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release IL-1β and IL-18 into the tissue environment, Target 5 – Anti-Oxidant Support
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and occurs in response to a wide range of factors, GSH and N-acetylcysteine (NAC) play particularly
including K+ and/or Cl- efflux from cells, low systemic important roles in anti-oxidant support in COVID-19.
pH, high glucose, ROS, cholesterol, uric acid, and other GSH and NAC are both components of normal human
factors. biology. GSH appear to play a key role in supporting both
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There are two signals that drive classical inflammasome the immune surveillance and anti-oxidant/anti-
assembly: inflammatory components of the strategy for addressing
care for patients with COVID-19. The biological role of
Signal-1 - cell membrane receptor stimulation by IL-1β. GSH in respiratory illnesses including ARDS has been
This induces an increase in cytosolic NFkB, which in reviewed. The role of GSH in promoting NK cells and
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turn induces gene expression of pro-IL-1β and inhibiting macrophage infection in TB has been
pro-IL-18. reviewed. 115
Signal-2 - (activation triggered by PAMPS & DAMPS) GSH plays a key role in the lung, with the level of
involves P2X7 receptor stimulation by extracellular GSH in the lung epithelial lining fluid (ELF) strongly
ATP from adjacent or nearby cells that are dying, influencing the extent of lung inflammation and
releasing their cytosolic ATP into the extracellular maintaining oxidant/anti-oxidant homeostasis. 101
space. It is noteworthy that Ion flux is an important GSH, in addition to its known anti-oxidant function
driver of NLRP3 activation, specifically K+ and and anti-inflammatory role, is essential for other functions
Cl- efflux out of the cell and elevated intracellular of the immune system, both innate and adaptive: these
Ca2+, so anything that inhibits K+ and Cl- efflux and include T-lymphocyte proliferation 116,117 phagocytic
lowers cytosolic Ca2+ will contribute to inhibition of activity of polymorphonuclear neutrophils (PMN) and
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NLRP3. Downstream of ion changes is ROS dendritic cell functions that are crucial to adaptive
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production from stimulated mitochondria that leads immune system activation, as DCs function as the
to NLRP3 formation, suggesting the utility of anti- professional antigen presenting cell (APC).
oxidants. N-Acetyl Cysteine. Oral NAC is readily absorbed
through the stomach and gut and is converted to cysteine
There is also a newer alternate/non-classical in the liver via first pass metabolism. The majority of
inflammasome activation of NLRP3 in monocytes cysteine is secondarily incorporated into GSH and
(not macrophages) that is K+ independent and requires released into systemic circulation. Availability of
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toll-like receptor 4 (TLR4) ligands, i.e., lipopolysaccharide cysteine is the rate limiting factor in GSH synthesis.
(LPS), a gram negative bacterial PAMP. This pathway’s The potentially crucial role of neutrophil extracellular
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activation suggests that measures taken to lower baseline traps (NETs) has been discussed above, including
LPS levels would have merit. Increased absorption of LPS promotion of thrombus formation, increased mucous
is found in intestinal dysbiosis, which is associated with viscosity, epithelial and endothelial cell destruction, and
chronic upregulation of systemic inflammation that is sepsis, and the role of IL-6 as a driver of NETosis. NAC
reversed by restoration of appropriate gut microbial downregulates NET formation through the
balance. 111 downregulation of ROS. NAC has been shown to exert
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Given that Signal-2 is stimulation of P2X7 receptors an anti-thrombotic effects, 121-123 and increase intraplatelet
by ATP spilled from the cytosol dying adjacent cells, it GSH and reduce platelet ROS. NAC is an accepted
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may be important to consider avoiding supplements treatment for patients with cystic fibrosis. In addition to
purported to contain ATP or promote ion imbalance per its directly mucolytic properties, the influence of NAC in
above. Those containing adenosine may also be reducing ROS and down-regulating NETosis might also
inappropriate, as adenosine induces T effector cell be expected to favorably influence these other observed
anergy. NET-mediated destructive effects in COVID-19 patients.
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NFkB. NFkB is the key pro-inflammatory protein Inhaled NAC is a well-recognized mucolytic agent
complex at the center of the NFkB / IL-1β and TNFα and has been a mainstay intervention in cystic fibrosis
activating loop that drives pro-inflammatory cytokine (CF) patients since the 1960’s. In addition to its mucolytic
production at the center of the immune response to properties, NAC is anti-inflammatory and antioxidant. In
pathogens and damage. NFkB is produced in response to one pediatric trial (N = 120 in NAC group), inhaled NAC
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Signal-1 (priming) of the NLRP3 inflammasome assembly was well tolerated long-term and attenuated rate of decline
cycle that produces IL-1β and IL-18 and drives pyroptosis in FEV1, outperforming other commonly used mucolytic
(a highly inflammatory form of programmed cell death). agents hypertonic saline and inhaled dornase-alfa.
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Inhibiting NFkB activation or stimulating IkB (inhibitor of In healthy adults with poor mucociliary escalator
KappaB) is therefore anti-inflammatory. In SARS-CoV-1, function, a 600 mg dose of oral NAC improved mucociliary
spike protein activation of IL-6 and TNFα were shown to escalator function by 35%, with washout yielding return to
occur through upregulation of NFkB. 113 baseline.
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Yanuck—Immuno-physiological Approach to COVID-19 Integrative Medicine • Vol. 19, No. S1 • Epub Ahead of Print 15