Airborne fine particulate matter induced pulmonary inflammation as well as oxidative stress in neonate rats.

"Study demonstrated acute exposure to fine PM induced airway inflammation as well as increased oxidative stress in addition to its direct toxic effect on airway epithelium cells."

Read more: CiteULike: Airborne fine particulate matter induced pulmonary inflammation as well as oxidative stress in neonate rats.:

Air pollution and circulating biomarkers of oxidative stress

"Chemical components of air pollutant exposures that induce oxidative stress and subsequent inflammation may be partly responsible for associations of cardiovascular morbidity and mortality with airborne particulate matter and combustion-related pollutant gasses"

Read more: CiteULike: Air pollution and circulating biomarkers of oxidative stress:

Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues

"our study suggests that PM2.5 exposure differentially activates the UPR branches, leading to ER stress-induced apoptosis through the PERK-eIF2alpha-CHOP UPR branch. This work provides novel insights into the cellular and molecular basis by which ambient PM2.5 exposure elicits its cytotoxic effects that may be related to air pollution-associated pathogenesis"

Read more: CiteULike: Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues:

Research Commentary on Protection of Radio-Collared Bears in St. Louis County, MN -Respect The Research and Protect Radio-collared Bears!

This is a research commentary in response to “reactions” and “no action” from public officials

to a request by Dr. Lynn Roger for protection for WRI collared- with-ribbons research bears from being

hunted in St. Louis County,MN. These bears have a higher incidence of mortality because it is legal to hunt

radio-collared animals in the state of Minnesota. Statistically and for this issue I am speaking of thirteen animals out of an estimated 11,000 or more black bears in Minnesota.  Dr. Garshelis, leading bear biologist for the DNR in 2008 explained in a report “the rate of mortality of collared-bears is “not sustainable” population-wide and has documented a high harvest rate of collared bears since 2003”. For this report, I believe he speaks generally of radio-collared bears in MN and includes those collared by the DNR. This report, Ecology and Population Dynamics of Black Bears in Minnesota, is available to the public and is posted on the Internet and is public information. For a number of years, the DNR has repeatedly (verbally and in published documents) discouraged the “harvesting” of radio-collared bears. Unfortunately, these attempts and verbal recommendations to prevent the harvesting of these animals have proved inadequate. For a number of reasons stated in the paragraphs below, immediate and enforceable legal steps with sanctions need to be implemented to ensure the health and safety of the bears and all the people involved with these important research animals.

The recent death of Dr. Rogers’ Sarah Bear has brought to light an issue that has needed to be addressed for a long time. It is an issue that has motivated a significant amount of unjust negative criticism for this kind of research and sheds a negative light on the WRI research in general which unnecessarily makes the grant application and permit process more difficult. Unfortunately, certain public officials and local media companies in Minnesota are adding fuel to this fire by openly criticizing Dr. Rogers’ methods. When all is said and done, the kind of observational study method of research Dr. Rogers’ uses provides a substantial amount of data and important information to a variety of audiences including ethologist, ecologists, wildlife biologists, veterinarians, educators and a host of different scientifically-based fields related to animals, in addition to those that study human and animal interaction. Probably, the two most famous researchers that have or have had similar research methods include Jane Goodall with a resume that touts 50 years of study of chimpanzees and the late Dian Fossy and her study of mountain gorillas. In the distant and recent past, state officials have made comments to the media which are biased, only half true or just plain laughable just to sway public opinion in their favor. What is dismissed or ignored is the fact there are numerous supporters both of the research and for protection of these bears in St. Louis County, MN. Plus, both Dr. Rogers’ who is an accomplished and prolific writer with numerous publications, and Sue Mansfield are both highly respected by their peers.

Unfortunately, parallel to biased comments by public officials, “critics” from the general public are speaking out against Dr. Rogers and the research in the press and the Internet. Many commenters have been downright “ugly” and vehement in voicing their disdain; they are also misinforming readers by misrepresenting the research while doing their best to discredit the value of the information and the reputations of both researchers. It is apparent from the present Internet buzz, a number of individuals had made a conscious plan and carried out the “hunting” and death of Sarah bear. One person went so far as to say, “the shooting of this bear was to send a message....”and there is a similar tone of “style” that includes “harsh language and untruths” meant to inflame and bully on several websites across the Internet. Most of the rhetoric shows anger directed towards specific individuals and/or the entire group of “donors” and “volunteer fundraisers and supporters” in the Lily community. In recent weeks, these comments have been directed at their “good deeds” including helping to secure a “sizable” grant for a State Park in Ely, MN and promoting companies important to the state and locals economies such as Coca Cola, General Mills and Pepsi. So at this point, one needs to ask, why the negativity from state officials and why do they insist on antagonizing the public by making false statements that only serve to increase the level of these types of harrassments?

To find a reasonable answer to this question, one only needs to review a little history about recent politics in Minnesota and provide a little background of the “mining industry” which is making attempts to get a stronger foothold in the Ely area. In recent years, just like many rural towns, the  economy downturn has had a negative impact on jobs and quality of life in this hurting community. It is estimated that an increase in industrial non-ferrous mining will bring a substantial increase in the amount of revenue and jobs to the state overall and an influx to the local economies as well. On the other hand, this kind of mining causes environmental damage with significant environmental costs that may be felt more at the local level and may include rising health care expenditures and secondary costs that are unpredictable, are unknown or under-estimated and may entail possible heavy financial penalties. Admittedly, the companies’ development plans include reimbursement for environmental damage if they can remain financially solvent which if history repeats itself in Minnesota, they may not! In the event of a hazardous spill, damage  reimbursement dollars can never replace the impacts such as damages to the environment that may take  decades or never recover and will never adequately address emotional or physical suffering from potential  serious permanent injury or death or the loss of recreational areas or the disruptions in habitats that will be  permanent or last longer than most peoples’ lifetime. So far, there have been few positive and mostly  discouraging reports that mine damages can be contained at a level that is “minimal”. Recently, the EPA sent  a “damming” report to developers of a planned mine south of Ely that says there is “no proof” “no proof” that the project will not result in water contamination. Critics argue that important factors were left out of this  report, but the general consensus amongst experts is that water contamination from the PolyMet and other proposed mines is inevitable. All of these events have occurred under the governance and leadership of Tim Pawlenty who had aspirations for the vice-presidency bid in the last presidential election and is currently trying to secure a Republican bid for the next presidential election. Of course, there are substantial benefits of public endorsements from “larger industries” because they have large memberships with lots of voters and  financial backing and therefore, lobbying power. Also under Pawlenty, there has been evidence of  governmental mismanagement and poor supervision including a spending scandal in the Department of Natural Resources and a supposed purposeful one-year delay in the release of data that shows a doubling of the incidence rate of cancer in taconite Iron Range miners from 1997 to 2005 compared to the report for the previous nine years. Reportedly, many that understand Minnesota politics believe this “suppression” of information was a political move.

So what does this all have to do with the bears you ask? Simple, it all comes down to the health and safety of the environment and in the end, who has “motivation” to advocate a specific political agenda that will have economic benefits but at substantial costs to public health and the health of the environment. There is a lot of history in relation to these study bears and the community that makes up part of their territory. A few years back, there were issues with a bear named Solo that eventually was “removed as a nuisance” from the Eagle’s Nest community to Michigan where she eventually died. In my personal opinion, there is merit in what Sue Mansfield said at the time, “something had changed at the Eagle’s Nest Isthmus to attract the animal.” Generally, animals do not acutely change their behaviors unless “lured” to do so and in this case, it is obvious that something motivated the bear to do so. The level and lack of cooperation from public officials on this issue and others and some of the media and certain members of the community who were so outspoken about it, leads one to suspect there is a perceived benefit from these “bear removals” and the negative publicity. Lately, I expect these perceived “benefits” have taken a “big hit” with the influx of “oneness and support” for bear education, the WRI and the NABC by the “Lily Community” and may reflect some of the most recent elevations in “ugly”chatter and the death of Sarah bear!

Mining operations utilize a significant amount of resources including water in many cases, produce a

significant amount of wastes even before the real operations begin and as noted above, there is a very high

risk for water contamination that may kill fish and fauna. Unfortunately, this poses a potential problem for  mining developers because Dr. Rogers will be the first to become aware of potential public health and environmental hazards from pollution. Importantly, this is a consequence of the specific nature of his research methods which includes bio-monitoring and the ability for the researchers to “walk with” and “follow the bears for long distances” in their natural habitat or “over hill and over dale” as I like to say! Any environmental or biological scientist can tell you the first signs of environmental damages are often first observed in effected wildlife, flora and fauna. From mining operations, specific pollutants that are expected include contamination from heavy metals and “noxious” odors. Studies have demonstrated exposures and both can lead to changes in behavior from neuro-inflammatory responses that effect cognition and instinct and in animals these changes may impact navigation and possibly increase or decrease expressions of fear and aggression. These same pollutants from mine sites which contaminate the purity of the natural food and water supply are known to potentially lead to epigenetic changes that can be passed to offspring for generations.

Animal studies in both bears and wolves demonstrate their superior sense of smell, intelligence and an “olfactory range” of several miles. Some reports say the bear’s olfactory capability has up to a 20 mile range and therefore their “bear scent sense” would include most of the area of mining interests near Ely. (This is at least as the crow flies and starting at different points.) For more background health information taken from polar bears studies for example, it says that “the insidious danger to many species comes incrementally, through the food web. Levels of mercury, other heavy metals and persistent organic pollutants (POPs) generated by industrial processes in southern latitudes are turning up in tissue samples of most arctic species, including polar bears. They are particularly vulnerable because of their reproductive biology and their place at the top of the arctic food web. On the other hand, adult females are able to offload some of these high concentrations of toxins to their offspring,“thereby, reducing their risks from exposures but increasing the risks in their cubs.” This problem of course would cause worry for the black bear researcher. Another problem is mining pollution would be comparable for metals but different because, as far as I am aware, there would be little or no contamination from persistent chemicals (POPS). However, it is also impossible to know what pollutants are already “lurking” in those environments. The same author from the resource above explains, “contaminants enter the web through precipitation tainted by winds blowing from the industrialized south” and this would closely mimic the particulate dust from waste blowing around and the settling of metal dust on drying beds and plants from these industrial sites. In the polar region, “the chemicals are first ingested by the smallest organisms on the tundra and in the water, and then passed to successively higher trophic levels.” (Hrynyshyn)

Both wolves and bears are near the tops of their food chain and have shared scavenging activities and therefore, they have an elevated risk for effects of exposure from mining waste particulates and volatile odors. Ammonia, a common waste pollutant from mining interacts well with other airborne gases, especially sulfates and nitrates, to produce particulate matter and can have a number of irritating effects including exciting chronic immune responses. (Unknown) In humans, exposure to particulate matter (PM) has been associated with a variety of health conditions including chronic inflammation and respiratory diseases such as allergies and asthma and more recently, implicated in diabetes and autoimmune-type diseases. Veterinarians have  identified many commonly known chronic environmentally-induced diseases in domestic animals but research  of their existence and prevalence data is very limited in wild animals for a number of different reasons.  Chronic exposure to irritants like ammonia, sulfur and other volatiles from hazard sites like mines and their  waste sites may modulate and precipitate unwanted behaviors in the different species including the lynx, the  bears, the raptors and the wolf populations that inhabit the area. Curiously, this was not addressed in a report  of the impact of these mines on wildlife which I read that was posted on the Internet. Generally, the  combination of the health effects of metals and volatiles augment one another and the effects of the will be  greater compared to the effects of each individually. Improper and unorganized feeding also may incite important and unsafe changes of behavior in a similar physiological manner. From most accounts, it is impossible to predict the extent of these kinds of environmental influences on genetic change because knowledge of specific epigenetic changes are limited for all species and even more so for wildlife. It also appears, there are a number of factors that influence epigenetic change and these may not be the same in similar or different environments and are more than likely, species specific.

Now I turn my attention away from the environmental aspects for a need to protect these bears to the recent comments made by state officials published in an online article from TwinCities.com. In this article, DNR Commissioner Holsten was quoted as saying he doubted he would rule for a “protection order for Rogers’s bears because it is not the type of research they protect because it involves social interactions between bears and humans.” Similarly, his description at this time, of the depth of research performed by Dr. Rogers and Sue Mansfield was very short-sighted and therefore, inaccurate. I am sure many of Dr. Rogers and Sue Mansfield’s peers would argue the Commissioner made an extremely simple and very limited assessment of both the kinds of information and data that is collected and their “professional” activities and accomplishments. Actually, the research of both Dr. Rogers and Sue Mansfield is quite involved, is labor, expense and time intensive and includes activities generally performed by biologists, animal ecologists and animal behaviorists. Their job description includes participating in the active scientific study of everything animals do and try to determine the biological and psychological motivations and significance for doing them. This involves investigating the relationship of animals to their environment, as well as to other organisms and not just humans and includes, but is not limited to how animals find and defend resources, avoid predators, choose mates and reproduce and care for their young. On the WRI website there is a complete list of research areas which Dr. Rogers and Ms. Mansfield are currently engaged in. 

