Neutrophil-mediated oxidative stress and albumin structural damage predict COVID-19-associated mortality

Abstract

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.

Redox imbalance in COVID-19 pathophysiology

“…Since the beginning of COVID-19, multiple reports have proposed a potential role of oxidant stress in its pathogenesis including the cytokine storm, endothelial cell death, coagulopathy and cellular hypoxia [ 6 , [19] , [20] , [21] , [22] ]. However, only a limited number of original research studies explored these responses [ [23] , [24] , [25] , [26] , [27] ]. Of note, there are studies describing the role of gasotransmitters (hydrogen sulfide and nitric oxide), cellular glutathione and lipid peroxidation in the pathogenesis of COVID-19 [ 10 , 27 , 28 ].…”

Insights into potential mechanisms of asthma patients with COVID-19: A study based on the gene expression profiling of bronchoalveolar lavage fluid

“…We tried to infer the upstream pathway activity via SPEED2 and upregulated genes were found, including H 2 O 2 , VEGF, IL-1 and so on. H 2 O 2 -mediated oxidative stress plays an important role in airway inflammation in asthma [ 95 ] and predicts COVID-19-associated mortality [ 96 ]. VEGF enhances disintegrin and metalloproteinase-33 expression and airway smooth muscle cell proliferation, which may be implicated in inflammation and airway vascular remodeling in asthma [ 97 ].…”

Molecular Mechanisms Related to Responses to Oxidative Stress and Antioxidative Therapies in COVID-19: A Systematic Review

“…Neutrophils are involved in COVID-19-related oxidative stress. After activation, they produce high levels of ROS as part of their defense mechanisms against pathogens and other targets that need to be destroyed [ 51 , 52 ]. Elevated levels of neutrophils are characteristic of severe COVID-19 patients [ 30 ], and a high neutrophil to lymphocyte ratio (NLR) was a predictor of poor prognosis from the early stage of the disease [ 53 ].…”

“…The level of 2-hydroxybutyric acid was significantly increased in hospitalized COVID-19 patients compared to controls [ 67 ]. While Cekerevac et al found that hydrogen peroxide levels were similar in all hospitalized patients, independent of disease severity [ 83 ], Badawy et al found high levels of plasma hydrogen peroxide and damaged serum albumin can be used as predictors of mortality in COVID-19 [ 52 ]. Moreover, with increased COVID-19 severity in hospitalized patients, increased levels of ischemia-modified albumin were observed [ 90 ].…”