spectra of spin-labeled fatty acids (SLFAs) bound with HSA in whole blood of control, survivor, and non-survivor subjects (n=10–11). Non-survivors’ HSA showed dramatically reduced protein packing order parameter, faster SLFA correlational rotational time, and smaller S/W ratio (strong-binding/weak-binding sites within HSA), all reflecting remarkably fluid protein microenvironments. Following loading/unloading of 16-DSA, we show that the transport function of HSA may be impaired in severe patients. Stratified at the means, Kaplan–Meier survival analysis indicated that lower values of S/W ratio and accumulated H2O2 in plasma significantly predicted in-hospital mortality (S/W≤0.15, 81.8% (18/22) vs. S/W>0.15, 18.2% (4/22), p=0.023; plasma [H2O2]>8.6 μM, 65.2% (15/23) vs. 34.8% (8/23), p=0.043). When we combined these two parameters as the ratio ((S/W)/[H2O2]) to derive a risk score, the resultant risk score lower than the mean (<0.019) predicted mortality with high fidelity (95.5% (21/22) vs. 4.5% (1/22), log-rank χ2=12.1, p=4.9×10−4). The derived parameters may provide a surrogate marker to assess new candidates for COVID-19 treatments targeting HSA replacements and/or oxidative stress.