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Figure 5. The relationships between TGFβ, GSH, ROS, fibrosis, alveolar inflammation, and NETosis in processes
occurring at sites of local infection/inflammation. As with all such maps, the reality of the underlying biology is
more deeply interconnected.

Figure 6. The impact of MDSC / TGFβ / ROS interactions on T Cells and NK Cells.

Glutathione-TGFβ Relationship. The reciprocally tissue, thickening of mucous secretions, and thrombus
inhibitory roles of TGFβ and GSH have been described. formation has already been discussed. Figure 5 describes
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GSH plays key roles in the context of respiratory the relationships between various factors in this process.
anti-inflammatory support and mitigating the risk of MDSCs. In chronic inflammatory states, in the tumor
fibrotic damage to lungs and other organs: microenvironment, and in infection, immature myeloid
cells can be diverted into becoming myeloid derived
• Taken up directly by macrophages through suppressor cells (MDSC’s), instead of maturing to their
micropinocytosis (anti-inflammatory) 101 normal fates as neutrophils, macrophages, and DCs. These
• Necessary for Th1 response 98-100 MDSCs pour out excessive amounts of TGFβ, driving
• Key inhibitor of TGFβ: 126 depletion of GSH and generation of additional ROS. This
■ TGFβ has been studied in SARS-CoV-1, in can become another factor in the further upregulation of
relation to lung fibrosis. inflammation and fibrosis. Added ROS will also drive
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■ TGFβ inhibits GSH formation enzymatically, so further expression of NETosis.
these are in reciprocal inhibition. 127 Both GSH and NAC have been shown to stimulate
■ TGFβ drives generation of ROS that damage the effector T cell proliferation. MDSCs take up cysteine as
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lung both directly and by inducing NLRP3 a means of depriving effector T cells of the capacity to
inflammasome formation, referenced above. activate. Given the preliminary evidence that extent of
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■ TGFβ promotes fibrosis, referenced above. lymphopenia is related to lethality of COVID-19, 2
adequacy of cysteine in tissues may be an important
The role of ROS in upregulating the NETosis that protective factor.
drives sepsis, destruction of epithelial and endothelial

16 Integrative Medicine • Vol. 19, No. S1 • Epub Ahead of Print Yanuck—Immuno-physiological Approach to COVID-19