Inflammation, Insulin Resistance and Decreased PPARs-- A Pathway to CFS?

I thought today I would review some points that I have made over the last several months about environmental illness specifically chronic fatigue syndrome. I do this today, because of recent research news that supports some of what I have been saying all along and that is that CFS is probably the result of stresses that alter cellular functioning and disrupt cellular metabolism. This is not a new thing but believe that many researchers  have failed to notice that many of the symptoms may be caused by alterations in glucose metabolism and insulin activity and include some influences like what occur in
sickness syndrome even though CFS and sickness syndrome are not the same thing. Sickness syndrome is a variety of changes that occur in the body as a response to sickness and provides a mechanism to fight whatever is causing the sickness. Personally, I can recognize it more in animals because humans have been taught that we "must" overcome --- and that goes for being ill too that usually leads to more sickness.

Michael Maes has probably been the leader in the idea of sickness syndrome in relation to CFS. In his last report, he definitely makes the distinction and I have to agree with him. CFS is not sickness syndrome and is more due to inflammation and oxidative and nitrosative stress and pathogenic conditions and permeability can be to blame. Again, I agree and am critical of some that try to base everything about CFS on oxidative stress because it does not really explain how one "gets there"! In my view, it all comes down to and the problem with labels and this always has been my issue..... IN this case, how can we understand where one illness like CFS starts and another one ends such as sickness syndrome if noone really has defined the former CFS well  in the first place?  It is my belief that sickness syndrome may be a prelude to CFS or maybe the beginning point of it, and different factors can inhibit or lead to a "full-blown" case of CFS and recognizing the biological factors that play a part may in fact, help to prevent CFS in its most severe form. As far as oxidative and nitrosative stress in CFS, I think if you just leave it at..then it is doing a disservice not only to the condition but to those who suffer from it. The reason I say this is because of the nature of oxidative/nitrosative stress --- it is a natural result of cellular processes. Just saying that CFS is caused from too much of these stresses does nothing to answer what is causing the overwhelming oxidative stress in the first place in CFS. Maes has implied that endotoxin may be a pathway to CFS and bacterial infection has potential for causing oxidative stress and changing environments and altered methylation. But the possibility that other environmental factors such as hyperglycemia and high-fat diets which promote bacterial translocation and consequently activate certain immune responses leadin to CFS also, can not be dismissed. I have suggested that the failure of the antioxidant system to adequately meet the needs of oxidative stress or maybe even at all to any real level may play a very important role.  In other blogs, we have noted that oxidative and nitrosative stress is needed to activate this system and nutritional and genetic factors may influence the speed and level of activation. So if we have overwhelming oxidative stress -- it makes sense that something like underactivation of the antioxidant system may be at fault or is just not working. So in essence, it should be a no-brainer to look at the Nrf2-Keap1 and other proteins it controls to get a better handle on what may be causing the failure of an adaptive immune response and elevations in inflammatory markers and oxidative stress that are obviously maladaptive.

Several new studies some evidence that a failure in the antioxidant system could contribute to CFS. It is not a direct road I admit, but considering I have been following these paths for 3 years now. They make sense to me, mainly because I look for the CFS from a more holistic and systems theory perspective. For someone that has been trained both in anthropology and biology, this perspective works better for me when I need to find out the answers to different questions that need to be investigated. In addition, one could ask what is a direct road or pathway in reference to disease anyway....to me, it is all relative and most always depends on personal interpretation.  Several months ago, I blogged that environmental pollutants may contribute to diabetes and insulin resistance. Since then several other reports conclude this may be the case and many studies have provided evidence how inflammation can lead to insulin resistance and diabetes through the down-regulation of genes and up-regulation of inflammatory cytokines. Several inflammatory markers, not just one, can contribute and can be produced as a consequence of the stress response including TNF-a, Il-1, Il-6. Some of these activate other responses that lead to neuroinflammation and also alteration of neurotransmitters and have other effects on brain chemistry which could be characteristic of the cognitive dysfunction associated with CFS.

It has been suspected that pollutants lead to the alteration of a class of class of genes. I refer to them most often as PARRs and may include PPAR-gamma, PARR-delta and PARR-alpha. I have discussed both PPAR-gamma and PPAR-alpha at length in different discussions and most notably, PPAR-gamma is an important anti-inflammatory which helps prevent the development of insulin resistance in addition to other functions and may help repress autoimmunity. (Klotz) Recently, a study of the combination of pioglitizone and caffeic acid, demonstrated significant improvement in a mouse model of chronic fatigue. In this study, the results showed improvements in running wheel activity, locomotor activity and anxiety. Other improvements included reductions in oxidative damage including  lipid peroxidation and nitrite concentration and increased glutatione and catalase levels in addition to altering mitochondrial function. When one digs a little deeper, interesting things appear related to the actions of these compounds. Caffeic acid is an antioxidant and anti-inflammatory that while having potential hazard qualities, also demonstrates the ability to " suppress MMP-9 enzyme activity and down-regulate NF-κB through inhibition of protein IKK and activation of Nrf2 (Lee) and other studies provide in vitro evidence it may effect DNA methylation.(Wipedia)" In contrast, pioglitizone is an anti-hyperglycemic medication and "stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α. Both of these compounds act through PARR-gamma directly or indirectly via Nrf which may explain why their benefits in the CFS model is synergistic compared to when they were used alone. (Kumar) Generally, PARRs modulates the transcription of the insulin-sensitive genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and the liver. (Wipedia)" What this says to me is that CFS very well could be considered a condition that is a consequence of significantly disrupted normal glucose uptake and cellular and energy metabolism and altered immune function in different tissues.

I have also postulated that the aryl hydrocarbon may play an important role in both CFS and MCS and there are several "conditions" that lead me to make this assumption and the hypothesis but unfortunately, how this interaction occurs is quite "muddy".  First,  it has been demonstrated that there is a close connection in the actions of the AhR and the Nrf2 in response to environmental pollutants and their "gene batteries".  Second, I have suggested that abnormal signalling from the AhR may influence the functioning of several proteins including the Nrf2 even though the specific mechanismin of how this is achieved is not entirely understood. Third, dioxin which persists in the environment, albeit at lower levels in the last decade in many locales but still present in food, has been associated with diabetes and activates the AhR. Four, for some time it has been believed the AhR may inhibit PPAR-gamma and therefore leads us to environmental conditions, at least physiologically, of elevated inflammation and an increased risk for diabetes. (Remillard)  Arguably, the role of the AhR on PPAR-gamma depends on the tissue. (Kitchner, Shin)  However, dioxins are bioaccumulative and activation of the AhR and its effects on PPAR-gamma may spill over to surrounding tissues.  Lastly, a new study has shown that Nrf2 drives PPAR-gamma in protecting against oxidant injury at least in the respiratory system. Taking all this into account, it is safe to at least suggest that CFS may be influenced by fluctuations in PPAR-gamma and the proteins that regulate it and factors that upregulate it may be beneficial or preventative against CFS. Because PPAR-gamma demonstrates inhibitory properties on autoimmune responses, its absence may play significantly in the "loss of tolerance" responses of chemical sensitivity and inflammatory bowel disease. Other studies show PPAR-gamma has as an important regulatory function with HO-1 and may be neuroprotective against Parkinson's (Lui, Schintu) and influences mitochondrial biogenesis through PGC-1a (Miglio). In other blogs, I discuss how certain nutritional compounds such as resveratrol and EGCG in different foods have shown some benefit and their modes of actions address some of the issues that are discussed in the paragraphs above.   IN addition, because these proteins can be effected by methylation this explains the inheritabilty factor that exists with CFS that is not explained just by the presence of oxidative stress.

