Journal Article

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

Badawy, Mohamed A, El-Messiery, Riem M, El-sayed, Hajar, Yasseen, Basma A, Abdel-Rahman, Engy A, Hammad, Mahmoud, Hatem, Ashraf, Dugan, Laura L, El Ansary, Mohamed, Elkhodiry, Aya A, Abouelnaga, Sherif, Hamdy, Rehab, Al-Halfawy, Ahmed, Elhadad, Alaa, Shedra, Asmaa M, Zidan, Mona, Kamel, Azza G, Ali, Sameh Saad, Al-Raawi, Diaa, Elsharkawy, Nahla

2021

Overview

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 H 2 O 2 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 [H 2 O 2 ]>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)/[H 2 O 2 ]) 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 χ 2 =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.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Adult / Aged / Aged, 80 and over / Albumin / Antioxidants / Case-Control Studies / Coronaviruses / COVID-19 / COVID-19 - mortality / critically ill COVID-19 patients / Egypt - epidemiology / Electron spin resonance / Electron Spin Resonance Spectroscopy / Fatty acids / Female / Human serum albumin / human serum albumin damage / Humans / Hydrogen peroxide / Hydrogen Peroxide - blood / Immunology and Inflammation / Inflammation / Leukocytes (neutrophilic) / Male / Microenvironments / Middle Aged / Mortality / neutrophils / Neutrophils - physiology / Oxidative Stress / Patients / Prospective Studies / Serum Albumin - adverse effects / Spectrum analysis / Structural Biology and Molecular Biophysics / Time Factors / Unloading