A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm

  1. Michael R Garvin
  2. Christiane Alvarez
  3. J Izaak Miller
  4. Erica T Prates
  5. Angelica M Walker
  6. B Kirtley Amos
  7. Alan E Mast
  8. Amy Justice
  9. Bruce Aronow
  10. Daniel Jacobson  Is a corresponding author
  1. Oak Ridge National Laboratory, Biosciences Division, United States
  2. University of Tennessee Knoxville, The Bredesen Center for Interdisciplinary Research and Graduate Education, United States
  3. University of Kentucky, Department of Horticulture, United States
  4. Versiti Blood Research Institute, Medical College of Wisconsin, United States
  5. VA Connecticut Healthcare/General Internal Medicine, Yale University School of Medicine, United States
  6. University of Cincinnati, United States
  7. Biomedical Informatics, Cincinnati Children’s Hospital Research Foundation, United States
  8. University of Tennessee Knoxville, Department of Psychology, Austin Peay Building, United States
4 figures, 1 table and 3 additional files

Figures

Functionally annotated network of genes involved in the hypertension-hypotension axis whose expression across the GTEx population is correlated and anticorrelated with the AGTR1 and AGTR2 receptors.

When ACE is downregulated and ACE2 and the BK pathway is upregulated in the lungs of COVID-19 patients it leads to the hypotension, vascular permeability, and the Bradykinin Storm that explains much …

Critically disrupted RAS and Bradykinin pathways in COVID-19 BAL samples.

(A) Significantly differentially expressed genes: red ovals indicate genes upregulated in COVID-19, blue are downregulated, colors are scaled to the log2-fold-change values for COVID-19. The overall …

The upregulation of hyaluronan synthases and downregulation of hyaluronidases combined with the BK-induced hyperpermeability of the lung microvasculature leads to the formation of a HA-hydrogel that inhibits gas exchange in the alveoli of COVID-19 patients.
Systemic-level effects of critically imbalanced RAS and BK pathways.

The gene expression patterns from COVID BAL samples reveal a RAS that is skewed toward low levels of ACE that result in higher levels of Ang1-9 and BK. High levels of ACE normally present in the …

Tables

Table 1
Potential therapeutic interventions, their targets, and predicted effect.
DrugTargetPredicted Effect
Danazol, StanozololSERPING1Reduce Bradykinin production
IcatibantBKB2RReduce Bradykinin signaling
EcallantideKLKB1Reduce Bradykinin production
Berinert,Cinryze,HaegardaSERPING1Reduce Bradykinin production
Vitamin DRENReduce Renin production
HymecromoneHAS1,HAS2, HAS3Reduce hyaluronan
TimbetasinTMSB4XIncrease fibrinolysis

Additional files

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