Dioxin Causes Changes in Blood Vessels Through AhR in Developing Zebrafish!

Dioxins: bioaccumulatives chemical compounds formed through combustion and manufacturing. Incidents include backyard burning, applications of herbicides, wastewater treatment, coal-fires, diesel trucks, cigarette smoke, etc(Wipedia)




A recent study shows "activation of Ahr2/Arnt1 pathway by TCDD and BNF affects the shape of certain blood vessels in the brain of developing zebrafish." Past studies have demonstrated a significant impact of AhR signaling on the immune system that may also alter the Nrf2 antioxidant system. For this reason, we have suggested an important relationship of AhR and Nrf2 signaling in environmental illness and alterations of blood flow may be a factor in environmental illness symptoms. Dinatale showed AhR signaling initiates an inflammatory cascade that includes Il-6 via Il-1 and NF-kappaB and present in autoimmune and chronic proliferative diseases.




CiteULike: Malformation of certain brain blood vessels caused by TCDD activation of Ahr2/Arnt1 signaling in developing zebrafish.:



Teraoka, H., Ogawa, A., Kubota, A., Stegeman, J. J., Peterson, R. E., and Hiraga, T. (2010). Malformation of certain brain blood vessels caused by tcdd activation of ahr2/arnt1 signaling in developing zebrafish. Aquatic toxicology (Amsterdam, Netherlands).
http://www.citeulike.org/user/HEIRS/article/7149860

Dinatale, B. C., Schroeder, J. C., Francey, L. J., Kusnadi, A., and Perdew, G. H. (2010). Mechanistic insights into the events that lead to synergistic induction of il6 transcription upon activation of the ah receptor and inflammatory signaling. The Journal of biological chemistry.
http://www.citeulike.org/user/HEIRS/article/7339715

Hormone Modulates Immune Cell Activation after Cigarette Smoke Exposure in Mice.

Recent study says leptin may modulate the immune responses from cigarette smoke. Other studies demonstrate that leptin and Il-6 may be involved with sickness syndrome and may include modulation of hormones that regulate behavior such as orexins and may contribute to inflammation-induced insulin resistance.

Notes: Recent study also demonstrates that cigarette smoke induced epigenetic changes in epithelial cells in vitro that may contribute to cancer growth.

CiteULike: Leptin Modulates Innate and Adaptive Immune Cell Recruitment after Cigarette Smoke Exposure in Mice.: "Vernooy, J. H., Bracke, K. R., Drummen, N. E., Pauwels, N. S., Zabeau, L., van Suylen, R. J. J., Tavernier, J., Joos, G. F., Wouters, E. F., and Brusselle, G. G. (2010). Leptin modulates innate and adaptive immune cell recruitment after cigarette smoke exposure in mice. Journal of immunology (Baltimore, Md. : 1950)."


HEIRS H&H






Harden, L. M., du Plessis, I., Poole, S., and Laburn, H. P. (2006). Interleukin-6 and leptin mediate lipopolysaccharide-induced fever and sickness behavior. Physiology & behavior, 89(2):146-155.
http://www.citeulike.org/user/HEIRS/article/4745011
Liu, F., Killian, J. K., Yang, M., Walker, R. L., Hong, J. A., Zhang, M., Davis, S., Zhang, Y., Hussain, M., Xi, S., Rao, M., Meltzer, P. A., and Schrump, D. S. (2010). Epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate. Oncogene, aop(current).
http://www.citeulike.org/user/HEIRS/article/7154109

Immune Differences Between Mice Strains Determine Susceptibility to Cigarettte Smoke

Snippet: Strain A and B showed differences in baseline production of ROS and H2O2 and also glutathione, Nrf2, heme oxygenase 1 and GPX2. This was associated with reduced HDAC2 expression, activation of NF-kappaB and higher basal levels of TNF-alpha and IL-6. CSE induced a decrease in HDAC2 protein levels strains, however, the level of HDAC2 was significantly lower in strain A than in strain B. (Names of mouse strains have been changed for purpose of simplicity.)
Comment: One can assume from this there is significant potential for different people (because of their genetic makeup that results in different expression of antioxidant and immune genes) to be more prone to the health consequences of cigarette smoke. This has important implication for health conditions including but not limited to conditions like COPD, asthma and also other conditions like MCS.

