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Integrated angiotensin-bradykinin inflammatory feedback model

Candidate: concept label1 source documents4 linked claims
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Aliases

RAS-bradykinin feedback model

Extracted Explainers

What the tool is doing

This model proposes that angiotensin and bradykinin receptor signaling can amplify inflammation by increasing ADAM17, which then reduces ACE2 and increases pro-inflammatory mediators.

Source 1DOI

What problem it solves

It provides a mechanistic explanation for how ACE2 loss could worsen inflammation despite ACE2 also serving as a viral receptor.

Source 1DOI

Alternatives

The abstract contrasts this view with simpler theories that lower ACE2 expression alone protects children from severe COVID-19.

Source 1DOI

Evidence Snippets

the angiotensin-bradykinin system is characterized by a powerful positive feedback loop that enhances inflammation through the Angiotensin and Bradykinin receptors that upregulate ADAM17, which in turn downregulates ACE2 and upregulates TNF- α and the pro-inflammatory receptor of the cytokine interleukin 6 (IL6).
Evidence 1Source 1DOIprovenance

Supporting Sources

Linked Claims

Claim 1comparative interpretationsupports2022Source 1DOI

Lower COVID-19 severity in children despite lower ACE2 expression may be consistent with higher expression of ATR2 and the anti-inflammatory arm of the renin-angiotensin system at young age.

Claim 2disease mechanism hypothesissupports2022Source 1DOI

Failure of ACE2 to reverse the pro-inflammatory angiotensin-bradykinin state, possibly induced by SARS-CoV-2-mediated ACE2 degradation, may underlie severe COVID-19 and post-infection manifestations including MIS-C.

Claim 3mechanistic relationshipsupports2022Source 1DOI

Age-associated increase in TACE/ADAM17 is proposed to drive ACE2 shedding from the cell membrane to serum, causing ACE2 cell protein to decline earlier and more steeply than ACE2 mRNA.

Claim 4mechanistic relationshipsupports2022Source 1DOI

The angiotensin-bradykinin system contains a positive feedback loop in which angiotensin and bradykinin receptors upregulate ADAM17, which downregulates ACE2 and upregulates TNF-alpha and the pro-inflammatory IL6 receptor.