HEALTH is a STATE of BALANCE
The CONUNDRUM that is COVID, Nrf-2/NF-kB, Endothelial Dysfunction & the Cytokine Storm
Health is a State of Balance
Our body’s are replete with checks and balances that are wired into our system. These control systems function to re-center us whilst at the same time defending us against the environment, chemicals, pollutants, microbial hazards and the ravages of aging. Disease and dysfunction may occur when these defenses are inadequate, but the morbidity may also be the result of when the response is too aggressive. Dysfunction may result when the response to the attack (real or perceived), is out of proportion and the damage is the driven by the body’s over-reaction. Autoimmune disease is an excellent case in point here.
Many of the hallmarks of COVID-19, the outcome of the SARS-CoV-2 infection have been described as being comparable to an autoimmune disorder. While the world has mentally moved on from the dangers, the SARS-CoV2 virus continues to be elusive and problematic. Hence it is still an opportunity to determine why the infection is so devastating and from those enquiries, learn to how to better manage other infections and autoimmune disease.
Cytokine Storm & the Endothelium
This term was used to describe the pathology of the Spanish Flu of 1918, albeit when the technology was available to make these evaluations. This was achieved when the Spanish Flu virus was harvested from frozen corpses found in the Canadian tundra, and then studied in the laboratory. Morbidity and mortality was clearly the result of the CYTOKINE STORM that was the body’s reaction to the infection. Not the virus itself. The same was true for SARS-CoV2.
It is important to recognize that not all cytokines are the problem children, the culprits are the Th1 cytokines, with examples being IL-1, TNF, IL-6. There are cytokines that seek balance and counteract the Th1 variety eg IL-4 and IL-10. Hence when we refer to a cytokine storm we are actually being more specific, focusing on the damaging, pro-inflammatory Th1 cytokines.
A recent paper drew attention to IL-6 as an important mediator of morbidity with the COVID-19 condition (Nrf2, Cytokine IL6 and Endothelium in COVID). In this study, serum from subjects with COVID19, when applied to cultured endothelium caused:
Endothelial cell death (by apoptosis)
Diminished nitric oxide production
Suppressed Nrf2 activation and down regulation of genes that are under Nrf2 control.
All of these adverse consequences to exposure to the serum of COVID-19 subjects could be blocked by tocilizumab, an IL-6 receptor blocker, consistent with elevated IL-6 levels and defining a critical role of IL-6 in this pathology.
The flip side to Nrf2 as a regulator of gene expression is NF-kB. In simple terms these two transcription factors stimulate opposing systems that counteract each other. States of activated NF-kB, e.g., inflammation and oxidative stress are ones where Nrf2 are suppressed. Strategies to activate Nrf2 reduce the activity of NF-kB. They are truly opposing systems.
Oxidative Stress and Gene Expression
Oxidative stress, the cascade of reactive oxygen (ROS) and reactive nitrogen (RNS) species involved in host defense and inflammation, activates NF-kB. Importantly, activation of Nrf2 promotes the formation of antioxidant defenses that limit oxidative stress and turn off NF-kB.
Returning to the specific problem of COVID-19, serum from COVID-19 individuals have increased oxidant species, as indicated by higher DHE oxidation, increased protein carbonylation and augmented mitochondrial reactive oxygen species (ROS) generation and dysfunction. These oxidants activate NF-kB, which then codes fro excess cytokines including IL-6, which in turn suppresses the activity of Nrf2.
In essence, there is a true lack of balance. The authors of this recent study concluded that endothelial dysfunction related to SARS-CoV-2 infection is linked to an IL-6-dependent decrease in the endothelial antioxidant defense. Pharmacological activation of Nrf2 may decrease endothelial cell damage in individuals with severe COVID-19.
As a researcher there is a certain personal satisfaction in the identification of endothelial dysfunction as a critical driver for disease states. It was my discovery back in the ‘80’s that showed that the endothelium was a major player in cardiovascular disease (Endothelium & Cardiovascular Disease), followed by the subsequent Nobel winning discovery that the endothelium made nitric oxide from L-arginine. When one discovers a fundamental regulator of health and wellness, and its converse - disease, that stands the test of time, it is a satisfying legacy.
Natural Product that can restore Nrf2 and NF-kB Balance
Research has identified risk factors that are linked to endothelial dysfunction with COVID-19 including low levels of Vitamin D and K2. I have previously eluded to the critical importance of supplementation with both of these vitamins for immunity, and specifically COVID-19 (Managing COVID-19 with Supplemental Vitamins D3 and K2 ). It is unwise to underestimate the importance of Vitamins D3 and K2 (as menaquinone 7, MK7) in managing the adverse outcomes of COVID-19. Certainly there is an endothelial component to these benefits.
When seeking a balance in the activity of the gene expression regulators Nrf2 and NF-kB there are other natural products that have excellent track records. My personal favorites, based on research and decades of personal ingestion are Cat’s claw and astaxanthin. Cat’s claw, in my opinion, is the strongest natural product for down-regulating NF-kB although astaxanthin is effective. Astaxanthin is powerful regulator of Nrf2, and both are superb antioxidants. Astaxanthin is the most potent pure free radical in nature.
Both need to be used as supplements. Diet is not enough with the main dietary source of astaxanthin being salmon, but it takes 6 fillets a day of salmon to equal a 6mg dose of astaxanthin. Cat’s claw is a vine the Amazon Rainforest, and while it is highly revered in the jungle, it is not a supermarket shelf ingredient (unless as a supplement).
Conclusion
When there are severe insults, our systems may be pushed out of balance, establi
shing a sustained state of damage and dysfunction that ultimately may be fatal.. Health can be re-established when one aims to restore balance to the systems that have been knocked out of kilter. Appreciating the forces that need attention and the tools to re-establish balance are the critical first steps to long term health.
Nature has answers. However, they may be hiding in unusual places.