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.
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