Nalini Chilkov, LAc, OMD, is the founder of the American Institute of Integrative Oncology Research and Education and. She’s the author of the best-seller 32 Ways to Outsmart Cancer, and is recognized as an authority and pioneer in the fields of integrative cancer care, cancer prevention, and immune enhancement. She has also lectured at UCLA and UC Irvine Schools of Medicine, and is a frequent expert resource to the media. Dr. Chilkov’s OutSmart Cancer System utilizes her more than 35 years of experience with thousands of patients, as well as her passion for training front-line clinicians worldwide to become skilled and confident in serving the health needs of patients whose lives have been touched by cancer. Her private practice is located in Santa Monica, California.
Inflammasomes—the multi-protein complexes found in the cytosol or the intracellular space—are key mediators of lung immunity.
In normal inflammasome activation, the result is a clearance of noxious stimuli such as pathogens and environmental or metabolic toxins. However, the excessive activation of inflammasomes can result in increased and prolonged cytokine release, chronic inflammation, and pulmonary and endothelial damage.
Inflammasomes are formed in response to specific stimuli, including pathogenic microbes, environmental insults, and molecules derived from the host cell. As part of the innate immune system and the first line of defense, inflammasome activation leads to the release of pro-inflammatory cytokine IL-1B, along with IL-18 and pyroptosis in the lungs.
Pyroptosis is a form of programmed and rapid cell death initiated by the formation of the inflammasome. Pyroptosis is a highly inflammatory state that’s triggered in conjunction with intracellular pathogens, and is part of the microbial response.
INFLAMMASOME ACTIVATION AND DYSREGULATION
The NLRP3 inflammasome is the most prevalent and well-studied pulmonary inflammasome.
After exposure to some pathogens, NLRP3 Inflammasome activation is initiated in part by an efflux of potassium ions and an influx of calcium ions. At the same time, there’s an increase in pro-oxidative reactive oxygen species (ROS) and destructive lysosomal proteases. There’s also activation of both macrophages and NF-kB, the nuclear factor that’s upstream of a cascade of intracellular pro-inflammatory pathways..
All of this creates a pro-inflammatory environment, prone to thrombus and fibrin formation, with high levels of oxidative stress and proteolytic enzymes. In other words, this is war. When this response is mobilized, an infection can be resolved and the inflammatory cascade should then turn off—with equilibrium restored.
But with inflammasome dysregulation comes tissue damage, excessive cell death, and chronic inflammatory states leading to chronic damage, fibrosis, and dysfunction. Some chronic diseases are also associated with dysregulation of the inflammasomes and upregulation of NF-kB and inflammatory cytokines.
The respiratory distress experienced by patients suffering from this type of inflammation is not always responsive to exogenous oxygen therapy because not only are the alveoli damaged and dysfunctional, but there is also endotheliitis in the capillary beds surrounding the alveoli.
Endotheliitis leads to hypercoagulation, thrombus formation, and the inability of the alveoli in the lungs to deliver oxygen to the circulatory system. Hypoxia is also a signal for activation of the NLRP3 inflammasome, which further compounds dysregulation. Together, this creates a perfect storm.
NATURAL COMPOUNDS THAT MODULATE INFLAMMASOME ACTIVATION
Some natural compounds can act as regulators and modulators of pulmonary NLRP3 inflammasome activation and its sequela. Phytochemicals—including lectins, flavones, flavonoids, stilbenes, catechins, and other phenolic compounds derived from both food and therapeutic plants—have been found to modulate the NLRP3 Inflammasome activation and down-regulate inflammatory cytokines IL-1B, TNFa, and NF-kB, as well as ROS. In addition, curcumin, resveratrol, and sulforaphane penetrate the blood-brain barrier and impact inflammasome activation and cytokine production in the brain.
Curcuminoids. These lipid-soluble polyphenol isolates are derived from the rhizomes of turmeric (Curcuma longa. Small amounts of curcuminoids are also found in ginger (Zingiber) rhizomes.
Curcumin is widely studied, and has been found to be a negative regulator of the NLRP3 inflammasome expression via multiple pathways. It’s also been shown to be a mediator of inflammatory signals, including NF-kB, TNFa, and downstream cytokines such IL1B. And curcumin’s bright yellow color announces its value as a scavenger of ROS and modulator of oxidative stress—another trigger of inflammasome activation.
The most absorbable curcumin sources are lipid based. Therefore, curcumin-rich foods and supplements are enhanced with the addition of black pepper and healthy fats and oils.