For further reading: Ammonia, Methamphetamine, Cigarette Smoke and Parkinson's Disease

Blog Tags: Nrf2 , HO-1 , Tnf-a, Il-6



CiteULike: Reactivity of Mouse Alveolar Macrophages to Cigarette Smoke is Strain Dependent.: "Vecchio, D., Arezzini, B., Pecorelli, A., Valacchi, G., Martorana, P. A. A., and Gardi, C. (2010). Reactivity of mouse alveolar macrophages to cigarette smoke is strain dependent. American journal of physiology. Lung cellular and molecular physiology."

Ammonia, Methamphetamine, Cigarette Smoke and Parkinson's Disease

A number of noxious fumes and toxins are produced in the manufacturing process of the illegal drug methamphetamine and in recent months there have been a number of broadcasts on dangers associated with "meth lab homes". If you have missed these broadcasts it may interest you to know that 1 pound of meth produces 6 pounds of toxic chemicals. If you're not in the market for renting or buying a home, you might not be concerned by this now but these chemicals end up in the soil, air and water that surround the manufacturing site or are dumped along the roadside from mobile labs. Chemicals produced indoors from meth labs absorb into any porous material including carpets, clothing, blankets, food products, paint, flooring etc and get distributed onto all surfaces through air flow, ventilation and duct work and tracked into "clean" environments by contaminated shoes. Cars that house mobile labs are also a lifetime hazard because upholstery is porous and absorbs toxins.  

Most people are familiar with the fact that one of the most common chemicals associated with meth lab exposure is ammonia that can be toxic at certain amounts. Of course, the level of what determines the effects of toxicity is going to depend on the concentration, the route of exposure, the duration and metabolic characteristics of those exposed. Different people have different levels of detoxification that ultimately determines how serious the exposure to ammonia or to any chemical will be and there are a number of factors that influence this including genetics. One author explains ammonia toxicity can occur as a result of "alterations of ammonia metabolism including enzyme issues within the urea cycle, Reyes Syndrome and liver failure and the effects of these conditions may lead to brain edema and severe neurological impairment. Generally, it is now known that ammonia crosses the blood-brain barrier and interacts with a number of cellular processes including neurotransmission and brain metabolism." (Butterworth)

 For several years now, health experts have been aware that the illegal use of  methamphetamine may lead to long-lasting health consequences including dental disease and mental health problems in addition to those associated with addiction. Another consequence is an increased risk for Parkinson's disease for those who abuse methamphetamine, later in life. While there are a number of reasons for this, there are two that stand out in importance in addition to ammonia-inducing mitochondria dysfunction. The first is because of the vulnerability of certain neurons including those that regulate dopamine to the toxic effects of ammonia. There are also "lasting decrements in something called the dopamine transporter" and the elevation of oxidative stress by dopamine which damages tissues and causes neural injury. Luckily, under normal circumstances and at normal concentrations and when all things are working properly these kinds of toxic processes can be neutralized through the activities of antioxidants but meth labs are not considered normal circumstances and produce ammonia levels at much higher levels than normal.  

Unfortunately and as noted above, a number of physiological conditions influence how toxins are detoxified and levels of antioxidants may be reduced as a consequence of genetic polymorphisms, injury or the natural processes associated with aging. As far as antioxidant production in PD, the antioxidant system Nrf2 has been found to modulate the severity of toxicity associated with drugs and other toxic exposures. In experimental models, the loss of the expression of Nrf2  results in a greater loss of the dopamine transporter and much greater oxidative stress and greater neural damage.  While this process is more complex than what is explained here, the main point is expression of the Nrf2 is necessary to reduce the kinds of toxicity implicated in PD. (McCann) Nrf2 also regulates the production of certain cofactors necessary that are used in mitochondrial biogenesis which further influences neurological health. Oxidative stress at optimal levels is important for activation of different protective mechanisms including Nrf2 but too much is just too much to continue homeostasis (Widmer) and these conditions significantly complicate methods for treatment. Alterations in functions of antioxidant systems influence a number of diseases and specifically, dysfunction of the Nrf2 system has been implicated in several including cancer, respiratory diseases like COPD and autoimmune diseases.

