A Multiple-Hit Hypothesis Involving Reactive Oxygen Species and Myeloperoxidase Explains Clinical Deterioration and Fatality in COVID-19

Abstract

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.

Vascular Inflammation Is Associated with Loss of Aquaporin 1 Expression on Endothelial Cells and Increased Fluid Leakage in SARS-CoV-2 Infected Golden Syrian Hamsters

“…Secondly, the virus binds to angiotensin-converting enzyme 2 (ACE2) receptors, lowers ACE activity, and activates the kallikrein–bradykinin pathway leading to further vascular leakage [ 2 , 38 , 39 ]. Thirdly, an overwhelming immune response described as a “cytokine storm” activates reactive oxygen species (ROS) and contributes to an elevated consumption of the vasodilation regulator nitric oxide (NO) [ 2 , 40 ]. Finally, the exaggerated cytokine expression and the secretion of vasoactive molecules such as thrombin, histamine, bradykinin, thromboxane A2, and vascular endothelial growth factor (VEGF) result in a disruption of the vascular endothelium [ 2 ].…”

A Resource for the Network Representation of Cell Perturbations Caused by SARS-CoV-2 Infection

“…We checked whether this list of 75 host proteins was significantly enriched in genes annotated to pathways, using the ClueGO application [ 16 ] ( Figure 1 A) and identified an enrichment of genes that are involved in mitochondrial transport, tRNA processing, and maturation of proteins (e.g., RAB geranylgeranylation and N-Glycan biosynthesis) ( Table S2 ). Although mitochondrial dysfunctions have been linked to SARS-CoV-2 pathogenesis [ 17 , 18 , 19 , 20 ], no additional link between proteins enriched in the list and cell functions perturbed by viral infection was revealed by this classical GSEA approach. This could be explained by noting that many proteins in the list of the 75 SARS-Cov-2 binders are not annotated to pathways ( Table S2 ).…”

Cardiovascular Outcomes in the Acute Phase of COVID-19

“…Activation of neutrophils by viral infections can trigger various cellular mechanisms that can result in vasoconstriction, such as the release of prostanoids, lysosomal enzymes, as well as highly reactive oxygen species. Myeloperoxidases released from the azurophil granules of neutrophils play a particularly critical role in the attenuation of NO bioavailability [ 52 ]. These abnormalities also directly increase functional arterial stiffness.…”