TLR as Inflammatory Mediators: Why Ozone and MCS Do Not Mix

Several recent observations have revealed possible routes of physiological consequences of toxicant exposure (ie ozone) that may be related to symptoms of MCS. It has been suggested activation of TRP channels may play an important role causal in MCS. (Pall) Bessac and Jordt write, "that both the TRPA1 and TRPV1 receptor may contribute to chemical hypersensitivity, chronic cough, and airway inflammation in asthma, COPD, and reactive airway dysfunction syndrome" and other reports link TRPA1 to asthma.(Drug Disovery) Activations of these receptors will increase their expression, therefore, increasing the likelihood of activation (and symptoms) by exposures that activate them. Or on the other hand, Bessac writes, cross-desensitization exists by one chemical may desensitize it to another. As we noted over a year ago, changes in these receptors can occur by interactions with other proteins including IGF-1 and inflammatory cytokines that may alter these receptors functioning which may cause "aberrant signaling".

Recently it has been demonstrated that ozone activates TRPA1 channels and TRPA1 channels have been shown to be upregulated by the inflammatory cytokine MCP-1/ pathway which has been discussed at length in other blogs. Ozone and smoking promote a process called oxidation of phospholipids (oxPL) that generates ROS from NADPH oxidase activation, increase MCP-1, negatively regulate Nrf2 and are associated with autoimmune diseases such as lupus, RA and Parkinson's disease. OxPL are generated during inflammatory conditions and inhibit the full differention of dendritic cells and therefore restrict normal adaptive immune response. (Bluml) Recently other research has provided evidence that additional ozone reactions can be caused from abnormal enzymatic actions of glutathione which, by he way, is also regulated by Nrf2 through other proteins. In addition, ozone contributes to airway hypersensitivity and hyperresponsiveness through the modulation of TLR receptors and other green house gases may play a part in the "learned response" tied possibly to physiological response in MCS, may  potentiate the effects of lead-based paint and increase related health risks and cause panic-like behavior.

Just in case you have heard that ozone generators are physiologically calming...well, according to the research, quite the opposite seems to be true. For instance, as new study shows there is a sensor in the brain for CO2, another greenhouse gas, that will cause panic-attacks. Such behaviors are crucial for animals for survival to be able to "sense" and prevent biological suffocation and "aberrant signaling" of TLR receptor may decrease the threshold of activation of these sensors. Keely explains that "epithelial hypoxia" in the gut results in a 40-fold increase in translocation of gram-negative bacteria, regardless of intestinal barriar function. In the gut, hypoxia is associated with acute and chronic inflammation (ie IBD) and its presence initiates factors that exploits the intestinal environment to achieve the translocation process. One can assume that similar sensory processes that activate panic or flight response may be present in other tissues including the lungs and gut. Additionally, it has been demonstrated that viruses activate TLR receptors but the mechanism is slightly different.

TLR4 receptors recognize LPS endotoxin which is the a component of the wall of gram-negative bacteria. Several reports now suggest that a route of CFS is endotoxin exposure.Endotoxin is the result of lysis of bacteria from immune cells and therefore, will be present whereever there is inflammation. Of course, minimizing exposures that contain bacteria is one way to reduce TLR signaling. There are other TLR receptors that also initiate immune responses to other contaminants.   Recent evidence has demonstrated that saturated fat "angers" the immune system by interacting with TLR4 but the exact process of how saturated fat does this is unclear. Cani has noted that LPS in high-fat diets is 2 to 3 times greater and that LPS-containing  proportion is greater in the high-fat diet gut.  Other conditions may favor altered TLR4 signaling and because they initiate a variety of events inside the cell, the absence or dysregulation of the antioxidant system can lead to an exacerbation of inflammatory events because it modulates cytokines production such as pro-inflammatory Il-1 and Tnf-a and the anti-inflammatory cytokine Il-10 which modulates sickness syndrome. The antioxidant system Nrf2 supports other proteins in mitochondrial biogenesis which it has been reported that exposure to chemicals has an effect on cellular respiration and alters mitochondrial function.  Altered TLR signaling also may contribute to neuropathic pain. Other effects include alteration in neurotransmission such as dopamine which may contribute to Parkinson's disease and other neurodegenerative diseases.

I have written several essays on TLR receptors and how they interact with the immmune system from different environmental toxicants which can be read here. Also, to read citations for this article click here.

Chinese drywall linked to irritation. Is TRPA1 Activation a Factor?

Background: A past study has shown that H2S, cinnaldehyde and isothiocyanates can activate TRPA1 channels in the urinary bladder altering function.  (Gratske) This would suggest that the health effects of Chinese drywall are at least in part, mediated by the effect of both formaldehyde and H2S on TRPA1 channels.


The Consumer Product Safety Commission has some unsettling advice for people who live in homes built with Chinese-made drywall: "Spend as much time outdoors in fresh air as possible. According to the article.........."While hydrogen sulfide and formaldehyde were found at levels lower than the amount considered to be irritants, officials speculated that the two could be combining to produce higher levels of irritation than either would alone......Representatives of the formaldehyde industry said it is irresponsible to speculate that the two substances, at the levels found in the CPSC study, can act in a synergistic manner."

Read complete article.

Related article: Research Reveals Exactly How Coughing Is Triggered By Environmental Irritants

Transient receptor potential A1 (TRPA1) ion channel activity in the human urethra - evidence for a functional role of TRPA1 in the outflow region.
http://www.icsoffice.org/ASPNET_Membership/Membership/Abstracts/Publish/46/000027.pdf

Research reveals exactly how coughing is triggered by environmental irritants

Background: TRPA1 is sensitized by cytokines such as MCP-1 produces as part of the immune stress response.


Scientists have revealed how environmental irritants such as air pollution and cigarette smoke cause people to cough, in research published today in the American Journal of Respiratory and Critical Care Medicine. The authors of the study, from Imperial College London and the University of Hull, have identified the reaction inside the lungs that can trigger coughing when a person is exposed to particular irritants in the air. They suggest that their findings may ultimately lead to the development of new treatments for chronic coughing... Read more...

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Why smokers really 'itch' to quit

Why smokers really 'itch' to quit -- Activation of TRPA1 from use of "the patch".

Hydrogen Sulfide, Cigarette Smoke, Endotoxin and Particulate Matter -- The Toxic Effects They Have In Common!

Different chemicals have different modes of toxicity which can reduce, be additive or potentiate the effects of the others and alter other metabolic processes such as insulin release and activities of Nrf2 cell signaling.  Take four example, the four toxicants endotoxin, hydrogen sulfide (H2S), cigarette smoke and particulate matter. These pollutants are all common in the environment and can cause negative health effects in those that are susceptible, have certain chronic illnesses and/or multiple chemical sensitivity. Interestingly, one will note that all four are found in tobacco smoke and therefore, this probably makes cigarette more toxic at lower levels than each of the different agents on their own.

First of all, lets review a few important details about each of these toxicants. Cigarette smoke contains acrolein which is an aldehyde that has been implicated in the development of neurogenic inflammation. Cigarette smoke also has hundreds of chemicals. Some that have been identified and some that have not. The toxicity of many of the toxicants that have been identified are still unknown. Particulate matter (PM)are particles that are present in air pollution and reduce air quality. Their presence at higher levels are an irritant to almost anyone but at lower levels they may become irritants to individuals with special health conditions such as those patients with asthma and COPD. For PM, size matters! Finer particles are better able to travel down the windpipe and absorb into the lower lung tissue's protective layer and induce inflammation. Ultra-fine particles also have more surface area to bind chemicals which can elevate inflammatory responses even further. Exposures to hydrogen sulfide can be from endogenous sources such as intestinal bacteria or from production in the different cells. As we have noted, major sources of exogenous sources of H2S are from bacteria in contaminated drinking water from wells and groundwater and the waste of large animals feeding operations (CAFOS) that end up in rivers and streams. Of course, the source of endotoxin can be from those same sources but other sources include bacteria on food, smoke from wood and tobacco smoke, water-damaged buildings, animals, and from indoor contaminants like dust in the home and commercial and occupational settings. Contrary to popular belief, endotoxin is one of the most common pollutants in the environments because it can be found almost anywhere especially where there is water and is so small, that there is little, if any technology that is available to get rid of it. For instance, very few models of air filtration units have the ability to filter gram-negative bacteria which is the source of most endotoxin. 

Hydrogen sulfide has the ability to cause any number of health effects including death at high levels. As we noted above, it is produced endogenously by bacteria in the gut in addition to other cellulars sources including adipocytes (Fang) and the pancreas (Harrison). It has been shown that long-term exposure to endogenous hydrogen sulfide can impair the function of beta cells in the pancreas which may lead to insulin resistance and diabetes. Researcher's now believe that one way this occurs is through the generation of inflammatory processes from Il-1b that is produced by the liver may drive the inflammatory processes that effect the beta cells. Endotoxin has been associated with liver inflammation and inflammation in the liver has been associated with activation of neuroinflammation and sickness syndrome. Changes in Nrf2 signaling have been associated with insulin resistance and may be due to reductions in insulin secretion by damaged beta cells (Harrison) from H2S produced by pancreatic cells altering KATP channels and also from Il-1 production in the liver exerting a peripheral effect on pancreatic beta cells. Insulin has been shown to be an important signaler for HO-1 and Nrf2 under normal conditions. Harrison describes a five-fold increase in heme oxygenase -1 mRNA and a 4-fold increase expression in kidney epithelial cells by insulin induction. Long-term exposure to intestinal bacteria or other processes that produce copious amounts of H2S that activate cellular signal like nociceptors when detoxification is overwhelmed and cause pain, alter the microbiota and interact immunologically to cause inflammation that may contribute to autoimmune-type reactions. Also, the initiation of inflammatory processes in the liver and impaired insulin and Nrf2/HO-1 signaling and diabetes can generate long-lasting inflammatory processes in the brain and other peripheral complications may even be more detrimental. (Ehses)

It is interesting to note that both high levels and low levels of H2S are associated with diabetes. Dr. Whiteman from the Northcott Devon Medical Foundation reports reduced levels of H2S in the blood of patients with diabetes. Lower levels of H2S were found to be important clinical markers for microvessel functioning which is an important complication of diabetes (ScienceDaily). Considering that Nrf2 modulates the effects of H2S from HO-1,this has important implications for the role of Nrf2. Maybe homeostasis becomes unbalanced at both high and low H2S levels which may be a consequence of impaired Nrf2 signaling. Oh describes that H2S and Ho-1 can inhibit the damaging effects of NO and NF-kappaB from LPS endotoxin and that down-regulation of H2S/CSE in lung injury pathology includes down-regulation of NO/iNOS and upregulation of CO/HO-1 (Zhou). (Jee whiz, I feel like I am on a roller coaster ride - up, down, up, down! Just kidding!) The point here is how we see the modulation of two neurogasotransmitters.

Recently it has been reported that antagonizing TRPA1 channels for a prolonged period reduces some of the symptoms associated with diabetic hypersensitivity (Wei). Hyperglycemia is an important consequence of insulin resistance and diabetes which produces alterations in mitochondrial function and as Bonnard shows from his findings the mitochondrial dysfunction is a consequence of insulin resistance and result of ROS generation in diet-induced diabetic mice. Diet is an important source for the ingestion and propagation of intestinal bacteria in the intestinal tract. Mitochondrial dysfunction generates reactive species especially H2O2 from NADPH which can alter cell signaling and cause further damage to cells.

Fibromyalgia is suspected to be at least in part, a condition associated with neuropathic pain in which nociception plays an important role. Ro presents evidence that both TRPV1 and TRPA1 contribute to muscle nociception and hyperalgesia and elevations inflammatory mediators, H2O2 and other ROS increase their expression as well as, sensitize them. In addtion, chronic and consistent activation of TRP channels may lead to endoplasmic reticulum stress and the effects of ER stress are usually attenuated through HO-1 (Liu) but Fallahi shows in his presentation that Nrf2 signal decline following activation of the ER stress response. Andre explains aldehydes, which acrolein is one in cigarette smoke and also present in cooking oil and combustive products, are the main cause of neurogenic inflammation mediated through TRPA1 and suggests this channel may add to smoking pathologies. Acrolein also triggers endoplasmic reticulum stress. Haberzetti writes acrolein is also produced from the metabolism of numerous drugs, in addition to be a major irritant in cigarette smoke and through his observations, he determined that exposure to acrolein induces ER stress including the unfolding response and implicates NF-kappaB and production of cytokines as important factors in the process. Zhang demonstrated that acrolein up-regulates HO-1 through the gene promoter Nrf2 and silencing Nrf2 attenuated significantly the response of HO-1 to acrolein. The result of which could include an increase in the toxic effects of smoking. From this study one can see that Nrf2 knock-out would increase sensitivity in the respiratory tract to cigarette smoke.  Roy reveals further details in showing that acrolein can either lead to an adaptive response at low doses, presumably through the up-regulation of HO-1 through Nrf2 or lead to death processes. At higher doses, mitochondrial-induced apoptotic processes are more apt to ensue. This is also the case if the adaptive process can not mitigate the effects of the toxicant.

