Persistently Increased Systemic ACE2 Activity Is Associated With an Increased Inflammatory Response in Smokers With COVID-19

  1. Gagandeep Kaur
  2. Shaiesh Yogeswaran
  3. Thivanka Muthumalage
  4. Irfan Rahman

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Abstract

Background: Tobacco smoking is known to be involved in the pathogenesis of several cardiopulmonary diseases. Additionally, smokers are highly susceptible to infectious agents due to weakened immunity. However, the progression of lung injury based on SARS-CoV-2-mediated COVID-19 pathogenesis amongst smokers and those with pre-existing pulmonary diseases is not known. We determined the systemic levels and activity of COVID-19 associated proteins, cytokine/chemokines, and lipid mediators (lipidomics) amongst COVID-19 patients with and without a history of smoking to understand the underlying susceptible factor in the pathogenesis of COVID-19.

Methods: We obtained serum from healthy (CoV−), COVID-19 positive (CoV+), and COVID-19 recovered (CoV Rec) subjects with and without a history of smoking. We conducted a Luminex multiplex assay (cytokine levels), LC/MS (eicosanoids or oxylipin panel), and ACE2 enzymatic activity assays on the serum samples to determine the systemic changes in COVID-19 patients.

Results: On comparing the levels of serum ACE2 amongst COVID-19 (positive and recovered) patients and healthy controls, we found a pronounced increase in serum ACE2 levels in patients with COVID-19 infection. Furthermore, ACE2 enzyme activity was significantly increased amongst COVID-19 patients with a smoking history. Also, we analyzed the levels of Angiotensin 1–7 (Ang1–7) peptide, the product of enzymatic action of ACE2, in the serum samples. We found significantly high levels of Ang1–7 in the serum of both CoV+ and CoV Rec patients. Our data further demonstrated a smoking-induced increase in serum furin and inflammatory cytokine [IFN γ ( p = 0.0836), Eotaxin ( p < 0.05), MCP-1 ( p < 0.05), and IL-9 ( p = 0.0991)] levels in COVID-19 patients as compared to non-smoking controls. Overall, our results show that smoking adversely affects the levels of systemic inflammatory markers and COVID-19 associated proteins, thus suggesting that COVID-19 infection may have severe outcomes amongst smokers.

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  1. Version published to 10.3389/fphys.2021.653045
  2. ScreenIT

    SciScore for 10.1101/2021.01.14.21249836: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: Ethics/Approval: All the procedures performed in this study comply with the protocols approved by the Institutional Review Board /Research Subject Review Board (RSRB) committee at the University of Rochester Medical Center, Rochester, NY with an approval number CR00002635.
    IACUC: The University of Rochester Institutional Biosafety Committee approved the study (study approval number: Rahman/102054/09-167/07-186; identification code: 07-186) Human Blood serum collection: Sera from COVID-19 positive and COVID-19 recovered patients were obtained from BioIVT (Westbury, NY, USA).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Assessment of pro-inflammatory mediators in blood sera using Luminex multiplex assay: The levels of pro-inflammatory cytokines/chemokines like MCP-1, IL-8, IFN-γ, TNF-α and IL-7 in the sera were measured by Luminex multiplex assay using Bio-Plex Pro™
    Bio-Plex
    suggested: None
    Pro™
    suggested: (PRO, RRID:SCR_002902)
    Statistical Analyses: All statistical calculations were performed using GraphPad Prism 8.0.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Though we were able to show variations in systemic inflammatory and lipid mediators on SARS-CoV2 infection, our study had some limitations. The sample cohort used for this study was relatively smaller and comprised of a relatively homogenous demographics. It is important to conduct these experiments on a larger sample population with a heterogeneous demographics to deduce better conclusions. Also, we intend to use patient serum from healthy or COVID-19 negative individuals in the future to compare the variations amongst COVID-19 positive, recovered and healthy subjects. The persistently elevated ACE2 activity in the COVID-19 recovered patients provides evidence for a much thorough investigation into the long-term health effects of SARS-CoV2 infection in smokers. Such an exploration is crucial to understand the mechanistic role of intact and circulating ACE2 in COVID-19 and deduce if recombinant ACE2 could develop as a therapy. In conclusion, we show that the systemic ACE2 activity, Furin levels and cytokine release is upregulated amongst COVID-19 patients with a smoking history, thereby rendering them more susceptible to severe symptoms and disease outcomes. We also show that smoking adversely affects the systemic levels of inflammatory markers and COVID-19 related proteins, thus suggesting that COVID-19 infection may have severe outcomes amongst smokers which is reflected systemically. We also provide evidence for inflammatory systemic spillover due to COVID-19 which could b...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2021.01.14.21249836 on medRxiv