Notes:

• Endotoxin is considered potential pathway to CFS and inhibits PPAR-gamma through Tnf-a (Zhou)
• It as been suggested that XMRV may play a role in CFS - I would suggest that while XMRV may be a piggy-back condition, any pathogen or infection or pollutant that inhibits PPARs and increase inflammatory mediators contribute to CFS.

Related Tags: Nrf2 , PPAR-gamma , PGC-1a,



Cho, H.-Y. Y., Gladwell, W., Wang, X., Chorley, B., Bell, D., Reddy, S. P., and Kleeberger, S. R. (2010). Nrf2-regulated ppargamma expression is critical to protection against acute lung injury in mice. American journal of respiratory and critical care medicine, 182(2):170-182. http://www.citeulike.org/user/HEIRS/article/6854883?show_msg=already_posted

Kumar, A., Vashist, A., and Kumar, P. (2010). Potential role of pioglitazone, caffeic acid and their combination against fatigue syndrome-induced behavioural, biochemical and mitochondrial alterations in mice. Inflammopharmacology. http://www.citeulike.org/user/HEIRS/article/7474822

Yang, J.-Y. Y., Della-Fera, M. A. A., Rayalam, S., Ambati, S., Hartzell, D. L., Park, H. J. J., and Baile, C. A. (2008). Enhanced inhibition of adipogenesis and induction of apoptosis in 3t3-l1 adipocytes with combinations of resveratrol and quercetin. Life sciences, 82(19-20):1032-1039. http://www.citeulike.org/user/HEIRS/article/7537205

Pioglitazone. Wipedia. Retrieved on July 24, 2010. http://en.wikipedia.org/wiki/Pioglitazone

Caffeic Acid. Wipedia. Retrieved on July 24, 2010. http://en.wikipedia.org/wiki/Caffeic_Acid

Zhou, M., Wu, R., Dong, W., Jacob, A., and Wang, P. (2008). Endotoxin downregulates peroxisome proliferator-activated receptor-gamma via the increase in tnf-alpha release. Am J Physiol Regul Integr Comp Physiol, 294(1):R84-92. http://www.citeulike.org/user/HEIRS/article/2439726

Remillard, R. B. and Bunce, N. J. (2002). Linking dioxins to diabetes: epidemiology and biologic plausibility. Environmental health perspectives, 110(9):853-858.  http://www.ncbi.nlm.nih.gov/pubmed/12204817

Kintscher, U. and Law, R. E. (2005). Ppargamma-mediated insulin sensitization: the importance of fat versus muscle. Am J Physiol Endocrinol Metab, 288(2):E287-291. http://www.citeulike.org/user/HEIRS/article/3824606

Shin, S., Wakabayashi, N., Misra, V., Biswal, S., Lee, G. H., Agoston, E. S., Yamamoto, M., and Kensler, T. W. (2007). Nrf2 modulates aryl hydrocarbon receptor signaling: Influence on adipogenesis. Mol. Cell. Biol., 27(20):7188-7197. http://www.citeulike.org/user/HEIRS/article/3787182

Klotz, L., Burgdorf, S., Dani, I., Saijo, K., Flossdorf, J., Hucke, S., Alferink, J., Novak, N., Beyer, M., Mayer, G., Langhans, B., Klockgether, T., Waisman, A., Eberl, G., Schultze, J., Famulok, M., Kolanus, W., Glass, C., Kurts, C., and Knolle, P. A. (2009). The nuclear receptor ppargamma selectively inhibits th17 differentiation in a t cell-intrinsic fashion and suppresses cns autoimmunity. J. Exp. Med., 206(10):2079-2089.  http://www.citeulike.org/user/HEIRS/article/5778777

Liu, S. H. H., Yang, C. N. N., Pan, H. C. C., Sung, Y. J. J., Liao, K. K. K., Chen, W. B. B., Lin, W. Z. Z., and Sheu, M. L. L. (2010). Il-13 downregulates ppar-gamma/heme oxygenase-1 via er stress-stimulated calpain activation: aggravation of activated microglia death. Cellular and molecular life sciences : CMLS. http://www.citeulike.org/user/HEIRS/article/6826740

Schintu, N., Frau, L., Ibba, M., Caboni, P., Garau, A., Carboni, E., and Carta, A. R. (2009). Ppar-gamma-mediated neuroprotection in a chronic mouse model of parkinson's disease. The European journal of neuroscience, 29(5):954-963. http://www.citeulike.org/user/HEIRS/article/4136907

Miglio, G., Rosa, A. C., Rattazzi, L., Collino, M., Lombardi, G., and Fantozzi, R. (2009). Ppargamma stimulation promotes mitochondrial biogenesis and prevents glucose deprivation-induced neuronal cell loss. Neurochemistry international, 55(7):496-504. http://www.citeulike.org/user/HEIRS/article/5345204

Lee, Y., Shin, D.-H. H., Kim, J.-H. H., Hong, S., Choi, D., Kim, Y.-J. J., Kwak, M.-K. K., and Jung, Y. (2010). Caffeic acid phenethyl ester-mediated nrf2 activation and ikappab kinase inhibition are involved in nfkappab inhibitory effect: Structural analysis for nfkappab inhibition. European journal of pharmacology, 643(1):21-28. http://www.citeulike.org/user/HEIRS/article/7394789

Infection/Endotoxin in Chronic Fatigue, Fibromyalgia and Multiple Chemical Sensitivity.

Definition: Endotoxin: a toxic component of bacteria not excreted by live bacteria but induces the inflammatory cascade and production of NO. (Endotoxin)

 An increasing number of scientific publications support the hypothesis that endotoxin infection and sickness syndrome may be important factors in environmental illnesses including fibromyalgia, chronic fatigue syndrome and quite possibly MCS. In fact, sickness syndrome would be a reasonable and holistic approach for explaining many of the behavioral, physical and emotional complications that are common in environmental illness. Sickness syndrome is described as the presence of a variety of symptoms including malaise, fatigue, sleep disturbances, appetite changes, brain inflammation, mood changes such as anxiety and depression and a host of other symptoms that occur as a reponse to injury or infection.  These responses occur both in humans and animals and some propose it is in part, adapative responses that are generated to alter the responses of the host and their social network. Over the past several years, there has been an significant amount of research on sickness syndrome. The occurence of which can be attributed to inflammatory cytokines that alter neurotransmission and genetic expression. There have been studies that show altered gene expression in environmental illnesses; the consequences of which can be quite severe and unexpected. Il-10 is an anti-inflammatory cytokine that has been shown to modulate the severity of sickness syndrome through interaction with HO-1. HO-1 is also a cytokine that is induced by activation of Nrf2, although there are other pathways that can induce this antioxidant. Recently, it has been demonstrated that the protective effect of an endogenous peptide thryotropin, against the damaging effect on the dopamine system from paraquat, is due to the chemicals ability to activate Nrf2 to reduce reactive species and increase the antioxidant glutathione. Other studies have demonstrated that thyrotropin is able to reverse hyperglycemia by increasing beta cell function and reducing programmed cell death. (Luo) Insulin resistance and diabetes are suspected to be important consequences of the sustained presence of inflammation and inflammatory cyokines that are characteristic of environmental illnesses.