Nociceptive behavior seems to be an important part of many of the environmental illnesses including fibromyalgia, airway hypersensitivity and other lung disease, degenerative diseases and multiple chemical sensitivity(MCS), just to name a few. One symptom often reported by those who suffer from MCS is a chronic and annoying cough from cigarette smoke and air pollution. Birrell recently showed that activation of TRPA1 by its agonists can lead to chronic cough and incidentally the "agent" he used in his experiment was acrolein which activated both TRPA1 and vagal nerves. The author points out that current cold remedy treatments are usually not effective for this kind of cough and there a number of TRPA1 ligands, and therefore are number of TRPA1 triggers that can generate a cough. This study might help to explain the persistant cough in many MCS patients. Of course, many chemicals can bind to particulate matter and therefore activate TRPA1 receptor and stimulate chronic cough. Caterina notes that TRPA1 can be activated in a different manner than just binding and this is achieved by TRPA1 ligands attaching themselves to cysteine residues on the channel which may change the structure and lengthen the time of activation. Bang explains that activators of TRPA1 are reactive eletrophile species. Meaning they are all able to effect gene expression by reacting with nucleic acids, proteins and other small molecules (Farmer) and include acrolein, mustard oil, iodoacetamide etc.  In addition, there are also non-electrophile activators which include menthol, THC, camphor and others. (Bang) TRPA1 also reacts to the ROS, H2O2. In addition, these compounds induce the expression of the enzymes of the Nrf2 detoxification system. Caterina explains, "there may be a so-far unexplained mechanism of cooperation between Nrf2 and TRPA1 that has not been identified". He could be referring to the now understood role of nociception and the ER stress response which involves PERK/Nrf2 or may be referring to some other mechanism. Madeira demonstrates that H2S is protective against gastic damage and in a similar study this is achieved by the down-regulation of NO and the up-regulation of CO/HO-1. He also suggests that TRPV1, at least in this case, plays some part in this protection. The similarities between Caterina's and Madiera's study are worth noting and may suggest interaction between TRP receptors and Nrf2 is important for the protective benefits of the gasoneurotransmitters.

The aryl hydrocarbon (AhR) may be another important factor in multiple chemical sensitivity. In addition to smoke mediated COX-2 and prostaglandin production and contributing to inflammation induced lung disease, the AhR is involved in the detoxification of polyaromatic and polyhalogenic hydrocarbons. Both classes include a number of chemicals that are present in the environment and used in manufacturing and agriculture. Also, abherrant functioning of the AhR is believed to be responsible for mediating the toxicity of dioxins which is also in cigarette smoke. In addition, to the ER stress response activation from cigarette smoke. Cigarette smokes also activates the AhR and also alters adipocyte differentiation and down-regulated the expression of adiponectin, PPAR-gamma and other markers and elevated MCP-1(Shimada) . There may be some negative control of the Nrf2/HO-1 pathway by cigarette smoke which can elevate levels of adiponectin and suppress levels cytokine levels (Kim). The absence of the aryl hydrocarbon is responsible for toxicities of other chemicals as well. It was reported last week that endotoxin which has been shown to be a trigger for chronic fatigue syndrome, is detoxified by the activities of the aryl hydrocarbon. Any dysfunction in this protein could lead to unexpected consequences and an increased sensitivity to endotoxin. It is important to remember here that Nrf2 is both modulated and modulates the AhR. Abnormal signaling by either one could lead to consequences related to toxicity. In addition, the beneficial activities of the AhR are inhibited by Tnf-a. Impaired Nrf2 which modulates the inflammatory mediator will only add to toxic effects in a negative way. Recent studies show endotoxin  causes endoplasmic reticulum failure "possibly by actions of the mitochondria" which would lead again, to reduction of Nrf2 (Koslov).   Endotoxin is extremely common in the environment in air and water pollution and therefore, it should be of particular concern for those with multiple chemical sensitivities as well as other conditions including those with dysfunction in immune regulation.

Related Reference:

• Slide Presentation: Loss of nrf2 dependant signaling following induction of endoplasmic reticulum stress.

Citations and Original Document