In his statement, the DNR Commissioner explains the DNR is not motivated to “offer protection because the research is limited to social research between bears and humans” because they are not all inclusive and do not reflect the interests of the sportsman (ie. hunters). Technically, there is only one area that provides details about the research of the interactions of bears and humans on the WRI research activities list. All the other areas mentioned are bear related and include land tenure and social systems of bears, bear communication, daily and seasonal travel patterns, food and weight, reproduction, hibernation, care and development of cubs, play behavior, morphology and physiology of bears, bear signs, habitat, responses to environmental factors, and factors that effect research methods including the benefits of using different technology for collecting data. These are all necessary for bear education and for the understanding of it by the general public, wildlife-career oriented students and the sportsman. To restate, Holsten argues the DNR does not “protect social research on human and bear interaction.” In response, this could partly explain the escalating numbers of conflicts between people and bears in Minnesota because the DNR is not adequately addressing or educating the public about “bear preventive” measures. From his own comments and with further explanation on the WRI website, the DNR Commissioner explains he does not support their role in areas of the research which includes “educating the public so they better understand bear behavior, doesn’t support researching elements that may increase conflict between humans and bears or research that analyzes, describes and provides data into the human behaviors and cultural factors that increase “nuisance” behaviors, and doesn’t support research on factors that contribute to bear attacks, garbage and odor containment, etc.” (Rogers) All I have to got to say to this is, WHY NOT!? Obviously, he really doesn’t understand much of what Rogers’ research is about even though he is critical of it in public statements or maybe he does understand it and if he does, maybe he needs to publicly define what “ is the DNR’s role is in terms of bear education and then maybe redefine it!” I could place a bet, the majority of the public are open to more education, if it will reduce property loss and risk of injury and mortality! It is quite clear, there is very little representation for public concerns, at least in these concerns with the DNR. If he is a pubic representative, then why isn’t he addressing the needs of his public?

In the same article, DNR Biologist, Dr. Garshelis made several interesting comments including “he doesn’t think Rogers’ bears should get special protection. Further, he says, “by giving them (meaning Dr. Rogers’ bears) legal protection and not ours, it gives the perception that those bears are more important. Lynn (Dr. Rogers) might think that and people might believe that, but I do not think that.” From my perspective, I don’t believe Dr. Rogers ever meant to exclude other radio-collared bears, but does have a right as a business manager to focus his attentions and resources on “WRI” collared-with-ribbons research bears. Whatever regulations the DNR puts in place for their own collared bears, it really up to them anyway! All in all and from this latest interview with DNR representatives, it appears this interview like so many others in the past, sets the stage for the public and media to receive more incorrect information and misrepresentation of the research. Unfortunately, a lot of it the public is getting directly from DNR officials which only adds to the “half-truths” that are popping up in the media! So what is the intent behind all of this misinformation? Is it political, most definitely! Personally I feel the level at which the DNR is criticizing Dr. Rogers’ work and putting his bears in the middle , is NOT RIGHT and NOT FAIR! In this case, public officials should let the research explain the data and leave it at that.... and stop using the bears as political scapegoats and turning them into “objects” to force a political agenda!

The critical question here is why the DNR obviously supports mining development in the Ely area and ignores the potential and obvious benefits of Dr. Rogers research. Those bears, just by being bears, are “instruments” to monitor the health of areas that may be negatively affected by environmental damage. This is true, even with the bad data the mining operations are providing and bad environmental reports they have been receiving from the EPA. This is in addition to the fact that the mining industry carries a very high risk for injury and disability. In any case, with allowance and no interference for continued study and research of these bears, there is opportunity for Dr. Rogers to offer a relatively good and cost-effective mechanism for habitat surveillance and in the case of an “mine event” he may be the first to identify early the environmental impact. Importantly, there is no doubt in my mind, both researchers would report anything that didn’t seem quite right!

In conclusion, it is important to consider taking immediate steps and legislation to see these animals are kept

safe and at this point, it is not just the animals that are now in harms way. I hope the preceeding paragraphs has made it more clear about what really underlies the ridicule and reservations about this valuable research

and the real issue needs more consideration by a number of people in different agencies in Minnesota government. I hope I have expressed the point that the “real” issues here have nothing to do with preventing

the right to hunt, nor is it just about the bears but mostly about whether the safety of people and their pets, the environment and wildlife is more important than the games public officials’ play with their politics.

HEIRS Research

Independent Health and Environmental Researcher

www.heirs-online.com/  http://bear-research.heirs-online.com/

Research Citation Library: HEIRS Library

My bio is available through a link at my website at www.heirs-online.com under About HEIRS! For further reading, I encourage you to browse my citation library that will help in the understanding of this document. Tags to search include methylation, heavy metals, particulate matter, air pollution and specific names of heavy metals like copper and other environmental factors related to what is mentioned in this document including, endotoxin, inflammation, epigenetics, mining, etc. Specific documents are also filed by groups including heavy metals and genetics, mining, etc. You can also access my research blogs on the right corner at http://www.heirsresearch.blogspot.com/ http://bear-research.heirs-online.com and Facebook. Please feel free to email me at heirs_health@heirs-online.com for more information or clarifications.

The original of this document is available here at Research Commentary . The sources used in this document are also located here.

Gulf War Syndrome, Chemical Sensitivity and Why Benefits of CPAP!

It has only been in the not-to-distant past that officials and medical experts have come out and admitted that Gulf War Syndrome is an actual disease and while many that have tried to find the cause the "true cause" is not yet known. In previous blogs, I have discussed how Gulf War Syndrome shares many of the same symptoms as other environmental conditions and are often co-morbid and include chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivity and other environmental factors may contribute to fascilitate the condition that is commonly regarded as Gulf War Syndrome. One well-respected research blogger, Dr. Art Ayers, explains that CFS, MCS and fibromyalgia "can be induced by organophosphate pesticide exposure. In GWS, two insults seem to be needed: acetylcholine signal disruption and inflammation. He says that in the effected individuals the acetylcholine mimetics (pesticides, pyridostigmine) disrupted the nervous system and numerous immunological, infectious, chemical and emotional stresses generated a high level of chronic inflammation. The vaccine against anthrax and exposure to burning oil wells may have contributed to inflammation." Without a clear understanding of what causes GWS, physicians and health experts are mostly at a loss on how to treat it and clearly, most of the research is now focused on providing effective therapies until a cure is found for it.

In recent weeks, two interesting studies have been released that show CPAP (continuous positive airway pressure) may be beneficial in treating symptoms of Gulf War Syndrome with sleep disordered breathing. In the pilot study, findings demonstrated improvements in many symptoms including pain, fatigue, cognitive function, sleep quality, physical and mental health. The researchers' concluded from this experiment that CPAP can greatly improve overall health in GW patients with sleep disordered breathing which may be a distinguishing factor in veterans with GWI compared to veterans without Gulf War Illness. (Amin)  While this research is preliminary it provides interesting insight into GWS. Admittedly, there are reported side-effects associated with CPAP use and the pros and cons of it should be addressed fully with a qualified physician even if CPAP is taken out of the research lab and used as therapy for GWS.