A recent published study showed that there is brain disfunction in multiple chemical sensitivity (Orriols) and last week I suggested that some of the cognitive effects could be from an altered expression of BDNF. Of course, there are any number of factors such as malnutrition and inflammation that can influence cognitive function. Neurotransmitter regulate and can alter cognition and are modulated by factors that produce "sickness syndrome".  According to the author of the recent MCS study, SPECT scans showed alterations in the regions of the brain including the cingulus, striatum and the hippocampus in addition to others. Pekary et al explains that a common environmental toxin LPS has the potential to alter the expression of thyrotropin which may have an impact on LPS toxicity. The study showed elevations of cytokines and corticosterone after LPS with a transient drop in T3. Other results showed a decrease in thyrotropin-releasing hormone in certain areas of the brain while increasing it in others. Thyrotropin has been shown to improve recovery after neurological dysfunctions such as brain trauma and epilepsy in humans and animals and be neuroprotective against NMDA neurotoxicity. (Pizzi) These regions the author noted are areas that are associated with the neuroimmunomodulatory effects of sickness and injury and danger and appear to be similar to those effected in MCS SPECT scans. Also, a sustained elevation in TRH was present in b-cells accompanied by LPS-impaired insulin secretion. From these findings, the author concluded that thyrotropins can mediate and moderate the behavioral and toxic effects of LPS. In addition, LPS elevates inflammatory cytokines including Tnf-a, Il-6 and Il-1b and also increases expression of TLR receptors 2 and 4 and causes a prolonged sickness behavior in aged animals. Taking these findings into account and the fact that thryotropin mediate their positive effects through Nrf2, then one can assume that alterations in the antioxidant system may exacerbate the toxic effects generated by LPS endotoxin  It is also important to mention that Nrf2 levels drop as a consequence of the aging process(Godbout). This could lead one to propose that Nrf2 alterations from aging and other impairments and LPS may at least in part, mediate the effects in MCS. There has been evidence that hyperglycemia (which can be reversed with thyrotropin) sensitizes TRPV1 receptors which is implicated in MCS (Pall) and diabetes complications and TRPV1 may have direct or indirect effect on the release of neurotransmitters. (Pabbidi) Neuropeptides releases from capsaicin-sensitive efferents provide a protective mechanism against LPS but also increase bronchoconstriction which can increase airway hyperresponse. (Elekes) From these results and other studies, I have suggested that insulin resistance and hyperglycemia from chemical exposures may contribute to some of the inflammatory responses in MCS.

Endotoxin or LPS has been implicated as a possible pathway to the development of chronic fatigue syndrome. Above we noted that LPS increases the expression of toll-like receptors 2 and 4. Toll receptors recognize certain components on bacteria and transduces bacterial invasion through this recognition and has important relevance in preventing infection (Light) and expressed on a variety of cells including dendritic cells, B cells, neutraphils and macrophages. Defects in TLR expression can lead to an increase in susceptibility to infection from a number of pathogens while aberrant signaling of TLR such as from LPS are implicated in causing sepsis or even inflammatory or autoimmune-type conditions. (Harding) Activation of TLRs can lead to initiation of the the inflammatory pathway NF-kappaB and LPS endotoxins are ligand of TL4. Interestingly, saturated fats (bad fat) can induce inflammatory markers through TLR4 and therefore, saturated fats can alter gene expression through TLR4 interaction. For instance, the main component of coconut oil, lauric acid, has been demonstrated to potentiate the inflammatory effects of LPS COX-2. (Lee)  The just published Light study on chronic fatigue syndrome shows an increase in TLR4 after exercise and Light suggests this is due to "lesser fitness" in CFS patients. Light goes on to further explain that Il-10 is upregulated in CFS patients after exercise and one of its roles is to inhibit the production of Tnf-a which is also consistent with recent reports of an anti-inflammatory profile in FM. This and other studies of CFS revealed symptom flares may be related to cytokine activity postexercise. Notably, Tnf-a was elevated in muscle and Light explains that fatigue and muscle pain in CFS might be from the enhanced activation of "fatigue" and "nociceptive" afferents supplying muscle. Other supporting evidence of muscle involvement included elevations of ASIC3 channels that are often increased by muscle and joint inflammation. The elevation of Il-10 in the Light study was correlated to those patients with prolonged fatigue and pain but who also had elevations in pro-inflammatory cytokines and evidence of overall enhanced immune response. LPS has been shown to have a close relationship with sensory nerves and TLR4 receptors have been found on sensory nerves. The interaction between LPS and TLR4 may enhance the complications of TRPV1 activation. (Clark) In addition, Suter demonstrated that TLR2 and TLR4 are necessary for nerve-induced microglia activation and pain sensitization. (Suter)The presence of nociceptors on trigeminal nerves that suggests they recognize bacterial products and contribute to pain during infection. (Ball)

Citations and Original Document

Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

A study that was published last year suggested that MCP-1/CCL2/CCr2 and eotaxin may be good biomarkers for fibromyalgia and identify a genetic component to the condition. (Zhang) Since then, researchers have noted that both chronic fatigue syndrome and fibromyalgia may be classified as inflammatory conditions when the exact cause of symptoms is not known. Interestingly, MCP-1 can cause inflammatory responses and therefore has the potential of contributing to sickness behavior syndrome which is a condition that results in behaviors often associated with people that are ill. Sickness behavior does not seem exclusive of human beings because similar behaviors have been observed in other animals. Maes concludes that oxidative and nitrosative stress contribute to the development of chronic fatigue which result in an increase inflammation, NF-kappaB, COX2, iNOS and damage to lipids and proteins. He further explains that triggers include strenuous exercise, LPS from gram negative bacteria, viruses and pshycological or physical stress. A few of the symtoms associated with sickness syndrome include fatigue, malaise, appetite changes, anxiety, depression, weight changes, sleep alterations and numerous others. (Maes) Previous studies show it can be stimulated by a variety of conditions including IGF-1, Tnf-a and Il-1b the latter two are produced as part of the stress response and modulated by the Nrf2 system that also stimulates induction of antioxidants. (Dantzer) Nrf2 has been shown to modulate metabolic homeostasis in adipocytes and is now linked with obesity. Nrf2 is responsible for detoxification of electrophiles and xenobiotics and the function of it can be altered by any number of environmental factors including but not limited to metals, nutrition, and other protein interactions such as the AhR which also may play a very important role in chemical sensitivity.

The severity of sickness syndrome has been demonstrated to be determined on the prevalence of the anti-inflammatory immune complex IL-10. When it is present the duration of sickness syndrome is less and the effects like memory and learning impairment are also decreased. (Richwine) Il-10 has been shown to reduce the levels of IFN-gamma and Tnf-a- induced production of superoxide and nadph oxidase 1 (NOX1) which would suggest prevention of ROS generation from it. (Kamizota) Il-10 also stimulates the induction of HO-1 and therefore may activate the Nrf2 pathway but HO-1 can act independantly. Inhibition of HO-1 significantly reduces the protective effects of Il-10 on Tnf-a by LPS. Lee et al shows that this relationship also involves carbon monoxide, a gasoneurotransmitter, on the protective effects of Il-10. Therefore this further suggests a possible involvement of Nrf2 considering that Nrf2 modulates the effects of carbon monoxide. (Lee) De Wilde demonstrated that production of Il-10 is completely abolished with inhibition of HO-1.

