September 2020

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

Figure. Systemic-level Effects of Bradykinin Storm
The gene expression patterns from COVID bronchoalveolar lavage samples reveal a Renin Angiotensin System 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 lungs are responsible for generating system-wide angiotensin-derived peptides. The Bradykinin Storm is likely to affect major organs that are regulated by angiotensin derivatives. These include altered electrolyte balance from affected kidney and heart tissue, arrhythmia in dysregulated cardiac tissue, neurological disruptions in the brain, myalgia in muscles, and severe alterations in oxygen uptake in the lung itself. Red colors indicate upregulation and blue downregulation.

In late 2019, a new virus named SARS-CoV-2, which causes a disease in humans called COVID-19, emerged in China and quickly spread around the world. Many individuals infected with the virus develop only mild symptoms including a cough, high temperature, and loss of sense of smell; while others may develop no symptoms at all. However, some individuals develop much more severe, life-threatening symptoms affecting the lungs and other parts of the body including the heart and brain.

SARS-CoV-2 uses a human enzyme called ACE2 like a ‘Trojan Horse’ to sneak into the cells of its host. ACE2 lowers blood pressure in the human body and works against another enzyme known as ACE (which has the opposite effect). Therefore, the body has to balance the levels of ACE and ACE2 to maintain a normal blood pressure. It remains unclear whether SARS-CoV-2 affects how ACE2 and ACE work.

When COVID-19 first emerged, a team of researchers in China studied fluid and cells collected from the lungs of patients to help them identify the SARS-CoV-2 virus. Here, Garvin et al. analyzed the data collected in the previous work to investigate whether changes in how the body regulates blood pressure may contribute to the life-threatening symptoms of COVID-19.

The analyses found that SARS-CoV-2 caused the levels of ACE in the lung cells to decrease, while the levels of ACE2 increased. This in turn increased the levels of a molecule known as bradykinin in the cells (referred to as a ‘Bradykinin Storm’). Previous studies have shown that bradykinin induces pain and causes blood vessels to expand and become leaky, which will lead to swelling and inflammation of the surrounding tissue. In addition, the analyses found that production of a substance called hyaluronic acid was increased and the enzymes that could degrade it greatly decreased. Hyaluronic acid can absorb more than 1,000 times its own weight in water to form a hydrogel. The Bradykinin-Storm-induced leakage of fluid into the lungs combined with the excess hyaluronic acid would likely result in a Jello-like substance that is preventing oxygen uptake and carbon dioxide release in the lungs of severely affected COVID-19 patients. Therefore, the findings of Garvin et al. suggest that the Bradykinin Storm may be responsible for the more severe symptoms of COVID-19.

Further experiments identified several existing medicinal drugs that have the potential to be re-purposed to treat the Bradykinin Storm. A possible next step would be to carry out clinical trials to assess how effective these drugs are in treating patients with COVID-19. In addition, understanding how SARS-Cov-2 affects the body will help researchers and clinicians identify individuals who are most at risk of developing life-threatening symptoms.

Source: Gavin MR, Alvarez C, Miller JI, et al. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. eLife 2020;9:e59177 DOI: 10.7554/eLife.59177. Use is per the Creative Commons License CCO.

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