Resveratrol. This stilbene polyphenol is found in abundance in the skin of red and purple grapes and in Japanese knotweed (Polygonum cuspidatum). The trans-resveratrol isomer is most biologically active.
Resveratrol has been widely studied and, like most polyphenols, has been shown to scavenge ROS and reduce oxidative stress Resveratrol upregulates the expression of sirtuin I, which is a deacetylase enzyme that inactivates multiple inflammatory genes. Resveratrol also activates AMPK, which negatively regulates NLRP3 inflammasome activation, NF-kB transcription, and IL1B secretion.
Epigallocatechin-3-gallate (EGCG). This compound is the major bioactive polyphenol in green tea (Camellia sinensis). EGCG has been shown to inhibit NLRP3 inflammasome activation, along with the expression of NF-kB, matrix metalloproteinases, IL1B, IL-6. and TNFa. EGCG’s antioxidant properties and ability to scavenge ROS are also well documented.
A single cup (8 ounces or 250 ml) of brewed green tea contains approximately 50 to 100 mg of EGCG. Dietary supplements generally contain larger amounts of EGCG catechins.
Sulforaphane glucosinolate (SFN). This natural compound is found in cruciferous vegetables like broccoli, cauliflower, Brussels sprouts, bok choy, cabbage, kale, and mustard and radish greens.
Sulforaphane is an isothiocyanate that’s produced from the precursor glucoraphanin in the presence of the myrosinase enzyme. Sulforaphane inhibits activation of multiple inflammasomes, including NLRP3, and leads to inhibition of IL1B secretion and NF-kB expression. It also quenches oxidative stress and ROS.
It’s best to lightly cook or massage cruciferous vegetables to liberate their phytochemicals. The highest-quality SFN dietary supplement products are derived from broccoli sprouts and broccoli seeds.
Quercetin. This flavonoid is found in a wide variety of fruits, vegetables, and herbs. Red apple and purple onion skins are particularly rich dietary sources.
Quercetin has been shown to block NLRP3 inflammasome activation, inhibit damage from ROS, modulate multiple inflammatory pathways, and downregulate NF-kB expression and IL1B secretion.
Quercetin is not highly absorbable on its own, and is best taken with healthy fats and oils or encapsulated as a lipid phytosome.
Ginsenosides. These majorly active saponin components are found in Panax ginseng. Ginsenosides attenuate NLRP3 Inflammasome activation, and reduce IL1B, IL-18, and TNFa levels and the expression of NF-kB.
Because ginseng standardization varies, look for the highest-quality products to ensure ginsenosides’ therapeutic and nutritive effects.
Modified citrus pectin (MCP). This low-molecular weight dietary fiber derived from the inner peel of citrus fruit is best known as a galectin-3 antagonist. Galectin-3 is widely found in immune and epithelial cells, and can negatively impact innate immune response by promoting NLRP3 inflammasome activation and pyroptosis.
While unprocessed food pectin is a large lectin molecule that can’t be digested or absorbed through the intestinal epithelium, MCP is an enzyme-processed product that yields a small esterified molecule that can be absorbed through the small intestine and enter the bloodstream.
By binding to and inactivating galectin-3, MCP downregulates the activation of the NLRP3 inflammasome, pyroptosis, and cell death, as well as secretion of inflammatory cytokines IL1B and IL6 and matrix metalloproteinases. MCP also inhibits hypercoagulation and thrombus formation, a sequela of dysregulated inflammasome function.
The highest-quality MCP products have the smallest particle size to ensure intestinal absorption.
Potassium. Due to the potassium efflux that occurs at the initiation of inflammasome activation, Joe Pizzorno, ND, recommends oral potassium repletion to support normal inflammasome regulation.
Most patients who eat a plant-based diet should consume enough potassium. However, elderly, very ill, or hospitalized patients who aren’t eating normally could be potassium depleted. Therefore, not only potassium repletion, but also broader electrolyte monitoring and repletion. is advised to promote normal functioning and stable physiology in compromised patients.
FOOD AS MEDICINE
Dysregulated inflammasome activation results in increased secretion of inflammatory cytokines, oxidative stress, tissue damage, mitochondrial damage, cell death, and loss of normal epithelial, alveolar, and endothelial function. Modulation and regulation of the inflammasomes influences not only acute innate immune responses, but also multiple chronic diseases and syndromes that are linked to inflammation.
The good news is that many of the natural compounds that influence inflammasome activity are phytochemicals found in food. Therefore, encouraging patients to eat a plant-rich, colorful rainbow diet—including a variety of herbs and spices rich in phytochemicals—has a powerful impact on inflammation control and long term-health.