Nrf2 is now associated with protective effects in adipocytes. Eotaxin is a chemokine that is elevated in obesity because adipose tissue seems to be the predominant source of it. It is also an important inhibitor of MCP-1 and is a common factor in allergic reactions. Its presence at the site of allergic inflammation suggests coordinated cellular responses of allergic inflammation where both MCP-1 and eotaxin are present. (Olgilvie) Tnf-a is overexpressed in obesity (Uysal) and associated with insulin resistance and inhibition of the expression of numerous genes including PPAR-gamma and adiponectin. It is also an important inducer for prolonging the half-life of eotaxin.

Summary:

• Maes has suggested that a pathway to chronic fatigue syndrome is by LPS endotoxin and therefore because the production of Il-10 modulates the severity of sickness syndrome through HO-1. We can suggest that the alteration in signaling of Nrf2 could ultimately lead to CFS and sickness syndrome.
• Nrf2 is conserved in different organisms, the homolog in C elegans is skn-1. (An)
• Nrf2 can be ethnically derived and therefore some populations may be more susceptible to some of the triggers and have an increased risk for chronic fatigue syndrome. (Marzec, Dinos)
• EGCG has been shown to have positive effects on chronic fatigue syndrome in a mouse model of CFS. Studies have shown that EGCG increases induction of HO-1 through Nrf2.
  

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Source Citations

Inflammatory Proteins and IL-10 in Obesity and Pathogenic Exposure: Implications for Sickness Syndrome and Fatigue!

Background: Sickness syndrome is a response to infection and inflammation and has been associated with production of Il-1b. Fatigue is a common symptom in environmental illness and may be a factor in sickness syndrome and recent studies provide evidence that activation of the Il-1 system may be a factor in causing the fatigue. Other studies demonstrate that Il-10 can modulate the severity of sickness syndrome through its interactions with HO-1 and other proteins such as BDNF.(Richwine) Richwine has also demonstrated that inflammatory processes increase in aged mice compared to adults. Meador has explained that IL-10 is associated with lower levels of inflammatory cytokines including Tnf-a, Il-1 and Il-6 in muscle and non-muscle.  The effects of aging on the expression of Il-10 would suggest alteration in SIRT1 or Nrf2/HO-1 and/or changes in expression of another gene that is effected by the aging process and high-fat diets.

New Research:
Title: Environmental and genetic factors influence the relationship between circulating Il-10 and obesity phenotypes.

Summary: "circulating IL-10 levels were associated not only with obesity status but also with genetic factors and with the exposure to environmental pathogens."

Citation: Bassols, J., Botas, P., Moreno-Navarrete, J. M., Delgado, E., Ortega, F., Ricart, W., and Fernandez-Real, J. M. (2009). Environmental and genetic factors influence the relationship between circulating il-10 and obesity phenotypes. Obesity (Silver Spring, Md.). http://www.citeulike.org/group/7167/article/5898650

Related Posts:

• Chronic Fatigue, Insulin Resistance, Il-10 and Sickness Syndrome
• CFS, Probiotics and Il-10
• Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

Additional References:
Richwine, A. F., Sparkman, N. L., Dilger, R. N., Buchanan, J. B., and Johnson, R. W. (2009). Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide. Brain, behavior, and immunity, 23(6):794-802. http://www.citeulike.org/user/HEIRS/article/4710107
Godbout, J. P., Chen, J., Abraham, J., Richwine, A. F., Berg, B. M., Kelley, K. W., and Johnson, R. W. (2005). Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. The FASEB Journal, 19. http://www.citeulike.org/user/HEIRS/article/4745254
Meador, B. M., Krzyszton, C. P., Johnson, R. W., and Huey, K. A. (2008). Effects of il-10 and age on il-6, il-1beta, and tnf-alpha responses in mouse skeletal and cardiac muscle to an acute inflammatory insult. Journal of applied physiology (Bethesda, Md. : 1985), 104(4):991-997. http://www.citeulike.org/user/HEIRS/article/5488212

How Changes in Neurons May Lead to Altered Cortisol in CFS/ME & Sickness Syndrome.

Background: Many research experts believe that endotoxin is a causal factor in the development of chronic fatigue syndrome. (Maes) In addition and as we have discussed on this blog, many of the symptoms may be attributed to sickness behavior or sickness syndrome. Generally, this is regarded as a reflection of immune responses that alter normal functions of hormones, neurotransmitters, etc. resulting in changes in behavior in humans and other animals.

We recently discussed how dysregulation of the hormone, ghrelin, may effect sickness behavior. A study just published provides more details about how another hormone may contribute to sickness syndrome and related alterations in behavior. According to the study, LPS endotoxin suppresses the neuronal circuitry in orexin and histamine neurons. As the abstract describes, the orexin neurons in the brain are important for behaviors including waking, feeding and reward-related behaviors and can be regulated by dopamine (Bubser), provide antinociceptive protection (Mobarakeh) and may reduce gastrointestinal injury through several mechanisms including injury from TLR signaling. In other blogs, we describe in detail how LPS from gram-negative bacteria and other environmental contaminants such as ozone can initiate inflammatory effects through TLR signaling and that genetic or environmental dysruption of the Nrf2 system will enhance the inflammatory effects.

Outside the brain, orexin neurons stimulate the production of cortisol in the adrenal glands and another studies shows orexin can time-dependantly raise cortisol levels as well as, influence steroidogenesis. Orexin studies have also revealed it regulates histamine release in the brain. Interestingly, narcolepsy which is suspected to be an autoimmune-related condition is associated with orexin deficiency. Aran proposes that streptococcus is an environmental trigger of narcolepsy. For this reason, the results of these studies in combination suggest that both gram-negative and gram-positive bacteria may contribute to sickness syndrome by altering orexin levels. In addition, orexin is a sexually-dimorphically expressed hormone which may help to explain the gender differences in the rates of environmental illness. (Johren)

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Sleepiness in CFS and Fibromyalgia May Be a Form of Narcolepsy!

In our recent blog discussed how orexin(hypocretin) effects sleep patterns and may have an important role in CFS and sickness syndrome. A new study using a pharmaceutical called sodium oxybate showed significant improvement in patients in fatigue with both chronic fatigue syndrome and fibromyalgia and point to the "real possibility" that sleep problems in these conditions are similar to narcolepsy. In addition, the study suggests, even though further study is warranted that both CFS and FM are similar or not the same condition because of the improvements seen in patients with them.  We have noted similarities to sickness syndrome in these conditions and have emphasized that sickness syndrome also occurs in animals and importantly, narcolepsy also is not exclusive to humans and in often seen in dogs. Some breeds more commonly than others.

Other recent discoveries indicate that the major pathophysiology of human narcolepsy "is the loss of lateral hypothalamic neurons that produce the neuropeptide hypocretin (orexin). Approximately 90% of people diagnosed as having narcolepsy with cataplexy are hypocretin ligand deficient." Narcolepsy is thought to be an autoimmune related disorder and can alter regulation of cortisol and influence steroid production which also may initiate panic.  In our recent blog, we wrote how streptococcus pneumoniae may be an important trigger of orexin-influenced narcoleptic sleep behavior. This is important because this pathogen effects the severity of H1N1 and may mean that patients with EI may be more susceptible to both. Parkinsonism is also associated with alterations in hypocretin and future therapies in PD may involve treatments involving orexin. Some suggest that narcolepsy and Parkinson's disease have a common and therefore, one must begin to hypothesize that CFS and fibromyalgia may have the same or similar causal factors as PD and and narcolepsy.