To date, even with these published findings, the reader is left with the question why CPAP may be effective for treating some symptoms of GWS. The author only makes the comment that GWS experience a "frequency of arousals related to apneas, hypopneas, and mild inspiratory airflow limitation."  Taking a more holistic systematic approach to understanding the nature of GWS ; one can draw some conclusions that provide at least a reasonable explanation of what may be occurring in GW patients with sleep apneas and why CPAP may provide at least "some" relief. CPAP has been used for quite some time to  treat sleep apneas and more recently has been used for a variety of other medical respiratory conditions. Budhiraja explains that sleep disordered breathing is often associated with hypertension and that "sleep apnea, hypocapneas and hypoxemia contribute to alterations in sympathetic activity, changes in the renin-angiotensin pathway, impede xanthine oxireductase production, cause endothelial dysfunction and lower levels of eNOS."  If you are a consistent reader of my feeds, chronic low-level inflammation contributes to endothelial dysfunction and higher risk for cardiovascular disease in many environmentally-induced health conditions.

Recently, it has been suggested that sickness syndrome contributes to symptoms in GWS and may explain  fatigue, pain and other behavioral changes as well. Sickness syndrome is in associated with elevated levels of cytokines including Il-1b and Il-6 and these inflammatory cytokines may also be associated with PTSD and CFS and are activated during the general response to stress which can lead to changes in genetic expression. Two researchers, Burioka and Steiropoulis found significant changes in Il-6 and Tnf-a, uric acid and immune complexes after CPAP. These findings suggest intermittent hypoxia contibutes significantly to inflammation and noted positive changes in patients that use regularly CPAP .  We have suggested that insulin resistance may be a critical factor in environmental illness and obesity and dietary influences may influence the severity of many environmental diseases including sickness syndrome, PTSD, MCS, CFS and fibromyalgia. To some extent, this can be explained by the fact that inflammatory cytokines and adipokines such as leptin and adiponectin can produce systemic changes. Patients with OSA have a higher prevalence of insulin resistance both in the obese and non-obese. (Lam)

In severa studies, agents such as pesticides, particulates and compounds emitted from fires and other environmental conditions that GW veterans may have been exposed too, exert an inhibitory and/or negative influence on cell function. (Gulati) For example, the metabolites of many toxic chemicals consistent with these types of exposures bio-accumulate in adipose tissue and contribute to inflammation and insulin resistance. (Nov) More specifically, it is proposed immune-mediate macrophages in adipose tissue contribute to insulin resistance and Tregs dampen this response and their reduction may contribute to insulin resistance. (Winer) Also, smaller particulates that bind to metals and hydrocarbons and contain endotoxin may infiltrate deeply into body tissues and through a complex process, end up in vessels and contribute to inflammation that leads to vascular disease.  (Li) An August 2010 study of Gulf War patients demonstrate high prevalence of problems with hypercoagulation which are also common in sleep apnea patients and can potentially be reversed by use of CPAP in some individuals. (Guardiola, Nichols)

Sleep apnea often accompanies obesity and for years, it has been assumed that inflammation is an important consequence of obesity. However, many experts now believe endothelial inflammation probably precedes obesity. Whatever the case may be, CPAP has demonstrated therapeutic effects on inflammation in obesity and this inflammatory process is similar in other environmentally-induced diseases. This leads one to assume its benefits may be achieved in the same way for GWS patients. Budhiraja and others have shown,  "CPAP therapy improves endothelial function, decreases the abnormally increased levels of circulating apoptotic endothelial cells, attenuates free radical production from neutrophils and monocytes, reduces the levels of C-reactive protein (CRP), a marker of vascular inflammation, increases vasodilator levels and mediates a decline in vasoconstrictor levels  in patients with sleep apnea altering blood flow. In the future, more studies may demonstrate CPAP may be of benefit for other "somatic" environmental illnesses as well.  (Gold, El Soth) In CPAP studies in obese patients, CPAP therapy has shown to reduce oxidative stress as well as, raise levels of SOD and alter nitrate and nitrite levels. Other changes that are reflected during CPAP adjustments also may have positive influences on physiology in a so-far unknown way. (Calero)

I have agreed with a few health experts and proposed due to my own experiences with several environmental diseases, severe reactions of MCS may be caused by the "lack of tolerance" to environmental conditions. Reactions develops to conditions that were considered normal and therefore, is more like an autoimmune disease and inflammatory cytokines and epigenetic changes in gene expression are contributory to this disruption. This "loss of tolerance" could explain why MCS patients develop extreme sensitivity to very low levels of pollutants such as those found in perfumes and detergents. Chemical sensitivity is also common in Gulf War veterans but the research disagrees with the Treg theory at least in part. Interestingly, a recent study demonstrated that post-natal exposure to flame retardents in animals leads to inhibitory functions on the AhR and a reduction of Tregs (Wahl)  and supports that the AhR modulates Treg production (Mezrich) and they may  be a factor at least in some types of reactions to certain toxins.  It would be interesting to examine different Treg ratios and to compare them with patients with MCS that are not GW patients and also compare this to other factors. Specifically, one example would be extenuating circumstances that dramatically effect stress response regulation. From my own experience, I would suggest actual stress and anxiety levels may alter certain markers because my own reactions are significantly different in different environments.

As far as chemical sensitivity, the idea of "loss of tolerance" is relatively new and may involve a better understanding of a "bridge" that links the immune system and metabolic homeostasis.  Because glucose and metabolic dysregulation seems to be concurrent with many environmental illnesses, one must consider metabolic syndrome as a risk factor for any environmental illness and there is little doubt some may contribute to GWS.  Hersoug hypothesizes that diseases like atopy, asthma and autoimmune diseases which are more common with obesity are the result of changes in adipokines including leptin, adiponectin, Il-6 and tumor necrosis factor (Tnf-a) secreted by white adipose tissue.  He adds that body weight contributes to an increase of these inflammatory mediators which in turn down-regulate regulatory T cells which in turn results in a reduction of the anti-inflammatory Il-10. He proposes that this process forms the basis of the idea of "loss of tolerance" and this author believes the loss of "Tregs" contributes significantly to chemical and environmental pollutant sensitivity. Other factors such as endotoxin and loss by genetics or environmental depression of Nrf2 and aberrant AhR signalling may augment the inflammation and allergic and non-allergic reactions and responses and may explain some of the sensitivity to "oil fires".  This may partially be explained by the fact that crude oil and coal dust contain significant amounts of polyaromatic hydrocarbons (PAH) and are ligands for the AhR. (Neff)  They are present in high amounts in diesel exhaust and disruption of the Nrf2 raises allergic airway inflammatory reactions to oxidative stress at much lower levels of diesel exhaust exposure. This may be true and does not dismis some reactions may be a consequence of diesel hydrocarbon content. (Li) Quinatana concludes the AhR, depending on the ligand, is able to modulate both Tregs and Il-17 which is often upregulated in inflammatory autoimmune diseases. It is easy to gather from all of this, that there is probably no simple answer to resolution of environmental disease except to prevent and limit exposures to the "activating" agents.

