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

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 [IFNγ(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.

SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients

“…However, longitudinal evaluation of soluble ACE2 in patient-matched samples showed a significant decrease, indicating that viral infection is significantly affecting ACE2 function. Indeed, soluble ACE2 measured in plasma showed a decrease over time, in line with previous reports [ 14 , 35 , 36 ]. Overall, we demonstrate that SARS-CoV-2 infection induces shedding of ACE2 from cell membranes, leading to increased levels of the soluble active form of ACE2 in situ; however, it is also found later on in plasma, when the infection has spread systemically.…”

The systemic renin-angiotensin system in COVID-19

“…Of interest, as in our previous (11) and present work, researchers in Canada reported an upward trajectory of soluble ACE2 at 7-day sampling (from baseline) that was independently associated with increased mortality risk among their 242 patients with COVID-19 (29). A relationship among ACE2, disease severity, and mortality emerged in yet another analysis, this one from Hungary, of 176 patients with COVID-19 (30), and ve additional studies have demonstrated elevated to highly elevated ACE2 levels in COVID-19 (31)(32)(33)(34)(35). Three other studies found no ACE2 elevation in COVID-19 (36-38), possibly because the included patients were less severely affected and/or ACE2 was measured only at the beginning of the disease course.…”

SARS-CoV2 Infection Alters Tryptophan Catabolism and Phospholipid Metabolism

“…Evidence suggests that perturbations in arachidonic acid pathways could lead to an imbalance between the pro-inflammatory metabolites of arachidonic acid including mid-chain hydroxyeicosatetraenoic acid (HETEs) and terminal HETE (20-HETE) [31]. Previous work by our group demonstrated increased levels of 15-HETE and 20-HETE in the serum of COVID-19-positive patients [32]. The elevated levels of arachidonic acid in the patient sera from COVID-19-positive individual further points towards the crucial nature of this metabolic pathway in the pathophysiology of COVID-19.…”

“…We obtained patient sera from COVID-19-positive (CoV) and COVID-19-recovered (Rec) subjects from BioIVT (Westbury, NY, USA) [32]. The de-identified samples did not require any local IRB requirements or consent forms under 45 CFR 46.102.…”