For Further Reading About Orexins in CFS, Sickness Syndrome and Fibromyalgia, see

• How Changes in Neurons May Lead to Altered Cortisol in CFS/ME & Sickness Syndrome. HEIRS, January 1, 2010.
• Hormone Linked to Panic Attacks Also Linked to Endotoxin and Sickness Behavior

Spitzer, A. R. and Broadman, M. (2010). Treatment of the narcoleptiform sleep disorder in chronic fatigue syndrome and fibromyalgia with sodium oxybate. Pain Practice, 10(1):54-59. http://www.citeulike.org/user/HEIRS/article/6512085
Zeitzera, J. M., Nishinob, S., and Mignotc, E. (2006). The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends in Pharmacological Sciences, (27):368-374. http://www.citeulike.org/user/HEIRS/article/6512089
Thannickal, T. C., Lai, Y.-Y., and Siegel, J. M. (2007). Hypocretin (orexin) loss in parkinson's disease. Medscape Today. http://www.citeulike.org/user/HEIRS/article/6512132

Immunosuppression in Environmental Illness By High Fat and Cytokines: Ameliorated By Green Tea Compound!?

A number of researchers now believe endotoxin from bacterial contaminants may be a pathway that leads to the development of chronic fatigue syndrome. In addition it has been determined that high-fat diets exacerbate inflammatory conditions by altering the TLR signaling pathway which contributes to the loss of suppression of inflammatory responses by regulatory T cells (tregs) after endotoxin injury. Many experts believe this loss of tolerance may play an important role in MCS which is a condition that exhibits symptoms that often appear autoimmune in nature. In the lungs, TLR signaling and other proteins induced by endotoxin lead to the increased expression of inflammatory mediators including IL-6 which suppress Treg expression resulting in loss of tolerance in the airway and increase inflammation. Incidentally, a very small amount of endotoxin can lower the threshold of immune reactions in some people and since humans do not live in sterile environments, we are consistantly exposed to endogenous and exogenous bacteria (and endotoxin) in the air we breath, the food we eat, the things we touch, etc.

EGCG, the compound in green tea, has been shown to provide relief in animal models of chronic fatigue syndrome and several studies show it may have several modes of action. Currently Tufts University is performing an in-depth analysis of EGCG and the preliminary results show EGCG has the capacity to regulate different subsets of T cells including those responsible for playing a role in the development of autoimmune-type disease such as tregs. In support of these preliminary findings, a few years ago, Yoneyama demonstrated EGCG can regulate IL-10 and does have substantial immunosuppressive properties.

Over the past few months I have written how humans and animals demonstrate sickness behavior and the related behavioral changes are consistent with many of the symptoms in CFS and may include fatigue, malaise, mood changes, decreased appetite, etc. Also, the severity of sickness syndrome is dependant on the production or absence of Il-10 which is necessary for Treg production. One inflammatory cytokine produced by endotoxin is Il-6 which has the ability to suppress Treg expression and is most often responsible for sickness syndrome behavior and the polyphenols in green tea inhibit the expression of it. Considering all of this, it makes sense the loss of Treg through abherrant signaling is a causal factor in the loss of tolerance and MCS, sickness syndrome and chronic fatigue syndrome. Lastly, Nrf2 along may influence and regulate Treg expression through HO-1 and Il-10.

CiteULike: A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury.: "Ma, X., Hua, J., Mohamood, A. R., Hamad, A. R. R., Ravi, R., and Li, Z. (2007). A high-fat diet and regulatory t cells influence susceptibility to endotoxin-induced liver injury. Hepatology (Baltimore, Md.), 46(5):1519-1529." http://www.citeulike.org/user/HEIRS/article/6496762
Duan, W., So, T., and Croft, M. (2008). Antagonism of airway tolerance by endotoxin/lipopolysaccharide through promoting ox40l and suppressing antigen-specific foxp3+ t regulatory cells. J Immunol, 181(12):8650-8659.
http://www.citeulike.org/user/HEIRS/article/3752381?show_msg=already_posted
Wu, D. Green tea egcg and t cell function in autoimmune inflammation.
http://www.citeulike.org/user/HEIRS/article/6496862
Yoneyama, S., Kawai, K., Tsuno, N., Okaji, Y., Asakage, M., Tsuchiya, T., Yamada, J., Sunami, E., Osada, T., and Kitayama, J. (2008). Epigallocatechin gallate affects human dendritic cell differentiation and maturation. Journal of Allergy and Clinical Immunology, 121(1):209-214. http://www.citeulike.org/user/HEIRS/article/6496680
Singal, A., Tirkey, N., Pilkhwal, S., and Chopra, K. (2006). Green tea (camellia sinensis) extract ameliorates endotoxin induced sickness behavior and liver damage in rats. Phytotherapy Research, 20(2):125-129.
http://www.citeulike.org/user/HEIRS/article/6496875

T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.

Over the past several months there has been a number of studies that shed light on the activities of a subset of immune cells called regulatory T-cells. Interestingly, these new findings may result in answering some important questions related to multiple chemical sensitivity which is a condition where patients become sensitive to agents normally found in the environment and these agents can be "natural" or manmade. Every MCS patient is different but their symptoms may include nausea, vertigo, brain fog, light sensitivity and others. Generally, reactions occur when MCS patients are exposed to concentrations of noxious stimulants, chemical agents or irritants that would not normally elicit a reaction in those without MCS. While there are many theories out there about what causes MCS, so far there are few that actually come close to understanding MCS and other facets of environmental illness. Unfortunately, many health experts are critical about the existence of MCS and try to classify it as a "psychomatic condition" while others are more open-minded and have begun to rally and now treat multiple chemical sensitivity as a "real" medical condition.

One MCS theory that is gaining in popularity and research support is that MCS is a condition that may be caused from a loss of tolerance and is similar in nature to inflammatory diseases that are commonly classified as autoimmune diseases. In this realm, there is no doubt that MCS could fit and recent studies provide more evidence that this could be the case. As we have noted all along several biological sub-systems, for lack of a better word, may play a part in the development of MCS and this kind of loss of tolerance or loss of homeostasis. The most recent findings support our belief that the development of MCS can be dependant on the dysregulation of Nrf2 which regulates a number of antioxidant proteins including HO-1 and NRF1 which is important for mitochondrial biogenesis. Over the past two years, we have discussed the function of this antioxidant system in modulating inflammatory cytokines. Also, important findings of vitamin D show it may be an important regulator and for MCS, it may be an important as a MCS therapy. Mainly because vitamin D can regulate regulatory Tcells and reduce autoimmune Th1 responses in association with Il-10. In the past several years a number of studies have shown that members in general population are deficient in vitamin D and supplementation of vitamin D reduces the incidence of several autoimmune conditions including MS, rheumatoid arthritis and inflammatory bowel disease. Deficiencies in vitamin D also is associated with metabolic sydrome and "itch". The latter being a common symptom in a number of autoimmune conditions as well as, multiple chemical sensitivity.

Late last year an interesting study was published that provides a little more insight on how regulatory T-cells (Tregs) may influence MCS and other environmental diseases including cancer. As the author notes in the abstract, air pollution is an important contributor to the development of environmental disease including asthma, allergy and multiple chemical sensitivity. Often the former two are co-morbid in MCS patients but not always and as Micovic explains, the assault by environmental insults including VOC results in an "abnormal immune response of lymphocytic subsets." Normally, the body is able to decipher the good and bad stimuli and develop a tolerance to those that are less noxious. Recent research findings support this process is achieved through the activities of Tregs and so is the "loss of tolerance". Interestingly, this researcher found in his experiments that normal chronic exposure to an air pollutant, increases the percentage of Il-10-dependant Tregs. On the other hand, a loss of tolerance may mean a reduction of Tregs or one of its associated proteins. In scientific studies, the destruction of Treg populations cause mice to spontaneously develop a "spectrum of autoimmune disease" (Micovic) and others displayed anaphylactic-type responses. Park clarifies how production of CD4+CD25 by Il-10 production provides a protective role against lung hypersensitivity, again, to chronic exposure to environmental antigens. Activation of nociceptors has also been implicated as a factor in MCS. (Pall) It was recently demonstrated that in a mouse model of autoimmune encephalitis, TRPV1 signaling is important in modulation of IL-10 and inhibition of TNF-a and Il-1b and subsequent increases of IL-17. (Tsuji) This explains why the TRPV1 receptor has become the focus in the development of therapeutic approaches to diabetes.

