COVID "The Bradykinin Hypothesis"

Elemental.medium.com “A Supercomputer Analyzed Covid-19 and an Interesting Theory Has Emerged” “A closer look at the Bradykinin hypothesis”

Figure from elifesciences.org

Summary of Article

Work of Dr. Daniel Jacobson et al. at Oak Ridge National Laboratory Tennessee.

Running a supercomputer for about one week this team analyzed more than 40,000 genes from 17,000 genetic specimens for “2.5 billion genetic combinations” of Covid-19 genes and had a “eureka moment…about how Covid-19 impacts the body: the bradykinin hypothesis.” Results were published in elifesciences.org

Known and new facts to explain the model

Covid-19 attaches to ACE2 receptors (ACE2R) that are highly abundant in the nose and then binds similarly in other tissues expressing the ACE2R like intestines, kidneys and heart.

Somehow then COVID up regulates ACE2R on other tissues, like the lung, making them more susceptible.

ACE2R, angiotensin converting enzyme receptor2, is part of the renin-angiotensin system (RAS) that has a critical role partly via bradykinin, angiotensin and aldosterone in controlling vasoconstriction and water retention-both important elements in regulating blood pressure. “Aspects of the RAS system are sex-linked” possibly explaining the greater morbidity and mortality in men.

The mechanism is as of yet unexplained but with COVID, ACE does not degrade bradykinin as effectively thereby creating “bradykinin storm” believed by these researchers to mediate many “of Covid-19’s deadly effects.”

Effects of too much bradykinin include;

Increased vascular permeability…leads to fluid accumulation in the lungs…immune cells leak out and then initiate more cytokine-mediated inflammation

By another pathway bradykinin stimulates increased production of hyaluronic acid which effectively absorbs water creating a hydrogel that fills the lungs of some patients. “it’s like trying to breathe through Jell-O” and is a reason “why ventilators have proven less effective in treating advanced Covid-19” and patients “can suffocate even while receiving full breathing support.”

Bradykinin storms can affect cardiac rhythm and lower blood pressure-“often seen in Covid-19 patients.” Bradykinin lowers blood pressure by inhibiting ACE thereby reducing vasoconstriction mediated by Renin. ACE inhibitors “cause dry cough and fatigue” hallmarks of Covid-19 infection.

Given bradykinin vascular affects bradykinin storm may be responsible for neurological findings including stroke, loss of sense of taste/smell and Covid toes.

How can we exploit this understanding for “bradykinin storm” in Covid-19 disease?

Many FDA-Approved RAS drug and other drugs could help but any such treatments will need formal clinical trials to achieve on-label FDA-Approval for the COVID indication. See table below.

Table from elifesciences.org