Multi-system involvement and rapid clinical deterioration are hallmarks of coronavirus disease 2019 (COVID-19) related mortality. The unique clinical phenomena in severe COVID-19 can be perplexing, and they include disproportionately severe hypoxemia relative to lung alveolar-parenchymal pathology and rapid clinical deterioration, with poor response to O₂ supplementation, despite preserved lung mechanics. Factors such as microvascular injury, thromboembolism, pulmonary hypertension, and alteration in hemoglobin structure and function could play important roles. Overwhelming immune response associated with “cytokine storms” could activate reactive oxygen species (ROS), which may result in consumption of nitric oxide (NO), a critical vasodilation regulator. In other inflammatory infections, activated neutrophils are known to release myeloperoxidase (MPO) in a natural immune response, which contributes to production of hypochlorous acid (HOCl). However, during overwhelming inflammation, HOCl competes with O₂ at heme binding sites, decreasing O₂ saturation. Moreover, HOCl contributes to several oxidative reactions, including hemoglobin-heme iron oxidation, heme destruction, and subsequent release of free iron, which mediates toxic tissue injury through additional generation of ROS and NO consumption. Connecting these reactions in a multi-hit model can explain generalized tissue damage, vasoconstriction, severe hypoxia, and precipitous clinical deterioration in critically ill COVID-19 patients. Understanding these mechanisms is critical to develop therapeutic strategies to combat COVID-19.

中文翻译：

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涉及活性氧和髓过氧化物酶的多重打击假说解释了 COVID-19 的临床恶化和死亡


多系统受累和临床快速恶化是 2019 年冠状病毒病 (COVID-19) 相关死亡率的标志。重症COVID-19的独特临床现象可能令人困惑，其中包括相对于肺泡实质病理学而言不成比例的严重低氧血症以及临床快速恶化，尽管肺力学保存完好，但对补充O ₂的反应较差。微血管损伤、血栓栓塞、肺动脉高压以及血红蛋白结构和功能的改变等因素可能发挥重要作用。与“细胞因子风暴”相关的压倒性免疫反应可能会激活活性氧（ROS），这可能会导致一氧化氮（NO）的消耗，一氧化氮是一种重要的血管舒张调节剂。在其他炎症感染中，已知激活的中性粒细胞会在自然免疫反应中释放髓过氧化物酶 (MPO)，从而有助于产生次氯酸 (HOCl)。然而，在严重的炎症过程中，HOCl 会与 O ₂在血红素结合位点竞争，从而降低 O ₂饱和度。此外，HOCl 会引发多种氧化反应，包括血红蛋白-血红素铁氧化、血红素破坏以及随后游离铁的释放，从而通过额外产生 ROS 和 NO 消耗来介导毒性组织损伤。将这些反应连接到多重打击模型中可以解释重症 COVID-19 患者的全身组织损伤、血管收缩、严重缺氧和临床急剧恶化。了解这些机制对于制定对抗 COVID-19 的治疗策略至关重要。