Silent hypoxia: higher NO in red blood cells of COVID-19 patients

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RESEARCH ARTICLE

Open Access

Silent hypoxia: higher NO in red blood cells of COVID-19 patients Esmaeil Mortaz1, Majid Malkmohammad2*, Hamidreza Jamaati3, Parisa Adimi Naghan3, Seyed MohamadReza Hashemian3, Payam Tabarsi1, Maohammad Varahram1, Hamidreza Zaheri3, Efsun Gonca Uğur Chousein4, Gert Folkerts5 and Ian M. Adcock6,7

Abstract Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has spread to almost 100 countries, infected over 31 M patients and resulted in 961 K deaths worldwide as of 21st September 2020. The major clinical feature of severe COVID-19 requiring ventilation is acute respiratory distress syndrome (ARDS) with multi-functional failure as a result of a cytokine storm with increased serum levels of cytokines. The pathogenesis of the respiratory failure in COVID-19 is yet unknown, but diffuse alveolar damage with interstitial thickening leading to compromised gas exchange is a plausible mechanism. Hypoxia is seen in the COVID-19 patients, however, patients present with a distinct phenotype. Intracellular levels of nitric oxide (NO) play an important role in the vasodilation of small vessels. To elucidate the intracellular levels of NO inside of RBCs in COVID-19 patients compared with that of healthy control subjects. Methods: We recruited 14 COVID-19 infected cases who had pulmonary involvement of their disease, 4 nonCOVID-19 healthy controls (without pulmonary involvement and were not hypoxic) and 2 hypoxic non-COVID-19 patients subjects who presented at the Masih Daneshvari Hospital of Tehran, Iran between March–May 2020. Whole blood samples were harvested from patients and intracellular NO levels in 1 × 106 red blood cells (RBC) was measured by DAF staining using flow cytometry (FACS Calibour, BD, CA, USA). Results: The Mean florescent of intensity for NO was significantly enhanced in COVID-19 patients compared with healthy control subjects (P ≤ 0.05). As a further control for whether hypoxia induced this higher intracellular NO, we evaluated the levels of NO inside RBC of hypoxic patients. No significant differences in NO levels were seen between the hypoxic and non-hypoxic control group. Conclusions: This pilot study demonstrates increased levels of intracellular NO in RBCs from COVID-19 patients. Future multi-centre studies should examine whether this is seen in a larger number of COVID-19 patients and whether NO therapy may be of use in these severe COVID-19 patients. Keywords: COVID-19, NO, Hypoxia

* Correspondence: [email protected] 2 Tracheal Disease Research Center, National Research Institute of Tuberculosisand Lung Diseases (NRITLD), Shahid Beheshti University of Medical Science, Tehran, Iran Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate c