Wildfire Smoke: Exposure PM2.5 and Lung Damage
What’s the Inflammasome Got To Do With It?
A Lesson in Immunology from Dr. Sam Yanuck
This is the fourth and final installment of a blog about the potential long-lasting health effects of wildfire/building smoke on human health. See previous Blogs on Wildfire Smoke Exposure here
Studies on the adverse health effects of wildfire smoke have mainly focused on exposures to high levels of fine and ultrafine particulate matter; irritant gases (hydrogen chloride, sulfur dioxide, hydrogen fluoride, nitrogen oxides, etc.); asphyxiant gases (carbon monoxide and hydrogen cyanide); organic chemicals such as formaldehyde, formalin, polyaromatic hydrocarbons (PAHs), dioxins (some of which are considered carcinogens), ozone, toxicant metals (lead, arsenic) and combustion-produced free radicals. All of these are incorporated into what is commonly known as PM2.5, which is already known to be responsible for a majority of the global burden of disease. The 2015 Global Burden of Disease Study Report indicated that ambient outdoor air pollution, particularly PM2.5, was the fifth leading risk factor for global mortality in 2015, with cardiovascular deaths accounting for highest number of these deaths.
If we look at the worsening lung function of the older adults in Seeley, Montana (a study detailed in the October 2020 blog)- respiratory damage from wildfire smoke exposure- particularly PM2.5- appears to be long-lasting and progressive.
Healthcare providers throughout the West Coast and Rocky Mountains are well aware of these exposures, we’ve all seen and witnessed the apocalyptic photos from this wildfire season- now expanding into December 2020- and have breathed the air. However, other than treating already existing asthma and COPD, most of us are at a loss for how to address the damage we know has already happened to many from the inescapable exposure.
EHS Faculty have made recommendations from the medical literature on wildfire and building smoke exposure (See Wildfire Smoke Action Plan and Protocol)
However, is there any more evidence for supporting our patient’s respiratory (and cardiovascular) health?
There may be more strategies to explore, based on our understanding of particulate matter exposures and the pathways resulting in inflammation and airway damage. And this is where inflammasome immunology comes in. The inflammasome is known to play a central role in asthma and COPD as well as pulmonary inflammation in general. In asthma, persistent activation of the NLRP3 inflammasome by inhaled irritants can lead to both overt pulmonary inflammation and exacerbation of asthma symptoms. Giving NLRP3 inhibitors in asthma animal models prevents acute airway and pulmonary inflammation.
Wait- What is the inflammasome?
I had to take a post-graduate course in Functional Immunology to really understand this so if it’s your first deep-dive into the inflammasome - welcome, you’re not alone. Much of the information in this blog was inspired by Dr. Sam Yanuck, who will be speaking at EHS2021 on: “Immunity and Viruses: The Inside Story”. His excellent post-graduate medical course on Functional Immunology can be found here.
The inflammasome complex is part of innate immunity’s early warning system and allows us to mount a response to environmental pollutants or endogenous toxic substances (including those resulting from infections). There are 5 classes of inflammasomes found both inside the cell and on the cell membrane, to cover every level of potential threat to the cell.
One class- the Toll-like receptor family is a type of inflammasome sensor system located on the cell membrane. The Toll-like receptor 4 (think of a toll booth) sits on the cell membrane and when lipopolysaccharides (LPS) migrate from the gut (when it is “leaky”) into the portal vein and into hepatocytes, TL-4 sounds the alarm, releasing cytokines and interleukins (tumor necrosis factor (TNF) α, interleukin (IL)-1β) involved in liver inflammation. Eventually chronic inflammation leads to NAFLD- all as a result of what we generally refer to as leaky gut and mediated by an alarm bell that just keeps going.
Inside the cell, the NLRP3 inflammasome (the most well characterized of all the inflammasomes) is a group of intracellular proteins that assemble into an active defense system when danger threatens the cell.
Primed by multiple cytokines and signals that sense the presence of damage to other cells, the inflammasome goes on the offensive. Multiple signals, coming from the presence of the threat are called pathogen-associated molecular proteins (PAMPs) or damage-associated molecular protein (DAMPs). PAMPs can come from intestinally-derived lipopolysaccharide (LPS), bacterial and viral RNA. PAMPs are found in dysbiosis and can contribute to atherosclerosis. DAMPs are found in damaged and/or dying cells that are pouring out reactive oxygen species (ROS), ATP, mitochondrial DNA, and NF-kB.
The inflammasome is also activated by HAMPs (homeostatsis-altering molecular processes) which include increased intracellular influx of Ca+2 or efflux of K+2. Calcium hydroxyapatite crystals are known promoters of inflammasome activation, which brings into question the use of calcium hydroxyapatite as a supplemental form of calcium (thank you Dr. Yanuck for this clinical pearl). K+2 efflux occurs in hypokalemia from nutritional deficiency or increased K+ loss.
Each one of these signals are able to prime the inflammasome to leap into action. AND all of these changes occur as a result of exposure to particulate matter in wildfire smoke and air pollution.
Once DAMPs or PAMPs signal the inflammasome, protective responses that contain and eliminate harmful agents are activated- inducing an interleukin army which then promotes a symphony of T cell responses- most commonly upregulating the inflammatory interleukins: IL-1β and IL-18.
