Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 21 6 2022 12 24 677 686 Behrouz Robat-Jazi Department of Medical Immunology, School of Medicine, Aja University of Medical Sciences, Tehran, Iran Khodayar Ghorban Department of Medical Immunology, School of Medicine, Aja University of Medical Sciences, Tehran, Iran AND Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran Mohammad Gholami Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran AND Department of Microbiology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran Esmaeil Samizadeh Department of Pathology, Imam Reza Hospital, Aja University of Medical Sciences, Tehran, Iran Zahra Aghazadeh Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran Mohammad Amin Shahrbaf Department of Medicine, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Maryam Dadmanesh Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran AND Department of Infectious Diseases, School of Medicine, Aja University of Medical Sciences, Tehran, Iran Negin Hosseini Rouzbahani Department of Medical Immunology, School of Medicine, Aja University of Medical Sciences, Tehran, Iran AND Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran Abbas Mirshafiey Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran 2022 08 15 2022 11 27 coronavirus disease of 2019 (COVID-19) can be complicated by acute respiratory distress syndrome (ARDS) and may be associated with cytokine storm and multiorgan failure. Anti-inflammatory agents, such as systemic corticosteroids, monoclonal antibodies, and nonsteroidal anti-inflammatory drugs (NSAIDs) can be used for this purpose. In this study, we evaluated the immunomodulatory effect of mannuronic acid (M2000), which is a novel NSAID, on COVID-19-related cytokine storms. This study was conducted in vitro on blood samples of 30 COVID-19 patients who presented with ARDS to a referral center. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples and incubated with phorbol myristate acetate for 24 hours. M2000 was administered with the dosages of 25 µg/well and 50 µg/well after 4 hours of incubation at 37°C. The quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to assess mRNA gene expression. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate the supernatant PBMC levels of interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. Both mRNA expression and the supernatant PBMC levels of IL-17, TNF-α, IL‑6, and IFN‑γ were decreased in PBMCs of COVID-19 patients treated with M2000 compared with the control  group. For the first time, it was observed that M2000 could be effective in alleviating the inflammatory cascade of COVID-19 patients based on an in vitro model. After further studies in vitro and in animal models, M2000 could be considered a novel NSAID drug in COVID-19 patients. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/3627 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/3627/1895