Hydrogel in alveoli - covid pneumonia mechanism and bradykinin hypothesis

Why high dose Vit D and corticosteroids seem to help

Early on in this coronavirus ‘pandemic’ the focus and fear targeted rapid onset pneumonia, and hence the panicked push for ventilators. China docs reported using CT scans to quickly diagnose patients, bypassing the PCR tests which were in limited supply at the time. One of the hypotheses that took hold and gained some traction, was the bradykinin hypothesis for mechanism of action. Given that most vaccines generate the spike protein which binds to ACE2, vaccine adverse reactions may, too, involve the RAS [renin-angiotensin-system] and hence, bradykinin [BK}.

https://pubs.asahq.org/monitor/article/84/11/1/110833/A-RAS-and-Bradykinin-Mediated-Mechanism-for-COVID

The angiotension converting enzyme [ACE] also works to activate bradykinin, not just angiotensinogen. And where does the BK come from? Well, SARS-CoV-2 infects the mast cells, especially in the lungs. And they release lots of factors, BK being one of them. [fyi-Mast cell stabilizers include Vitamin D3, ketotifen, cromoglycate, quercetin, luteolin, Vitamin C.]

From the study: “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.” Image source: Daniel Jacobson et al.via eLife Sciences (https://elifesciences.org/articles/59177)

In the BK induced cytokine storm, the lung upregulates hyaluronan [HA] synthases, downregulates the hyaluronidases. When combined with the vascular hyperpermeability, the alveoli fills with HA hydrogel - a ‘jello-like’ substance that does not exchange gases.

From the study: “Systemic-level effects of critically imbalanced RAS and bradykinin pathways.” Image source: Daniel Jacobson et al.via eLife Sciences (https://elifesciences.org/articles/59177)

So, we just have to get rid of all that mucus, right? Not so easy to do. The Hyaluronic acid [HA] breakdown half life is very long, in the range of months (designed to last, because it fills/lubes the joint spaces). What are the known regulators?

HA increases via synthesis when triiodothyronine [T3] tissue level is low, and synthesis is reduced when T3 is high. But there is no effect on degradation. Once HA is present, have to wait for it to slowly breakdown. Corticosteroids effect HA similarly to thyroid hormones, by regulating the rate of synthesis. Gonadal steroids do too, but in the opposite direction. That is, testosterone and estradiol directly enhance the synthesis of that ‘joint juice’ HA.

Butyrate [butyric acid] also regulates HA - stimulating accumulation at low dose but inhibiting it at high doses. And it is often used as a carrier vehicle for Vitamin D infusions — likely also for other steroids, including corticosteroids. So be aware of this when you see high dose infusions of lipophilic drugs, such as steroids. Effects may be due to nonspecific carrier effects.

REFERENCES

Mast cell stabilisers and covid-19 https://www.bmj.com/content/370/bmj.m2722/rr-3

COVID-19 Usurps Host Regulatory Networks.  https://www.frontiersin.org/articles/10.3389/fphar.2020.01278/full

A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm https://elifesciences.org/articles/59177

https://bgr.com/2020/09/01/coronavirus-drugs-that-work-bradykinin-storms-icatibant/

https://www.piquenewsmagazine.com/bc-news/new-research-aims-to-use-ct-scans-to-better-diagnose-covid-19-2510350

Dexamethasone regulation of glycosaminoglycan synthesis in cultured human skin fibroblasts. Similar effects of glucocorticoid and thyroid hormones https://www.jci.org/articles/view/111642

Regulation of Glycosaminoglycan Synthesis by Thyroid Hormone in Vitro. https://www.jci.org/articles/view/110694

n-Butyrate inhibition of hyaluronate synthesis in cultured human fibroblasts. https://www.jci.org/articles/view/112979

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