  

Notes:

• Interestingly, it has been suggested that cigarette manufacturers add ammonia to cigarettes to make it more addictive because it enhances the effects of nicotine. This is achieved by "the addition of ammonia in the manufacturing process which helps convert bound nicotine molecules in tobacco smoke into free nicotine molecules and commonly known as "freebasing." This process is similar to that of freebasing cocaine, the end result is an enhanced effect of the drug on the user. This becomes a real problem upon cigaratte exposure for those who may have inborn errors for ammonia detoxificaton or genetic alteractions in other protective pathways such as Nrf2. (Martin)
• It takes a number of months before a baby's detoxification system is developed and so exposures to toxins in the womb and after birth can take a tremendous toll on the "little ones".
• Alterations in metabolic pathways that influence the excretion of ammonia are negatively influenced by heavy metals. One can be exposed to them from exposure to methamphatamine or meth precursors.
• Elevated levels of ammonia have been implicated in health conditions such as autism and may contribute to different types of brain injury.
• Because physical activity improves neural function and toxic exposure may negatively influence olfaction which also dictates behavior --- there is potential for increase atrophy and damage. Olfactory deficits present themselves often years before PD motor deficits appear.  
• Sleep deprivation from drug abuse has potential to speed mitochodrial dysfunction and shut off the antioxidant system. (Kresiun) Hyperammonemia alters expression of orexins which have a responsibility in control of sleep wake cycles and as a result may alter circadian rhythm and hormone function. (Ahabach) Specific dopamine signals regulate orexins and studies show the loss of orexin neurons is correlated to disease severity of PD. (Bubser, Thannickal)

Reduced Striatal Dopamine Transporter Density in Abstinent Methamphetamine and Methcathinone Users: Evidence from Positron Emission Tomography Studies with [11C]WIN-35,428: "McCann, U. D., Wong, D. F., Yokoi, F., Villemagne, V., Dannals, R. F., and Ricaurte, G. A. (1998). Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: Evidence from positron emission tomography studies with [11c]win-35,428. J. Neurosci., 18(20):8417-8422." http://www.citeulike.org/user/HEIRS/article/6639032
Butterworth, R. F. (2001). Glutamate transporter and receptor function in disorders of ammonia metabolism. Mental Retardation and Developmental Disabilities Research Reviews, 7(4):276-279. http://www.citeulike.org/user/HEIRS/article/6639166
Martin, Terry. Boosting the Impact of Nicotine with Ammonia. About.com. Retrieved on February 7, 2010. http://quitsmoking.about.com/od/chemicalsinsmoke/p/nicoboost.htm
Emergency Protocal. Urea Cycle Disorders. The Neonate with Hyperammonemia. Retrieved on February 7, 2010. http://www.citeulike.org/user/HEIRS/article/6639971
Widmer, R., Kaiser, B., Engels, M., Jung, T., and Grune, T. (2007). Hyperammonemia causes protein oxidation and enhanced proteasomal activity in response to mitochondria-mediated oxidative stress in rat primary astrocytes. Archives of biochemistry and biophysics, 464(1):1-11. http://www.citeulike.org/user/HEIRS/article/6640113
Ahabrach, H., Piedrafita, B., Ayad, A., El Mlili, N., Errami, M., Felipo, V., and Llansola, M. (2009). Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats. Journal of neuroscience research. http://www.citeulike.org/group/5070/article/6638140
Kresiun, V. I. and Rozhkovskiĭ, I. a. V. (1991). [disruption of the structural organization of brain mitochondrial membranes during deprivation of the paradoxal sleep phase and correction for it using lithonite]. Ukrainskiĭ biokhimicheskiĭ zhurnal, 63(3):59-65. http://www.citeulike.org/user/HEIRS/article/6640249
Cagnon, L. and Braissant, O. (2009). Cntf protects oligodendrocytes from ammonia toxicity: intracellular signaling pathways involved. Neurobiology of disease, 33(1):133-142. http://www.citeulike.org/user/HEIRS/article/6640251?updated=1265582259
Inui, A. (1999). Cancer anorexia-cachexia syndrome: Are neuropeptides the key? Cancer Res, 59(18):4493-4501. http://www.citeulike.org/user/HEIRS/article/6640255
Hermenegildo, C., Montoliu, C., Llansola, M., Muñoz, M. D., Gaztelu, J. M., Miñana, M. D., and Felipo, V. (1998). Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic gmp pathway in cerebellar neurons in culture and in the rat in vivo. The European journal of neuroscience, 10(10):3201-3209. http://www.citeulike.org/user/HEIRS/article/6640260
Bubser, M., Fadel, J. R., Jackson, L. L., Meador-Woodruff, J. H., Jing, D., and Deutch, A. Y. (2005). Dopaminergic regulation of orexin neurons. The European journal of neuroscience, 21(11):2993-3001. http://www.citeulike.org/group/5070/article/6463668
Thannickal, T. C., Lai, Y.-Y., and Siegel, J. M. (2007). Hypocretin (orexin) loss in parkinson's disease. Medscape Today. http://www.citeulike.org/user/HEIRS/article/6640584

Nrf2 and Cigarette Smoke ---A Possible Link to B12 Deficiency.......?