Of course, one needs to consider the initial "trigger" and the resulting inflammatory immune response may be different through time and be altered through interaction with other other chronic environmental and behavioral factors such as exercise, diet and other noxious "agents" of exposure in one's environment.  The AhR may provide a clue or two because of its role in activation from dioxins and its aberrant signals could be enough to initiate inflammatory responses that may be important in GWS and chemical sensitivity. I have proposed that some of this is due to the communication channel between the Nrf2 and the AhR. Jensen explains that exposure to PAH AhR ligands suppress B cell production and suppress Il-6 and makes an important comment that any alteration in Il-6 can lead to assorted pathologies including autoimmune disease, vitiligo, lupus and multple sclerosis.  Under normal conditions, elevations in Il-6 increase significantly through time in response to endotoxin but when cells are exposed to dioxin or another AhR ligand, cells presented with much lower levels of Il-6. Jensen concludes, "Any environmental chemical capable of compromising this response has the potential to disrupt the regulation of many important stromal cell functions, including generation of inflammatory responses in general and the elaboration of several cytokines, including IL-6, to regulate blood cell development in particular."  In addition, Jensen's research shows that exposures of different AhR ligands including PAH which are prevalent both in indoor and outdoor environments may be different depending on the tissue and may lead to elevations in other inflammatory cytokines such as Tnf-a. Considering that these influences are common in the environment, they can serve to augment responses in GWS or any environmental disease for that matter. (Jensen) One potential consideration is that if alterations in cytokines contribute to blood abnormalities that contribute to hypoxic conditions,
improvements observed with CPAP may reflect improvements in blood parameters of one sort or another. (Incidentally, after my last chemical injury obvious symptoms could have been explained by blood abnormalities like these. Unfortunately, they were not diagnosed because of improper medical care by a licensed practitioner and brings up concerns about access to properly trained practioners for environmental disease which I have discussed at length in other blogs.)

Foster shows that impaired regulation to hypoxic condition in sleep apnea patients and CPAP increases blood flow to normal levels. Another study demonstrates "hypoxia and dioxin response pathways can compete for limiting cellular factor(s) and cross-talk that occur between the hypoxia and dioxin signal transduction pathways and identify Epo as an AHR-regulated gene." (Chan)  This suggests signal dysfunction may influence a battery of physiological and toxicological responses. Most recently in fish, there is evidence that hypoxia reduces the response of the AhR. (Matson) This brings to light two important concerns in light of the discussion here. One is that there is direct interaction between the AhR and the Nrf2 antioxidant system and two, the AhR is an activator of Tregs regulation. In this context, dysfunction could certainly lead to apneas and chronic inflammation. It also may lead to other impairments in the antioxidant system and possibly to chemical sensitivities with a lower Treg production and a "loss of tolerance". It is also worth pondering the extent of effects of blood cell production in relation to circadian rhythm and influence on the positive effects of CPAP (Burioka).

An alternative example of aberrant levels of Il-6 demonstrates the complexity of environmental disease in relation to inflammatory mediators. Curiously, a recent report shows how different factors may be instrumental and  suggest that stress and the effect of pyridostigmine bromide (PB) may be a plausible cause of GWS. Mauck says that his research shows that while stress normally upregulates muscarinic receptor density, the application of  pyridostigmine bromide or physostigmine reduces them. One of the muscarinic targets is the Nrf2 and may suggest a reduction in these receptors may also reduce or prevent the activation of Nrf2. In addition, GSK-3b inhibition also augments muscarinic signals and Treg expression. Thus, conditions where GSK-3b is upregulated may have a negative influence on both chemical sensitivity in GWS and also other types of chemical sensitivity.  The other part of the puzzle in these conditions may be explained and supported by evidence that shows pesticides may contribute to insulin resistance and diabetes and may negatively influence how the body reacts to infection. This could alter inflammatory mediator production and in turn, contribute to the neuroinflammatory process as shown through reductions of Il-6 by GSk-3b inhibition.(Beurel) Dioxins on the other hand, seem to contribute to insulin resistance independant of the AhR. (Hsu)

I have often said in other blogs that environmental illnesses seem more like a failure to adapt and the concept of down-regulation of Tregs provides a viable mechanism for "maladaptation" at least in multiple chemical sensitivity. It may end up that taking genetic expression and immune regulators into account could be what differentiates the forms of chemical sensitivity in autism and MCS from GWS. If Amin is correct and the presence of apneas can be a predictor of  GW syndrome, then one can presume dysregulation of glucose metabolism similar to that that would occur with obesity and the development of chronic inflammation even though GW patients may not be overweight may contribute to GWS. Obesity is a problem in all age groups and classes and is associated with Western diets and GSK-3b may also play its part. It is worth considering that Gulf War veterans that are overweight and eat a typical Western diet will be more at risk for more severe GWI symptoms and those with conditions that depress Nrf2 (which are often diet, exposure and epigenetic influences related) will be even more so!  One may suggest that a lifestyle that promotes healthy eating and low-inflammatory menu like a Mediterranean diet may provide some healthy benefits.





