Bradykinin Storm linked to Generalized “Anti-Parasitic” Potentially Lethal Response in COVID-19

My earlier discussions of innate immunity alluded to cascades linked to vascular, clotting, lung and cardiac damage linked, in turn, to non-specific generalized inflammation. Past studies have shown a link between nitric oxide (NO) production (vasodilator, neurotransmitter, second messenger pathway activator, antimicrobial and antiviral agent) and Bradykinin (vasoactive agent, edema and shock generator). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC408867/ and https://www.jacionline.org/action/showPdf?pii=S0091-6749%2802%2956700-2. A new study using supercomputer analysis of gene expression in COVID-19 patients https://elifesciences.org/articles/59177 supports the NO/Bradykinin and Angiotensin ll links. Angiotensin II type 2 receptor (AT2) is expressed at low levels and is restricted to the adrenal gland, brain, ovary, uterus, kidney, and heart. It is upregulated in pathological states such as salt depletion, heart failure, experimental cardiac hypertrophy, myocardial infarction, and vascular injury. AT1 stimulation promotes cellular growth and hypertrophy, while the AT2 antagonizes them. AT1 stimulation facilitates angiogenesis, while the AT2 inhibits this process. AT1 activation induces vasoconstriction, while AT2 activation causes vasodilation. These cellular and organ-level effects appear to act in intact animal models. For instance in cardiomyopathic hamsters, AT2 expression is upregulated in cardiac fibroblasts of the failing heart and appears to antagonize Angiotensin 1 receptor (AT1) which mediates interstitial fibrosis and cardiac remodeling. In a rat model of ischemic cardiomyopathy, the beneficial effects of AT1 blockade on cardiac remodeling and hemodynamics are inhibited by AT2 blockade. Beneficial effects of AT2 stimulation may be meditated through the bradykinin/nitric oxide (NO) cascade. Endothelial cells contain bradykinin type 2 receptors (B₂), which, when activated, potently stimulate production of NO. Although the effects of angiotensin II and NO seem to vary with the concentration of NO and the cell type involved, these two factors appear to play opposing roles in the cardiovascular system: angiotensin II is a potent stimulus for vasoconstriction and vascular smooth muscle hypertrophy, whereas NO has a vasodilator effect and has been shown to be an antiproliferative agent. Thus, in spontaneously hypertensive rats, AT2 activation has been shown to increase vascular cyclic guanosine 3′,5′-monophosphate (cGMP) levels, an effect that could be inhibited by B₂ blockade or by inhibition of NO synthase. Salt depletion, which activates the renin-angiotensin system (RAS), increases cGMP levels in the renal interstitial fluid, an effect that can be prevented by blocking NO synthase or AT2. Additional compelling evidence linking AT2 to the bradykinin/NO cascade has been shown through the AT2–mediated vasodepressor effect associated with an endothelium-dependent increase in aortic production of cGMP and activation of the kinin-kallikrein system. Angiotensin II stimulates AT2 in vascular smooth muscle, which leads to activation of the kinin-kallikrein system and bradykinin release. Bradykinin then binds to its receptor on adjacent endothelial cells, causing the release of NO and stimulation of cGMP. “Biochemicals that increase cGMP in tissues do so through oxygen and calcium-dependent mechanisms, apparently through a calcium-dependent NOS. Among these biochemicals relevant to vascular tissues are cholinergic (such as carbamylcholine) and alpha-adrenergic stimuli, bradykinin, histamine (which also raises cAMP levels), and serotonin. The calcium dependence has been demonstrated by the increase of cGMP levels with the treatment of cells with A23187 (calcium ionophore) and by the inhibition of this rise by calcium blockers such as tetracaine and verapamil. In vitro, cytotoxic levels of NO have been produced by isolated murine lung vascular endothelial cells treated with gamma-interferon and TNF. This NO production was L-arginine dependent, and the NO production and tumor cell lysis (M5076 reticulum sarcoma cells) were inhibited by dexamethasone. These results indicate not only a physiologic role for NO production by endothelial cells, but also an antitumor and pathophysiologic one.”— Type-B Cytochromes: Sensors and Switches by J.L. Kiel,https://a.co/eeOLKWC, 1995. The NO and Bradykinin link is prone to runaway effects because Bradykinin can induce more NO production and NO can induce increased Bradykinin activation. Therefore, in short, runaway positive feedback of these two without balance (breaking) leads to catastrophic shock and multiple organ failure. Perhaps this gives direction to developing life saving pharmaceutical applications.