Cigarette smoke has been demonstrated to induce a number of Nrf2 protective genes.If transcobalamine is important as a carrier for B12 and is upregulated by Nrf2 does this possibly suggest that Nrf-/- may make one more susceptible to conditions where B12 is needed as a metabolic cofactor? One might ask, for what other conditions might Nrf2 elevate expression of transcobalamine? Also, this may lead one to suggest there may be an important role for B12, in addition to that of free radical scavenger and as a vitamin since it so important for neural health. Could the loss of this function increase the damage to the CNS such as in dopaminergic neurons from toxic bioaccumulations of metabolic products. For instance, would this aggravate metabolic disruptions from homocysteine or ammonia?  

Rangasamy (2004). Genetic ablation of nrf2 enhances susceptibility to cigarette smoke - induced emphysema in mice. 114:1248-1259. Table 2....http://www.citeulike.org/user/HEIRS/article/6637967

Cigarette Smoking and Invasive Pneumococcal Disease - Implications for Severity of H1N1

Cigarette smoking is the strongest risk factor for pneumococcal disease among immunocompetant non-elderly people. (Nuorti) As we have noted, cigarette also disrupts the major antioxidant system Nrf2. A recent report has shown that pneumococcal disease makes complications from H1N1 much more severe. Because of the relationship of Nrf2 and its important influence on modulation of inflammatory processes. It is worth suggesting that the dysruption of Nrf2 may contribute to H1N1 infection complications and because there have been polymorphs in Nrf2 identified - these polymorphs may make a person either more at risk or less at risk for complications related to H1N1. The implications of this includes that unless a person understands these risk factors related to their own genetic makeup it is advisable to take a physician's advice that is based on recent knowledge and understanding instead of those who claim to be "experts" in environmental disease.


CiteULike: Cigarette Smoking and Invasive Pneumococcal Disease: "Nuorti, J. P., Butler, J. C., Farley, M. M., Harrison, L. H., McGeer, A., Kolczak, M. S., Breiman, R. F., and Team, T. A. B. C. S. (2000). Cigarette smoking and invasive pneumococcal disease. N Engl J Med, 342(10):681-689."


Tokairin, Y., Shibata, Y., Sata, M., Abe, S., Takabatake, N., Igarashi, A., Ishikawa, T., Inoue, S., and Kubota, I. (2008). Enhanced immediate inflammatory response to streptococcus pneumoniae in the lungs of mice with pulmonary emphysema. Respirology (Carlton, Vic.), 13(3):324-332. http://www.citeulike.org/user/HEIRS/article/2651950

Nuorti, J. P., Butler, J. C., Farley, M. M., Harrison, L. H., McGeer, A., Kolczak, M. S., Breiman, R. F., and Team, T. A. B. C. S. (2000). Cigarette smoking and invasive pneumococcal disease. N Engl J Med, 342(10):681-689. http://www.citeulike.org/user/HEIRS/article/6462894

Reddy, N. M., Suryanarayana, V., Kalvakolanu, D. V., Yamamoto, M., Kensler, T. W., Hassoun, P. M., Kleeberger, S. R., and Reddy, S. P. (2009). Innate immunity against bacterial infection following hyperoxia exposure is impaired in nrf2-deficient mice. J Immunol, 183(7):4601-4608.

Severity of H1N1 influenza linked to presence of Streptococcus pneumoniae. EurekAlert. December 31, 2009. http://www.eurekalert.org/pub_releases/2009-12/cums-soh123009.php

Heightened endoplasmic reticulum stress in copd lungs: The role of nrf2-regulated proteasomal activity.

Title: Heightened endoplasmic reticulum stress in copd lungs: The role of nrf2-regulated proteasomal activity.

Summary: "Impaired Nrf2 signaling causes significant decline in proteasomal activity and heightens ER stress response in lungs of patients with COPD and CS-exposed mice."

Malhotra, D., Thimmulappa, R., Vij, N., Navas-Acien, A., Sussan, T., Merali, S., Zhang, L., Kelsen, S. G., Myers, A., Wise, R., Tuder, R., and Biswal, S. (2009). Heightened endoplasmic reticulum stress in copd lungs: The role of nrf2-regulated proteasomal activity. American journal of respiratory and critical care medicine.

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