Cong describes in his paper that Tregs are believed to be "central to the prevention of autoimmune and inflammatory disorders and there are many types of these regulatory immune cells that exist including CD4+CD25+, Tr1, Tr3 and vitamin D-dexamethasone induced Il-10. Notably, we are talking about only a very small number of T cells in relation to the total number of immune cells. Therefore, unless highly specialized equipment and lab techniques are used an adequate representation of this kind of CD profile is virtually non-existent or available to the typical clinical physician. If you have read some of our blogs in the past, we discuss IL-10 quite extensively in relation to Il-10 as a modulator of the severity of sickness syndrome. Sickness syndrome is marked by a variety of symptoms including changes in appetite, mood, fatigue levels, neurotransmitters, etc that ultimately result in obvious behavioral changes and usually is considered a part of "sickness" and accompanies increases in cytokine production including Il-1 and Il-6. Sickness syndrome is not exclusive of humans and has been observed in animals. In addition, Il-10 has been shown to regulate Il-17 which is a cytokine normally associated with autoimmune-type disease and deficiencies in IL-10 correlate well to increases in fatigue and other sickness type behaviors which are characteristic of many environmental illnesses. One study shows that infection-induced inflammatory mediators including NO and TNF-a by GSK-3b, which is the off-switch for Nrf2, is achieved by inhibiting Il-10. Parkinson's diseases is considered an environmental illness and alteractions in the expression of the antioxidant HO-1 and GSK-3b increases the risk for its development. (Infante)

It is now recognized that Tregs interact with one another and in a study of asthma, the loss of IL-10 fails to "induce tolerance". Also, George demonstrates that suppression of autoimmune-type inflammatory conditions by Treg CD4+CD25+ is dependant on HO-1 often regulated through Nrf2. Rockwell recently discovered that the inflammatory cytokines Il-17 and IFN-gamma in systemic lupus, an autoimmune disease, are regulated by Nrf2 in CD4+ cells. It also regulates IFN-gamma in Th1 cells. Taking this information into account, this supports the HEIRS hypothesis that the dysfunction of the Nrf2 pathway either because of genetics or other environmental factors such as malnutrition may be critical to the development of MCS, in addition to, other environmental diseases.

Recent studies have also determined that age and mental stress can decrease the levels of Tregs and therefore, this may explain why mental stress exacerbates MCS and other environmentally-induced and autoimmune diseases. (Freier) One author suggests that in the gut, Tregs work commensally with gut bacteria to prevent intestinal inflammation and reduces expression of Il-17 implicated in carcinogensis and disregulation of this system may increase the incidence of colon cancer and may play a role in other cancers as well. (Erdman) We have suggested that the aryl hydrocarbon may contribute to symptoms of MCS and indeed, some some ligands and not others interfere with Treg expression and increase Il-17. (Quintana) To make matters more complex, the presence or absence of TLR signaling (which we have discussed exhaustively in the past) in a Il-10 -/- environment may increase the likelihood of the loss of suppression of autoimmune-type complications and lead to a "loss of tolerance" with "inocuos" pathogens such as bacteria that normally reside in the ihuman tissue such as the human gut. (Gonzales-Navajas) Notably, the relationship of Tregs, Il-10 and other factors such as GSK-3b provide an explanation of why Nrf2 activators (EGCG), vitamin D, probiotics that modulate intestinal immunity have demonstrated they reduce or alter response of inflammation, oxidative stress, and aid in the reduction of symptoms to noxious agents and have been shown to reduce the incidence of diseases including cancer and boost innate immunity. Drops in Tregs have been observed in patients with CFS (although studies conflict) and others show an abnormal immune phenotype and production of inflammatory cytokines associated with the illness is consistent with our premise that symptoms in CFS may be caused by sickness syndrome. Consequently, alterations of I-10 dependant tregs provides a mechanism for the increase risk for cancer in environmental illnesses such as CFS. It is worth mentioning that when dysregulation of the Nrf2 pathway occurs any number of aberrations in profiles may appear because the pathway controls so many different efflux proteins, transporters and enzymes. Of course, the initial trigger of illness and a patient's genetics may also lead to differences in lab profiles and explain why such a wide range of stimuli including endotoxin, perfumes, odors, oils, foods, terpenes, etc may initiate a response in MCS patients.




For original document and citations.


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Chronic Fatigue, Insulin Resistance, Il-10 and Sickness Syndrome

Definition:

• Bioaccumulation: refers to the accumulation of substances, such as pesticides, or other organic chemicals in an organism. (Wipedia)

Background: Several months ago we discussed an article the describes the results of a study that revealed a link between accumulation of chemicals and diabetes. That study also noted the relationship was correlated to a higher incidence of obesity. In addition, we have recently described that Nrf2 plays a homeostatic role in adipocytes it now appears Nrf2 plays a modulatory role in adipogenesis and when the Nrf2 activity is impaired there is a greater risk for obesity. We have also discussed at length that chemicals bioaccumulate in fat tissue where they produce inflammatory mediators and decrease regulatory and anti-inflammatory proteins such as PPAR-gamma (which when overregulated can contribute to obesity) and adiponectin and it is assumed now this is also true because high-fat diets may impair Nrf2 which influences the control of inflammatory responses mediators such as Tnf-a and MCP-1/CCL2/CCR2, may prevent or delay activation of the antioxidant system. Nrf2 also is responsible for gene expression for proteins important for mitochondrial respiration such as NRF1 and PPAR-a. The latter being a regulatory factor that cooperates with PGC-1a during mitochondrial biogenesis. Insulin resistance also impairs mitochondrial function and is quite a common characteristic that leads to diabetes and obesity.

Other important things we have noted recently are:

• 
  Sickness syndrome includes a number of behavioral symptoms including fatigue, malaise, increased sensitivity to pain, loss of appetite, anxiety, depression and numerous other symptoms. A recent study has demonstrated that the severity of sickness syndrome depends on the presence or absence of IL-10. If it is present the shorter and less severe the symptoms and if it is absent the patient will experience more severe pathology. In addition, we also noted that MCP-1 is activated by Tnf-a and IL-6 in peripheral tissue to caused neurotransmission in the brain that can incite the inflammatory cascade.
• We also noted that Il-10 is regulated by HO-1 which also is regulated by Nrf2. If the Nrf2 pathway is impaired or inhibited in adipocytes, there is greater opportunity for an elevated inflammatory response in those tissues and the body would have a reduced ability to detoxify an "bioaccumulating" agent that it might be exposed to such as pesticides and other environmental contaminants.
• We have also noted the Nrf2 system can be impaired by exposures to metals, aging factors, other genetic factors, hyperglycemia which is now considered a consequence of environmental or endogenous exposures (H2S).
• 
  
  The Nrf2 regulates and is regulated by the aryl hydrocarbon that mediates the detoxification of PAHs and HAHS including dioxin and ingredients in agricultural products. The toxicity of dioxin is mediated through the AhR and is abnormal function may have an extremely important role in toxicity of endotoxin which Maes describes as a pathway to the development of CFS.

