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.

Recent Links Added to the HEIRS Library!

1. The inhibitory effect of ghrelin on sepsis-induced inflammation is mediated by the MAPK phosphatase-1. http://www.citeulike.org/user/HEIRS/article/6430465#
2.Weight loss, body fat mass, and leptin in Parkinson's disease. http://www.citeulike.org/user/HEIRS/article/6429319
3. High-fat diet induces apoptosis of hypothalamic neurons. http://www.citeulike.org/user/HEIRS/article/4292700
4. Cellular localization of three vesicular glutamate transporter mRNAs and proteins in rat spinal cord and dorsal root ganglia. http://www.citeulike.org/user/HEIRS/article/6429237
5. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). http://www.citeulike.org/user/HEIRS/article/2997140
6. Sympathetic premotor neurons mediating thermoregulatory functions http://www.citeulike.org/user/HEIRS/article/6429118
7. Up-regulation in expression of vesicular glutamate transporter 3 in substantia nigra but not in striatum of 6-hydroxydopamine-lesioned rats http://www.citeulike.org/user/HEIRS/article/6428977
8. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors http://www.citeulike.org/user/HEIRS/article/6428976
9. Acute and subacute chemical pneumonitis http://www.citeulike.org/user/HEIRS/article/6428868
10. Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase-dependent manner http://www.citeulike.org/user/HEIRS/article/6428693
11. Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and GSK3β) on the risk of Parkinson's disease http://www.citeulike.org/user/HEIRS/article/6426071
12. Nrf2 Regulates Antioxidant Gene Expression Evoked by Oxidized Phospholipids in Endothelial Cells and Murine Arteries In Vivo http://www.citeulike.org/user/HEIRS/article/6425259
13. Air-pollutant chemicals and oxidized lipids exhibit genome-wide synergistic effects on endothelial cells http://www.citeulike.org/user/HEIRS/article/1496816
14. Cigarette Smoking Blocks the Protective Expression of Nrf2/ARE Pathway in Peripheral Mononuclear Cells of Young Heavy Smokers Favouring Inflammation http://www.citeulike.org/user/HEIRS/article/6425199
15. Coenzyme Q10 deficiency in myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardi. http://www.citeulike.org/user/HEIRS/article/6414392
16. TLR4 is Necessary for Hyaluronan-mediated Airway Hyperresponsiveness After Ozone Inhalation http://www.citeulike.org/user/HEIRS/article/6424875

Nrf2 as a Therapeutic Target for Stroke and Neurodegeneration

Tlr4 is necessary for hyaluronan-mediated airway hyperresponsiveness after ozone inhalation.

Garantziotis, S., Li, Z., Potts, E. N., Lindsey, J. Y., Stober, V. P., Polosukhin, V. V., Blackwell, T. S., Schwartz, D. A., Foster, W. M., and Hollingsworth, J. W. (2009). Tlr4 is necessary for hyaluronan-mediated airway hyperresponsiveness after ozone inhalation. American journal of respiratory and critical care medicine. http://www.citeulike.org/user/HEIRS/article/6424875

Oxidative Stress Caused by Ozone Exposure Induces Loss of Brain Repair in the Hippocampus of Adult Rats

Ozone is a greenhouse gas along with carbon dioxide, nitrous oxide, water vapor and methane. (Wipedia)

Oxidative Stress Caused by Ozone Exposure Induces Loss of Brain Repair in the Hippocampus of Adult Rats: "URL: Oxidative Stress Caused by Ozone Exposure Induces Loss of Brain Repair in the Hippocampus of Adult Rats

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Nitrogen Dioxide, Ozone & Lead Partner to Increase Pollution Dangers to Urban Children

The adverse health effects of ozone (O3) and nitrogen dioxide (NO2) have been known for decades. The Clean Air Act was established in 1963, but ambient a quality was not regulated until 1970, and by 1971 EPA had established one hour National Ambient Air Quality Standard (NAAQS) of 0.08 ppm for both O3 and nitrogen dioxide.

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Oxidative Stress from Low Dose Ozone Causes Neurodegeneration in the Brain

Oxidative Stress Caused by Ozone Exposure Induces Loss of Brain Repair in The Hippocampus of Adult Rats

Summary: "oxidative stress caused by low doses of ozone causes dysregulation of inflammatory processes, progressive neurodegeneration, chronic loss of brain repair in the hippocampus causing impaired memory, and brain plasticity changes in the rat analogous to those seen in Alzheimer's disease."

Rivas-Arancibia, S., Guevara-Guzman, R., Lopez-Vidal, Y., Rodriguez-Martinez, E., Gomes, M. Z., Angoa-Perez, M., and Raisman-Vozari, R. (2009). Oxidative stress caused by ozone exposure induces loss of brain repair in the hippocampus of adult rats. Toxicol. Sci., pages kfp252+.
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Note: ozone is ozone -- does not matter if it produced mechanically or from chemical components in air.

Houseplants Make Air Healthier

Houseplants Make Air Healthier