Obviously, this is not a mistake- the inflammasome originally evolved to protect the body and this inflammatory response has a purpose: IL-1β induces fever and promotes T-cell survival, B- cell proliferation, and antibody production, and supports the migration of leukocytes to a site of infection and invasion. IL-18 can act with IL-12 to induce interferon-γ (IFNγ) production by activating T- and NK-cells. This is all an efficient way to mobilize innate immunity and is meant, over the short-term, to attack, disarm, kill, and eliminate pathogens and foreign invaders- engulfing foreign matter for export and eliminating particulate matter and toxicants through the lymphatic channels.
But when chronically activated, the inflammasome promotes damaging responses found in what are now called “autoinflammatory disease”: obesity, type2 diabetes, rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, atherosclerosis, Alzheimer's disease, Parkinson's disease, and cancer. And as mentioned above, this list includes asthma and COPD.
Exposure to PM2.5 is one of the things capable of causing lung inflammation via potent IL-1β secretion, as particulate matter in the lungs activates the NLRP3 inflammasome activation.
The average arteriole is between 0.3 mm and 10 microns (µm) in diameter, and ultrafine particulate matter (which makes up the bulk of PM2.5) includes everything with a diameter of 1.0 mm or less. Ultrafine particulate matter can easily makes it way into the arterial system- not just in the lungs- but throughout the body and can be found embedded in the endothelial lining of arteries and arterioles, causing local and systemic inflammation. This is the mechanism through which particulate matter causes cardiovascular disease, where the presence of particulate matter in the linings of the vascular system directly triggers the inflammasome. And this is the reason that air pollution has a direct effect on increasing risk for Covid-19 infection.
Many drugs (biologics) and nutraceuticals have been shown to down-regulate the inflammasome but like the IL-1Ra, anakinra, biologics carry an increased risk of infection due to inhibition of neutrophil migration into the lungs that would ordinarily be necessary to fight pneumonia. Fortunately, the following inflammasome modulators, like resveratrol, do not appear to act as immune suppressants and don’t carry a risk for increased infection.
Phytochemicals/Nutrients and Their Effects on the Inflammasome
Resveratrol- Multiple studies show that resveratrol down-regulates the NLRP3 inflammasome in ischemia and hypoxia, radiation-induced IBD, renal fibrosis and prevents liver tissue injury in diabetic rats on high-fructose diets. But most importantly, resveratrol alleviated chronic “real-world” ambient particulate matter-induced lung inflammation and fibrosis by inhibiting NLRP3 inflammasome activation in mice given 50 and 100 mg/kg.bw. Resveratrol has also been shown to protect lung epithelial cells from damage by cigarette smoke exposure via the promotion of glutathione production intracellularly (where it counts).
Melatonin has been shown to improve mitochondrial dysfunction via inhibition of NLRP3 inflammasome in a mouse model of COPD.
Nicotinamide riboside was originally studied for it’s effect in athletic performance and improving mitochondrial function, but now has been applied to the treatment of cardiac and metabolic disease. It has also shown to be effective for down-regulating the NLRP3 inflammasome in diabetic mouse models where it significantly improved hepatic proinflammatory markers in mice including TNF-a, IL-6, and IL-1- all downstream markers of inflammasome activation.
Sulforaphane and EGCG (green tea extract) have both been shown to suppress the NLRP3 inflammasome in a mouse model of acute gout.
There are many other flavonoid-based compounds that have been found to down-regulate the NLRP3 inflammasome and it’s downstream inflammatory markers: NFkB, TNF-a, IL-6, IL-1B and IL-18.
Some are botanicals like:
Scutellaria baicalensis (Chinese skullcap) and Glycyrrhiza glabra (licorice)
Curcumin suppresses the NLRP3 inflammasome by blocking LPS activation, which has implications for a wide variety of endotoxin-generated problems.
And flavonoid components of many common foods:
Apigenin found in celery (and celery juice), parsley, chamomile tea
Quercitin found in capers (by far the highest source), apples and onions
Myricetin found in dock (it’s a vegetable), swiss chard, cranberries, chili peppers, blueberries, and garlic (and in small amounts in many fruits and vegetables)
Hydroxytyrosol, the antioxidant component of olive oil was shown to be a potent inhibitor of LPS (endotoxin)-induced inflammasome activation in mouse macrophages.
Dietary Components:
b-hydroxybutyrate (-induced by ketogenic diets, intermittent fasting, and exogenous use of b-hydroxybutyrate) was shown to suppress inflammasome formation in both fasted rats and rats given exogenous b-hydroxybutyrate. The mechanism here is an upregulation of cellular antioxidant production (superoxide dismutase, catalase) and a decrease in endoplasmic reticulum stress (caused by excessive reactive oxygen species).
Final Thoughts
The obvious and now necessary avoidance strategies for environmental toxicant exposure:
air and water filtration,
avoiding non-organically-grown food
addressing mold exposure and remediation
treating chronic infections
In addition to this- supporting and upregulating protective mechanisms that balance inflammation by minimizing inflammasome activation may help reduce respiratory tract inflammation and ensuing respiratory problems that would otherwise result from wildfire smoke exposure.
Here are a few obvious but crucial strategies from the critical article: Evidence Supporting a Phased Immuno-physiological Approach to COVID-19 From Prevention Through Recovery by Yanuck, et al.:
optimal glutathione levels via liposomal glutathione, NAC, selenium, etc.
supporting optimal potassium levels (hypokalemia is a known risk for inflammasome activation)
optimal HbA1c and fasting insulin levels (elevated glucose levels also are a risk factor for inflammasome activation).