A new study has revealed more important details about Il-10 that sheds more light on the symptoms associated with sickness behavior and chronic fatigue syndrome. This new study demonstrates that Il-10 is important for maintaining insulin sensitivity by protecting muscles from obesity-associated macrophage infiltration of inflammatory cytokines and diet-induced inflammatory responses. In the study, it was shown these cytokines include Tnf-a, Il-6, and CCR2. These are markers important in findings related to CFS and fibromyalgia and other environmental illnesses and develop (You can read about MCP-1 here) as part of the stress response from toxicant insults. This study indicates not only that IL-10 may be used as therapy for diabetes but one can suggest future therapies may also target environment illnesses that have presentations of fatigue, muscular pain and sensitivity. A past study demonstrated that Il-10 prevented alterations in Il-6 hepatic insulin action, signaling, and also Il-6 and lipid-induced insulin signaling in skeletal muscle and therefore support the findings from the study noted above. (Kim) Both studies provides evidence of an important role of Nrf2 in regulating metabolic homeostasis by regulating HO-1/IL-10 and demonstrates how its impairment or inhibition can lead to environmental illness.

Ghrelin: A Stomach Hormone Impacts Mood, Behavior, Sickness and Parkinson's Disease.

Background: In our last blog, we discussed the relationship of environmental toxicants on TLR receptor activation and reviewed how LPS endotoxin is a ligand for the TLR4 receptor. In addition, we mentioned how endotoxin and TLR plays a role in immune related disorders including RA and neurodegenerative disease and that it is also implicated as a causal factor in a number of environmental diseases including chronic fatigue syndrome. Generally, TLR signaling may contribute to a number of  conditions considered environmental diseases through the interaction and modulation of inflammatory cytokines. Lastly, in the past we noted that oxidation of phospholipids occurs at the site of inflammation and provides a small level of protection against TLR signaling but not against against Il-1 and Tnf-a. The level of TLR protection is dependant on the balance between the types of involved phospholipids. Smoking and ozone increase one type, PGCP that prevents the protection by Nrf2 against this type of stress.

A recent study has provided evidence that a stomach hormone called ghrelin may prevent or slow the onset of Parkinson's disease. As we noted above, TLR signaling has been implicated in the development of the condition and this study helps to provide insight in to a possible as to why. As Wipedia explains, ghrelin is a hormone that is produced in the stomach and the pancreas to produce the feeling of hunger. It also is produced in the part of the brain called the hypothalamus and stimulates secretion of growth hormone in the pituitary gland. Importantly, it is a hormone needed for learning and cognitive functioning necessary for adaptive behaviors and stimulates the endothelial form of nitric oxide. Ghrelin levels fluctuate during a 24-hour period and consequently this hormone has important implications in alterations of sleep duration, stress-induced depression, obesity and anorexia nervosa. Researchers are also focusing their attention on how alterations of ghrelin production may influence the development of addictive behaviors.

In 2006, Wang demonstrated that LPS endotoxin can inhibit the production of ghrelin and that exogenous application of ghrelin may normalize endotoxic-induced digestive dysfunction. There are findings of different studies that show that LPS endotoxin can raise or lower this hormones secretion and it is highly likely, other immune interactions, individual circumstances and genetics may impact this. In any event, the increase or decrease of ghrelin levels has important health consequences.   Wang's findings have important applications for environmental illness practioners considering that intestinal disease are often co-morbid with environmentally-induced conditions. Parkinson's disease is considered an environmental illness because it is exacerbated or believe to be caused by environmental factors. No doubt genetic factors play a part but there is mounting evidence that environmental toxicants may influence genetic disposition for the development of the disease. Understanding the relationship of ghrelin to Parkinson's disease (PD) is dependant on understanding that lower actions of ghrelin in the brain are associated with an increase in the loss of dopamine and lower dopamine levels in the brain are consistent with the etiology of PD. The author of this recent study remarks that further study will be needed to determine whether ghrelin can be used as a biomarker for PD or at least help to identify an increase in vulnerability. In any case, considering that LPS endotoxin may inhibit the production of ghrelin, normalizing ghrelin levels systemically may have the potential to have a positive impact on diseases where low/altered dopamine levels play a role such as PD and ADHD.

Dr. Lutter of UT Southwestern points out that "regulated" control of the production of this hormone is important for regulating behavior and mood and therefore, alterations in ghrelin may influence that condition of sickness syndrome. Lutter's findings show that ghrelin regulates mood, stress and energy levels and while blocking ghrelin production may provide a mechanism for weight control it can also increase feelings of depression and anxiety. In his experiments he found that ghrelin increases during stress and elevations can last for weeks after the stress event ends and animals which did not respond normally to ghrelin exhibited more depressive or anxious behaviors. The above findings may help to identify at least some of the causes of behavioral changes in this PD and other environmentally-induced illnesses. Another experiment demonstrated that endotoxemia in dogs resulted in an increase in leptin and ghrelin which correlated to an increase in NO, inflammatory mediators, cortisol and injury markers. Interestingly,  ghrelin increases occurred in cachetic mice with cancer with symptoms of changes of metabolism so the increase or decrease in ghrelin production may be dependant on production of cytokines such as TNF-a. Other studies show it attenuates other cytokine-induced anorexia and therefore, chnages in ghrelin production/secretion should be considered a factor in behavioral appetite changes associated with sickness and wasting syndrome (Hataya). Evidence shows that exogenous ghrelin inhibits Il-1 and TNF-a while augmenting the synthesis of Il-10 in endotoxin-stimulated immune cells. Waseem explains this modulatory action of ghrelin warrants further investigation. As we have explained in other blogs, Il-10 modulates sickness syndrome through HO-1 and therefore ghrelin has potential to indirectly modulate antioxidant mechanisms.

Because ghrelin has important roles in a number of animal behaviors, future research findings may provide important  insight and provide natural and pharmacological treatments for a number of diseases where ghrelin production is a factor.

The Balance Within: The Science Connecting Health and Emotions















The Psychoneuroimmunology of Chronic Disease: Exploring the Links Between Inflammation, Stress, and Illness












View original document and citations.

Chronic Fatigue, Insulin Resistance, Il-10 and Sickness Syndrome

Definition:

• 
  Bioaccumulation: refers to the accumulation of substances, such as pesticides, or other organic chemicals in an organism. (Wipedia)
  

Background: Several months ago we discussed an article the describes the results of a study that revealed a link between accumulation of chemicals and diabetes. That study also noted the relationship was correlated to a higher incidence of obesity. In addition, we have recently described that Nrf2 plays a homeostatic role in adipocytes it now appears Nrf2 plays a modulatory role in adipogenesis and when the Nrf2 activity is impaired there is a greater risk for obesity. We have also discussed at length that chemicals bioaccumulate in fat tissue where they produce inflammatory mediators and decrease regulatory and anti-inflammatory proteins such as PPAR-gamma and adiponectin. It seems also the consequences of high-fat diets may impair Nrf2 which influences the control of inflammatory responses mediators such as Tnf-a and MCP-1/CCL2/CCR2, may prevent or delay activation of the antioxidant system. Nrf2 also is responsible for gene expression for proteins important for mitochondrial respiration such as NRF1 and PPAR-a. The latter being a regulatory factor that cooperates with PGC-1a during mitochondrial biogenesis. Insulin resistance also impairs mitochondrial function and is quite a common characteristic that leads to diabetes and obesity.