Amin, M. M., Belisova, Z., Hossain, S., Gold, M. S., Broderick, J. E., and Gold, A. R. (2010). Inspiratory airflow dynamics during sleep in veterans with gulf war illness: a controlled study. Sleep & breathing = Schlaf & Atmung. http://www.citeulike.org/user/HEIRS/article/7756111
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Omurtag, G. Z., Tozan, A., Sehirli, A. O. O., and Sener, G. (2008). Melatonin protects against endosulfan-induced oxidative tissue damage in rats. Journal of pineal research, 44(4):432-438.  http://www.citeulike.org/user/HEIRS/article/2674835
Gulati, K., Banerjee, B., Lall, S. B., and Ray, A. (2010). Effects of diesel exhaust, heavy metals , and pesticides on various organ systems: Possible mechanisms and strategies for prevention and treatment. Indian Journal of Experimental Biology, 48:710-721. http://www.citeulike.org/user/HEIRS/article/7753532
Calero, G., Farre, R., Ballester, E., Hernandez, L., Daniel, N., and Montserrat Canal, J. M. (2006). Physiological consequences of prolonged periods of flow limitation in patients with sleep apnea hypopnea syndrome. Respiratory medicine, 100(5):813-817. http://www.citeulike.org/user/HEIRS/article/7756347
Singh, A. K. and Jiang, Y. Lipopolysaccharide (lps) induced activation of the immune system in control rats and rats chronically exposed to a low level of the organothiophosphate insecticide, acephate. Toxicology and Industrial Health, 19(2-6):93-108. http://www.citeulike.org/user/HEIRS/article/7796
Li, R., Ning, Z., Cui, J., Yu, F., Sioutas, C., and Hsiai, T. (2010). Diesel exhaust particles modulate vascular endothelial cell permeability: implication of zo-1 expression. Toxicology letters, 197(3):163-168.  http://www.citeulike.org/user/HEIRS/article/7284279
Nov, O., Kohl, A., Lewis, E. C., Bashan, N., Dvir, I., Ben-Shlomo, S., Fishman, S., Wueest, S., Konrad, D., and Rudich, A. (2010). Interleukin-1beta may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation. Endocrinology, 151(9):4247-4256. http://www.citeulike.org/user/HEIRS/article/7752881
Budhiraja, R. and Quan, S. F. (2009). When is cpap an antihypertensive in sleep apnea patients? Journal of clinical sleep medicine : JCSM, 5(2):108-109. http://www.citeulike.org/user/HEIRS/article/7752952
Amin, M. M., Gold, M. S., Broderick, J. E., and Gold, A. R. (2010). The effect of nasal continuous positive airway pressure on the symptoms of gulf war illness. Sleep & breathing = Schlaf & Atmung. http://www.citeulike.org/user/HEIRS/article/7756404
Hersoug, L.-G. G., Husemoen, L. L., Sigsgaard, T., Madsen, F., and Linneberg, A. (2010). Indoor exposure to environmental cigarette smoke, but not other inhaled particulates associates with respiratory symptoms and diminished lung function in adults. Respirology (Carlton, Vic.), 15(6):993-1000.  http://www.citeulike.org/user/HEIRS/article/7582695
Hersoug, L.-G. G. and Linneberg, A. (2007). The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance? Allergy, 62(10):1205-1213. http://www.citeulike.org/user/HEIRS/article/1640991
Winer, S., Chan, Y., Paltser, G., Truong, D., Tsui, H., Bahrami, J., Dorfman, R., Wang, Y., Zielenski, J., Mastronardi, F., Maezawa, Y., Drucker, D. J., Engleman, E., Winer, D., and Dosch, H.-M. M. (2009). Normalization of obesity-associated insulin resistance through immunotherapy. Nature medicine, 15(8):921-929. http://www.citeulike.org/user/HEIRS/article/5398151
El Solh, A. A., Akinnusi, M. E., Baddoura, F. H., and Mankowski, C. R. (2007). Endothelial cell apoptosis in obstructive sleep apnea: a link to endothelial dysfunction. American journal of respiratory and critical care medicine, 175(11):1186-1191.  http://www.citeulike.org/user/HEIRS/article/7756664
Burioka, N., Miyata, M., Fukuoka, Y., Endo, M., and Shimizu, E. (2008). Day-night variations of serum interleukin-6 in patients with severe obstructive sleep apnea syndrome before and after continuous positive airway pressure (cpap). Chronobiology international, 25(5):827-834. http://www.citeulike.org/user/HEIRS/article/7748469
Steiropoulos, P., Kotsianidis, I., Nena, E., Tsara, V., Gounari, E., Hatzizisi, O., Kyriazis, G., Christaki, P., Froudarakis, M., and Bouros, D. (2009). Long-term effect of continuous positive airway pressure therapy on inflammation markers of patients with obstructive sleep apnea syndrome. Sleep, 32(4):537-543. http://www.citeulike.org/user/HEIRS/article/7756944
Lam, J. C. M. and Ip, M. S. M. Obstructive sleep apnea and the metabolic syndrome: Osa and insulin resistance. Medscape Today. http://www.citeulike.org/user/HEIRS/article/7765845
Gaurdiola, J., Matheson, P., Cavijo, L., Wilson, M., and Fletcher, E. (2001). Hypercoagulability in patients with obstructive sleep apnea. Sleep Medicine, 2(6):517-523. http://www.citeulike.org/user/HEIRS/article/7790684
Nichols, Denise. Original Hypercoagulation Study on Gulf War Veterans. (August 20, 2010) Veterans Today. http://www.veteranstoday.com/2010/08/20/original-hypercoagulation-study-on-gulf-war-veterans/
Salvador, Lourdes. CPAP Machine Improves Gulf War Illness Symptoms for Some. American Chronicle. http://www.americanchronicle.com/articles/view/180225
Espada, S., Rojo, A. I., Salinas, M., and Cuadrado, A. (2009). The muscarinic m1 receptor activates nrf2 through a signaling cascade that involves protein kinase c and inhibition of gsk-3beta: connecting neurotransmission with neuroprotection. Journal of Neural Chemistry, 110(3):1107-1119. http://www.citeulike.org/user/HEIRS/article/7791380
Mauck, B., Lucot, J. B., Paton, S., and Grubbs, R. D. (2010). Cholinesterase inhibitors and stress: Effects on brain muscarinic receptor density in mice. Neurotoxicology. http://www.citeulike.org/user/HEIRS/article/7395495
Beurel, E. and Jope, R. S. (2010). Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes. Neuroscience. http://www.citeulike.org/user/HEIRS/article/7264009
Jensen, B., Leeman, R., Schlezinger, J., and Sherr, D. (2003). Aryl hydrocarbon receptor (ahr) agonists suppress interleukin-6 expression by bone marrow stromal cells: an immunotoxicology study. Environmental Health: A Global Access Science Source, 2(1):16+. http://www.citeulike.org/user/HEIRS/article/3802484?show_msg=already_posted
Chan, W. K., Yao, G., Gu, Y.-Z., and Bradfiel, C. A. (1999). Cross-talk between the aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways. The Journal of Biological Chemistry, 274(17). http://www.citeulike.org/user/HEIRS/article/7795717
Foster, G. E., Hanly, P. J., Ostrowski, M., and Poulin, M. J. (2007). Effects of cpap on cerebral vascular response to hypoxia in obstructive sleep apnea patients. Respiratory and Critical Care Medicine, 175(7):720-725. http://www.citeulike.org/user/HEIRS/article/7795723
Matson, C. W., Timme-Laragy, A. R., and Di Giulio, R. T. (2008). Fluoranthene, but not benzo[a]pyrene, interacts with hypoxia resulting in pericardial effusion and lordosis in developing zebrafish. Chemosphere, 74(1):149-154. http://www.citeulike.org/user/HEIRS/article/7795748
Neff, Jerry. Bioaccumulation in marine organisms: effect of contaminants from oil well produced water. 2004. Pg 241. http://books.google.com/books?id=ABIQ_FGKOZcC&lpg=PA241&ots=v-kRmNZQY5&dq=polyaromatic%20hydrocarbons%2Bhypoxia&pg=PA241#v=onepage&q&f=false
Li, Y. J. J., Takizawa, H., Azuma, A., Kohyama, T., Yamauchi, Y., Takahashi, S., Yamamoto, M., Kawada, T., Kudoh, S., and Sugawara, I. (2010). Nrf2 is closely related to allergic airway inflammatory responses induced by low-dose diesel exhaust particles in mice. Clinical immunology (Orlando, Fla.). http://www.citeulike.org/user/HEIRS/article/7730119?show_msg=already_posted
Hsu, H.-F. F., Tsou, T.-C. C., Chao, H.-R. R., Kuo, Y.-T. T., Tsai, F.-Y. Y., and Yeh, S.-C. C. (2010). Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on adipogenic differentiation and insulin-induced glucose uptake in 3t3-l1 cells. Journal of hazardous materials, 182(1-3):649-655. http://www.citeulike.org/user/HEIRS/article/7383158?show_msg=already_posted
Wahl, M., Guenther, R., Yang, L., Bergman, A., Straehle, U., Strack, S., and Weiss, C. (2010). Polybrominated diphenyl ethers and arylhydrocarbon receptor agonists: Different toxicity and target gene expression. Toxicology letters, 198(2):119-126. http://www.citeulike.org/user/HEIRS/article/7408849
Mezrich, J. D., Fechner, J. H., Zhang, X., Johnson, B. P., Burlingham, W. J., and Bradfield, C. A. (2010). An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory t cells. Journal of immunology (Baltimore, Md. : 1950), 185(6):3190-3198. http://www.citeulike.org/user/HEIRS/article/7795863
Ho, P. P. and Steinman, L. (2008). The aryl hydrocarbon receptor: a regulator of th17 and treg cell development in disease. Cell Research, 18(6):605-608. http://www.citeulike.org/user/HEIRS/article/3709745

TLRs Regulates Reactions to Particulate Matter and Other Contaminant Considerations~!

