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Bradykinin and the Coronavirus

There’s a new paper that a lot of people are talking about recently that presents a rather large unifying hypothesis about the effects of the coronavirus (and suggests some new modes of treatment as well). This is the “bradykinin hypothesis”, and before digging into it, it might be worth a paragraph to talk about what bradykinin is.

It’s a 9-amino-acid peptide, and it’s got a ton of biological activity. Bradykinin lowers blood pressure by dilating blood vessels, but it causes contraction of the smooth muscle in the lungs and in the gut. It’s a diuretic in the kidney, and in the nervous system it’s involved in the sensation of pain. Bradykinin receptors (there are two types) can signal to attract neutrophils (giving it a role in allergy and inflammation), and its pathways have also shown up in the functioning of several types of cancer cells. So there’s a lot going on! People taking angiotensin-converting-enzyme (ACE) inhibitors are getting bradykinin effects as well, because ACE is one of the enzymes involved in processing the larger precursor peptide down to bradykinin itself (as it does for angiotensin and its precusor). In fact, the dry cough that’s a side effect of some ACE inhibitors may well be a bradykinin-mediated effect, via hypersensitivity of nerves in the upper airway. And the bradykinin B2 receptor forms an actual protein complex with angiotensin-converting enzyme itself, although all the functions behind this haven’t been worked out.

That ACE part of the story is where this new paper comes in. The multicenter team behind it re-examined the composition of lung fluid collected from coronavirus patients, and found that the disease lowered the amount of ACE and increased the amount of ACE2 (readers will recall that the latter is the surface protein that the coronavirus uses as a cellular entry point). ACE2, in fact, appears to increase by 200-fold (it’s normally not found in high levels in lung tissue). Angiotensin II itself goes up by more than 30-fold, and renin (another enzyme involved upstream in the formation of angiotensin) and the two angiotensin receptors all go up several hundredfold.

These imbalances cause bradykinin levels to increase – in fact, most of the proteins involved in bradykinin production and signaling are undetectable in such lung fluid under normal conditions, but go up sharply during coronavirus infection, while enzymes that are involved in bradykinin degradation go down. In the lung tissue, this new imbalance causes pain, dilated blood vessels, and increased vascular permeability. The bradykinin system also has complex links to blood coagulation, which could tie in with some of the observed coronavirus pathology in that area as well.

At the same time, another set of proteins seems to be similarly deranged: the ones involved with hyaluronic acid (also known as hyaluronan). That’s a large carbohydrate polymer that’s found throughout extracellular fluids – in the joints, for example – and its involved with all sorts of wound repair, cell migration, and tissue surface effects. As with bradykinin, the enzymes involved in its production are all ramped up rather steeply in the coronavirus patient samples, and the ones involved in its degradation are all down. HA can be rather thick and slippery, and the authors believe that having it produced in excess in the lungs during coronavirus infection is a major factor in making things worse. In fact, its overproduction has already been associated (pre-pandemic) with respiratory distress, low oxygen levels, and even with some of the radiological findings (“ground-glass” opacities) that are also associated with coronavirus infection. The HA system has been tied in some work to the renin-angiotensin system, although that’s also a complex story, since there are many states of hyaluronic acid polymer and various proteins and receptors that respond to their presence. As this new paper notes, though, HA has already been implicated as a player in coronavirus pathology.

So the authors are proposing a “bradykinin storm” model, where increased bradykinin levels tie into all sort of coronavirus pathologies. The model fits many of these well, and also suggests other clinically observed features such as low potassium (hypokalemia) and low Vitamin D. It’s a very appealing theory, but it’s also important to remember that a lot of very appealing theories in this business turn out not to be true. Or not completely true. Or not true in the ways that were originally thought. The way to find out is through clinical testing. To be honest, I’m worried that this proposal is almost too neat and form-fitting; rarely do you get something that falls together this well. It’s also quite possible that you could come up with a reasonable set of literature references and previous reports that cast many of these connections into doubt – the medical literature is large, and you can find support for a lot of things if you’re putting together a brief for the prosecution. But overall, I find this work pretty plausible.

To that point, a very good feature of this work is that it immediately suggests several interventions with FDA-approved drugs. Not all of these are actionable (for example, androgenic steroids decrease bradykinin production, but do a hell of a lot of other things besides!) But icatibant (brand name Firazyr) is an antagonist of bradykinin B2 receptors, and ecallantide (brand name Kalbitor) is an inhibitor of kallikrein, a key enzyme in bradykinin production. Both of those would seem to be directly targeting the proposed mechanisms. Hymecromone is a small molecule that’s known to inhibit the synthesis of hyaluronic acid. And thymosin beta-4 is a protein that could tie into the connection between bradykinin activity and coagulopathies; a version of this protein has been in human trials as Timbetasin. As mentioned above, vitamin D supplementation might also be beneficial – its receptor has connections with vascular permeability and with the renin/angiotensin system, and its deficiency has already been noted as a rsk factor in the current pandemic. I agree with the authors that controlled trials of all of these therapies would seem very worthwhile – hymecromone is a particular standout from what I can see, being generic and inexpensive, and if it can directly improve lung function in severe coronavirus patients, that would be a real accomplishment. Its weak point is that it has caused diarrhea as a side effect with even further potassium lowering, so you might want to give that with potassium supplementation (?) I am most definitely not a clinician, though, so I’ll leave my suggestions out of it.


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