Other important things we have noted recently are:

• Sickness syndrome includes a number of behavioral symptoms including fatigue, malaise, increased sensitivity to pain, loss of appetite, anxiety, depression and numerous other symptoms. A recent study has demonstrated that the severity of sickness syndrome depends on the presence or absence of IL-10. If it is present the shorter and less severe the symptoms and if it is absent the patient will experience more severe pathology. In addition, we also noted that MCP-1 is activated by Tnf-a and IL-6 in peripheral tissue to caused neurotransmission in the brain that can incite the inflammatory cascade.
• We also noted that Il-10 is regulated by HO-1 which also is regulated by Nrf2. If the Nrf2 pathway is impaired or inhibited in adipocytes, there is greater opportunity for an elevated inflammatory response in those tissues and the body would have a reduced ability to detoxify an "bioaccumulating" agent that it might be exposed to such as pesticides and other environmental contaminants.
• We have also noted the Nrf2 system can be impaired by exposures to metals, aging factors, other genetic factors, hyperglycemia which is now considered a consequence of environmental exposures (H2S).
• The Nrf2 regulates and is regulated by the aryl hydrocarbon that mediates the detoxification of PAHs and HAHS including dioxin and ingredients in agricultural products. The toxicity of dioxin is mediated through the AhR and is abnormal function may have an extremely important role in toxicity of endotoxin which Maes describes as a pathway to the development of CFS.
• As animals with Nrf2 impairments age they develop an autoimmune type syndrome that makes them less able to handle toxins and more susceptible to certain diseases which most often leads to shorter lifespans.

A new study has revealed more important details about Il-10 that sheds more light on the symptoms associated with sickness behavior and chronic fatigue syndrome. This new study demonstrates that Il-10 is important for maintaining insulin sensitivity by protecting muscles from obesity-associated macrophage infiltration of inflammatory cytokines and diet-induced inflammatory responses. In the study, it was shown these cytokines include Tnf-a, Il-6, and CCR2. These are markers important in findings related to CFS and fibromyalgia and other environmental illnesses and develop (You can read about MCP-1 here) as part of the stress response from toxicant insults. This study indicates not only that IL-10 may be used as therapy for diabetes but one can suggest future therapies may also target environment illnesses that have presentations of fatigue, muscular pain and sensitivity. A past study demonstrated that Il-10 prevented alterations in Il-6 hepatic insulin action, signaling, and also Il-6 and lipid-induced insulin signaling in skeletal muscle and therefore support the findings from the study noted above. (Kim) Both studies provides evidence of an important role of Nrf2 in regulating metabolic homeostasis by regulating HO-1/IL-10 and demonstrates how its impairment or inhibition can lead to environmental illness.



Bock, K. and Kohle, C. (2006). Ah receptor: Dioxin-mediated toxic responses as hints to deregulated physiologic functions. Biochemical Pharmacology, 72(4):393-404. http://www.citeulike.org/user/HEIRS/article/4664272
Zhou, M., Maitra, S. R., and Wang, P. (2008). The potential role of transcription factor aryl hydrocarbon receptor in downregulation of hepatic cytochrome p-450 during sepsis. International journal of molecular medicine, 21(4):423-428. http://www.citeulike.org/user/HEIRS/article/4122627
Hong, E.-G. G., Ko, H. J. J., Cho, Y.-R. R., Kim, H.-J. J., Ma, Z., Yu, T. Y., Friedline, R. H., Kurt-Jones, E., Finberg, R., Fischer, M. A., Granger, E. L., Norbury, C. C., Hauschka, S. D., Philbrick, W. M., Lee, C.-G. G., Elias, J. A., and Kim, J. K. (2009). Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle. Diabetes. http://www.citeulike.org/user/HEIRS/article/5711648
Kim, H.-J. J., Higashimori, T., Park, S.-Y. Y., Choi, H., Dong, J., Kim, Y.-J. J., Noh, H.-L. L., Cho, Y.-R. R., Cline, G., Kim, Y.-B. B., and Kim, J. K. (2004). Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes, 53(4):1060-1067. http://www.citeulike.org/user/HEIRS/article/2679201
Beyer, T. A., Xu, W., Teupser, D., Keller, U. A. D., Bugnon, P., Hildt, E., Thiery, J., Kan, Y. W., and Werner, S. (2007). Impaired liver regeneration in nrf2 knockout mice: role of ros-mediated insulin/igf-1 resistance. European Molecular Biology Organization. http://www.citeulike.org/user/HEIRS/article/5711724

Scientists Identify Potential New Method For Treating Sleeping Sickness

Very interesting......

Scientists Identify Potential New Method For Treating Sleeping Sickness: "Scientists Identify Potential New Method For Treating Sleeping Sickness"

Attenuation of the influenza virus sickness behavior in mice deficient in toll-like receptor 3. Brain, behavior, and immunity.

"Certain sickness behaviors occur consistently in influenza-infected humans and mice. These include body temperature changes, somnolence, and anorexia..... Therefore virus-associated dsRNA detected by TLR3 appears to play a substantial role in mediating several aspects of the influenza syndrome in mice."

Majde, J. A., Kapás, L., Bohnet, S. G., De, A., and Krueger, J. M. (2009). Attenuation of the influenza virus sickness behavior in mice deficient in toll-like receptor 3. Brain, behavior, and immunity. http://www.citeulike.org/user/HEIRS/article/6048823

CiteULike: Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia

CiteULike: Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia: "Henry, C., Huang, Y., Wynne, A., Hanke, M., Himler, J., Bailey, M., Sheridan, J., and Godbout, J. (2008). Minocycline attenuates lipopolysaccharide (lps)-induced neuroinflammation, sickness behavior, and anhedonia. Journal of Neuroinflammation, 5(1):15+."

CiteULike: Latitudinal variation of immune defense and sickness behavior in the white-crowned sparrow (Zonotrichia leucophrys).

CiteULike: Latitudinal variation of immune defense and sickness behavior in the white-crowned sparrow (Zonotrichia leucophrys).: "Owen-Ashley, N. T., Hasselquist, D., Råberg, L., and Wingfield, J. C. (2008). Latitudinal variation of immune defense and sickness behavior in the white-crowned sparrow (zonotrichia leucophrys). Brain, behavior, and immunity, 22(4):614-625."

Hormone Linked to Panic Attacks Also Linked to Endotoxin and Sickness Behavior

CiteULike: Lipopolysaccharide challenge-induced suppression of Fos in hypothalamic orexin neurons: their potential role in sickness behavior.: "Gaykema, R. P. and Goehler, L. E. (2009). Lipopolysaccharide challenge-induced suppression of fos in hypothalamic orexin neurons: their potential role in sickness behavior. Brain, behavior, and immunity, 23(7):926-930."

Runaway vigilance hormone linked to panic attacks. National Institute of Mental Health. http://www.citeulike.org/user/HEIRS/article/6463151

Sickness behaviour pushed too far - the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma

CiteULike: Sickness behaviour pushed too far - the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma: "Clark, I., Budd, A., and Alleva, L. (2008). Sickness behaviour pushed too far - the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma. Malaria Journal, 7(1):208+."

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
Gold, A. R., Dipalo, F., Gold, M. S., and Broderick, J. (2004). Inspiratory airflow dynamics during sleep in women with fibromyalgia. Sleep, 27(3):459-466. http://www.citeulike.org/user/HEIRS/article/7756324
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