In this article, the author explains "it is plausible that PM2.5 contains bacterial or mycoplasma lipoproteins, which are known activators of TLR2 . Because PM2.5 contain high concentrations of a large number of metals. One or more of these metals could be involved in increased TLR2- mediated cytokine production triggered by microbial lipoprotein constituents of the PM2.5. In this regard, it is interesting that TLR2 has been implicated in proinflammatory cytokine expression by airway epithelial cells stimulated with air PM containing high amounts of metals. Another possibility is that PM2.5 cytokine-inducing effects are mediated by an indirect mechanism, via the generation of endogenous “danger” host molecules activating macrophages via TLR2."

Note: Recent findings by Notch show a potentiation effect between cyanobacteria and heavy metals and thus support an important mechanism although the mechanism remains to be elicited. In addition, one must always consider alterations in methylation which can be caused by endotoxin and heavy metals. Walsh and Usman demonstrated that in autism there is alterations in the functioning of metallotheinin protein which modulates and detoxifies metals. (Treat Autism and AD/HD, Wright) In other blogs, we have explained that metallotheinin inhibits GSK-3b (Wang)which can turn off the Nrf2 antioxidant system. This could explain why there are reports that the antioxidant system is negatively effected by metals (and by endotoxin)and thus, one must also consider that in mixed environmental pollutants, there is a reduction of function of this system. In addition, there is also potential that the AhR and metals interact to influence antioxidant and detoxification. These interactions of metals and the AhR are currently being investigated through a number of projects. (Korashy) Further study may shed more light on the interactions of the Nrf2 and AhR gene batteries and how they are effected by metals from environmental exposures.

Shoenfelt, J., Mitkus, R. J., Zeisler, R., Spatz, R. O., Powell, J., Fenton, M. J., Squibb, K. A., and Medvedev, A. E. (2009). Involvement of tlr2 and tlr4 in inflammatory immune responses induced by fine and coarse ambient air particulate matter. Journal of Leukocyte Biology, 86. http://www.citeulike.org/user/HEIRS/article/7367529

Vita. Hesham Korashy, PhD. Retrieved on June 29, 2010.
http://faculty.ksu.edu.sa/hkorashy/Pages/index.aspx

Notch, E. G., Miniutti, D. M., Berry, J. P., and Mayer, G. D. (2010). Cyanobacterial lps potentiates cadmium toxicity in zebrafish (danio rerio) embryos. Environmental toxicology.
http://www.citeulike.org/user/HEIRS/article/7367622

Heavy Metals. Treat Autism and ADHD. Retrieved on June 30, 2010. http://www.treatautism.ca/?page_id=126

Wang et al. Inactivation of GSK-3 by Metallothionein PreventsDiabetes-Related Changes in Cardiac EnergyMetabolism, Inflammation, Nitrosative Damage, and Remodeling. Diabetes. June 2009. Pgs. 1391-1402.

Wright, R. O. and Baccarelli, A. (2007). Metals and neurotoxicology. The Journal of Nutrition.
http://www.citeulike.org/user/HEIRS/article/7367642

Exposure to Metal-rich Particulate Matter Modifies the Expression of Candidate MicroRNAs in Peripheral Blood Leukocytes

CiteULike: Exposure to Metal-rich Particulate Matter Modifies the Expression of Candidate MicroRNAs in Peripheral Blood Leukocytes: "Bollati, V., Marinelli, B., Apostoli, P., Bonzini, M., Nordio, F., Hoxha, M., Pegoraro, V., Motta, V., Tarantini, L., Cantone, L., Schwartz, J., Bertazzi, P. A., and Baccarelli, A. (2010). Exposure to metal-rich particulate matter modifies the expression of candidate micrornas in peripheral blood leukocytes. Environmental Health Perspectives."

Nrf2 Is a Key Transcription Factor That Regulates Antioxidant Defense in Macrophages and Epithelial Cells: Protecting against the Proinflammatory and Oxidizing Effects of Diesel Exhaust Chemicals

CiteULike: Nrf2 Is a Key Transcription Factor That Regulates Antioxidant Defense in Macrophages and Epithelial Cells: Protecting against the Proinflammatory and Oxidizing Effects of Diesel Exhaust Chemicals: "Li, N., Alam, J., Venkatesan, M. I., Eiguren-Fernandez, A., Schmitz, D., Di Stefano, E., Slaughter, N., Killeen, E., Wang, X., Huang, A., Wang, M., Miguel, A. H., Cho, A., Sioutas, C., and Nel, A. E. (2004). Nrf2 is a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells: Protecting against the proinflammatory and oxidizing effects of diesel exhaust chemicals. J Immunol, 173(5):3467-3481."

The benefits of whole-house in-duct air cleaning in reducing exposures to fine particulate matter of outdoor origin: A modeling analysis.

Macintosh, D. L., Minegishi, T., Kaufman, M., Baker, B. J., Allen, J. G., Levy, J. I., and Myatt, T. A. (2009). The benefits of whole-house in-duct air cleaning in reducing exposures to fine particulate matter of outdoor origin: A modeling analysis. Journal of Exposure Science and Environmental Epidemiology, aop(current). http://www.citeulike.org/user/HEIRS/article/4219503

Disruption of the transcription factor nrf2 promotes pro-oxidative dendritic cells that stimulate th2-like immunoresponsiveness upon activation by ambient particulate matter.

Williams, M. A., Rangasamy, T., Bauer, S. M., Killedar, S., Karp, M., Kensler, T. W., Yamamoto, M., Breysse, P., Biswal, S., and Georas, S. N. (2008). Disruption of the transcription factor nrf2 promotes pro-oxidative dendritic cells that stimulate th2-like immunoresponsiveness upon activation by ambient particulate matter. J Immunol, 181(7):4545-4559. http://www.citeulike.org/user/HEIRS/article/3716629


For further reading:

How Activation of Antioxidant System Nrf2 Reverses Endothelial Dysfunction in Vascular Disease and Environmental Illness!

Background: Vascular disease is an important consequence of  diabetes and is associated with endothelial dysfunction from hyperglycemia. Other conditions can contribute to endothelial dysfunction and a decrease in NO in endothelial tissue or loss of NO bioavailability. Certain agents and the loss of heat shock proteins which is important for sustained coupled activity contributes to the uncoupling of eNOS and endothelial dysfunction . Uncoupling of eNOS elevates the production of superoxide causing oxidative stress.Both eNOS uncoupling and oxidative stress have been implicated as factors in environmental illness.(Pall)

Heiss recently demonstrated that Nrf2 increases the bioavailability of NO while reducing reactive species and assists in the maintenance of coupling of eNOS. Kim explains that loss of Nrf2 results in increased susceptibility to oxidative and electrophilic stress but also enhances tissue injury because of an impairment in the "adaptive response".  Impairments of the Nrf2 system have been associated with a number of diseases such as asthma, atherosclerosis, colitis and COPD. Incidentally, heat shock proteins are included in a class of genes whose expression may be Nrf2-dependant.

Studies have shown that inflammation, endothelial dysfunction, and endothelial damage mediators are upregulated upon exposure to particulate matter (PM) and therefore, environmental pollutants can compromise overall vascular health. Particulate matter is of concern because it is small enough to be carried deep into the lungs where it promotes the production of inflammatory cytokines. In a study published in 2008, TNF and inflammatory cytokines was associated with ultra-fine particulate matter PM2.5 while a 7-day exposure of PM2.5 was negatively associated with the number of white blood cells in exposed children. In addition, these children had increased levels of endothelin-1 and subclinical inflammation. This study suggest that children exposed to PM may be at risk for cardiovascular disease, stroke and other diseases later in life. (Calderón-Garcidueñas) These findings support others that showed higher hospitilizations for children  and higher mortality rates in the elderly over 75 years of age exposed to PM2.5. (Jimenez and Linares)

Recent Research:

Title: Activation of Nrf2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease.

According to this author "nrf2 by the dietary activator sulforaphane, limited to concentration ranges found in plasma after consumption of broccoli, increased the expression of protective enzymes under ARE-linked transcriptional control and prevented metabolic dysfunction in endothelial cells induced by hyperglycemia.........decreasing the expression of nrf2 exacerbated ROS production in both normoglycemic and hyperglycemic cultures which provides evidence that ROS generation can be reduced by Nrf2 and that sulforaphane acts through Nrf2 to achieve reductions and prevent endothelial cell damage."

Summary: These findings provide the biochemical basis for the link of a vegetable-rich diet with decreased endothelial dysfunction, including that part of the Mediterranean diet, suggesting that dietary exposure to nrf2 activators derived from cruciferous vegetables may have be involved.

Notes:

• Resveratrol has been demonstrated to improve endothelial function and suppress oxidative stress such as superoxide from NADPH. (Soylemez) In the blog, A Small Book on the Benefits of Resveratrol we explained how other studies have shown some of its activities are regulated through SIRT1 and elevates a number of antioxidants and increases the expression of GCH1 which prevents the elevations in superoxide and (HEIRS Nutrition) alters eNOS expression.

Citation: Xue, M., Qian, Q., Adaikalakoteswari, A., Rabbani, N., Babaei-Jadidi, R., and Thornalley, P. J. (2008). Activation of nf-e2–related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes, 57(10):2809-2817. http://www.citeulike.org/user/HEIRS/article/3438451
Cheng, J., Ou, J.-S., Singh, H., Falck, J. R., Narsimhaswamy, D., Pritchard, K. A., and Schwartzman, M. L. (2008). 20-hydroxyeicosatetraenoic acid causes endothelial dysfunction via enos uncoupling. Am J Physiol Heart Circ Physiol, 294(2):H1018-1026. http://www.citeulike.org/user/HEIRS/article/5919352
Kim, J., Cha, Y.-N. N., and Surh, Y.-J. J. (2009). A protective role of nuclear erythroid 2-related factor-2 (nrf2) in inflammatory disorders. Mutation research. http://www.citeulike.org/user/HEIRS/article/5884341
Pall, Martin. (2007) Explaining "Unexplained Illness". Harrinton Park Press. Pg 34-35.
Kwak, M.-K., Wakabayashi, N., Itoh, K., Motohashi, H., Yamamoto, M., and Kensler, T. W. (2003). Modulation of gene expression by cancer chemopreventive dithiolethiones through the keap1-nrf2 pathway. Journal of Biological Chemistry, 278(10):8135-8145. http://www.citeulike.org/user/HEIRS/article/883885
Calderón-Garcidueñas, L., Villarreal-Calderon, R., Valencia-Salazar, G., Henríquez-Roldán, C., Gutiérrez-Castrellón, P., Torres-Jardón, R., Osnaya-Brizuela, N., Romero, L., Torres-Jardón, R., Solt, A., and Reed, W. (2008). Systemic inflammation, endothelial dysfunction, and activation in clinically healthy children exposed to air pollutants. Inhalation toxicology, 20(5):499-506. http://www.citeulike.org/user/HEIRS/article/5919414
Heiss, E. H., Schachner, D., Werner, E. R., and Dirsch, V. M. (2009). Active nf-e2-related factor (nrf2) contributes to keep endothelial no synthase (enos) in the coupled state: the role of reactive oxygen species (ros)-, enos- and heme oxygenase (ho-1) levels. The Journal of biological chemistry. http://www.citeulike.org/user/HEIRS/article/5886348
Jiménez, E., Linares, C., Rodríguez, L. F., Bleda, M. J., and Díaz, J. (2009). Short-term impact of particulate matter (pm2.5) on daily mortality among the over-75 age group in madrid (spain). The Science of the total environment, 407(21):5486-5492. http://www.citeulike.org/user/HEIRS/article/5395518
Linares, C. and Díaz, J. (2009). [impact of particulate matter with diameter of less than 2.5 microns [pm2.5] on daily hospital admissions in 0-10-year-olds in madrid. spain [2003-2005]]. Gaceta sanitaria / S.E.S.P.A.S, 23(3):192-197. http://www.citeulike.org/user/HEIRS/article/5919502
Soylemez, S., Sepici, A., and Akar, F. Resveratrol supplementation gender independently improves endothelial reactivity and suppresses superoxide production in healthy rats. Cardiovascular Drugs and Therapy. http://www.citeulike.org/user/HEIRS/article/5919555

Ultra-fine Particles, Particularly Harmful To Health, Can Now Be Traced

Ultra-fine Particles, Particularly Harmful To Health, Can Now Be Traced

ScienceDaily (2009-10-05) -- Limit values for fine dust emissions are based on total particle weight. It is the ultra-fine particles, however, that are particularly harmful to health. A new technique separates them by size and identifies their composition -- directly where they arise. ... > read full article

A single exposure to particulate or gaseous air pollution increases the risk of aconitine-induced cardiac arrhythmia in hypertensive rats

A single exposure to particulate or gaseous air pollution increases the risk of aconitine-induced cardiac arrhythmia in hypertensive rats

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