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

Elevated Ammonia and Endotoxin: Implications for Synergistic Toxicity in Environmental Illness

Background: I happened on an article this morning that no doubt has important health implications, at least for I and others with impairments of detoxification are concerned. I doubt it evoked much interest by the "Powers That Be" that study this stuff everyday but none-the-less, it seems important for me, not to dismiss it so readily. What I write here are my own thoughts and I by no means am or claim to be, an expert on autism and autistic behavior.

As you may recall, we recently discussed the similiarities of autism and other environmental illnesses including ADHD and multiple chemical sensitivity. Previous studies have shown that certain exposures may inhibit metabolic pathways such the one for production of methionine synthase important for DNA synthesis and repair and may increase concentrations of homocysteine, a potentially toxic byproduct of methionine metabolism. To demonstrate, the inhibition of this pathway by nitrous oxide causes lasting impairment in spatial working memory in aged rats via mitochondrial swelling and subsequent neuronal death.(Culley) In line with this thinking,severa; studies provide evidence that inhibiting or the presense of impairments in pathways such as the one for methionine synthase or others may contribute to a number of mental and physical health conditions including environmental illnesses such as mood disorders, Alzheimer's, autism and MCS.

In the past, I have noted several "remedies" including B12, Q10 and tetrahydrobiopterin recommended for chemical sensitivity which are also commonly used therapies for autism. Curiously, methylhydrofolate is a precursor of BH4 and often prescribed to reduce ammonia levels produced as a side-effect from different supplement treatments and also ammonia produced from gut-derived exogenous bacteria. In addition to hyperammonemia, excess ammonia may lead to elevations in production of nitric oxide synthase and enhanced nitric oxide, free radicals and oxidative stress.

Jalan and Bernuau propose that endotoxin may increase the severity of complications associated with hyperammonemia which of course may have important safety implications for a number of occupational and residential settings including farms and agricultural areas. In this article the authors explain, the "ammonia is detoxified by astrocyctes in the brain". Notably, the deficiency of protective pathways which protect astocytes such as Nrf2 should be an important concern. Jalan further explains that "during hyperammonemia, astrocytes swell from the effect of glutamine. In addition, recent studies show these cells are more swollen in animals exposed to endotoxin and interestingly, the swelling of the atrocytes occur in an environment of an intact blood brain barrier which indicates a functional abnormality. It is assumed that astrocytes are critical managers of blood flow and it may be that during hyperammonemia the astrocytes are sensitized to a "second hit" by LPS endotoxin. The author also proposes other mechanims may be involved in the astrocyte swelling in addition to the ammonia-glutamine hypothesis and one may suggest it includes the activation of P53 and its suppressive effects on Nrf2. (Panickar, Faraonion) The author also mentions pharmacological pre-treatment doses of amiloride, a diuretic used to treat congestive heart failure and hypertension, were required that were 200 fold higher in animals with hyperammonemia in association with exposure to endotoxin." This should demonstrate to anyone whether toxicologically inclined or not, that "something just ain't right",,,,!

He goes on to say, "several substances have been shown to cross the BBB under hepatoxic conditions such as acute liver failure. Incidently, he points out ammonia induces the expression of GLUT1, a transporter across the BBB and this report suggests a non-specific increase in permeability of the BBB and proposes hyperammonia could "unlock" the BBB." It has been shown that ammonia can "alter endothelial cell gene expression and transporter function." (Belanger Of course, this is an important issue to consider whenever a condition of hyperammonemiua occurs. It very well could contribute to the neuroinflammatory consequences in pathological conditions such as autism and conditions that where elevated homocysteine levels impair renal function and as this article suggests, exposures to endotoxin exacerbate related metabolic consequences.

Jalan, R. and Bernuau, J. (2007). Induction of cerebral hyperemia by ammonia plus endotoxin: Does hyperammonemia unlock the blood–brain barrier? Journal of Hepatology, 47(2):168-171. http://www.citeulike.org/user/HEIRS/article/6556614
Essa, M. M. and Subramanian, P. (2006). Hibiscus sabdariffa affects ammonium chloride-induced hyperammonemic rats. eCAM. http://www.citeulike.org/user/HEIRS/article/6556740
Panickar, K. S., Jayakumar, A. R., Rao, K. V. R., and Norenberg, M. D. (2009). Ammonia-induced activation of p53 in cultured astrocytes: Role in cell swelling and glutamate uptake. Neurochemistry International, 55(1-3):98-105. http://www.citeulike.org/user/HEIRS/article/4523207
Faraonio, R., Vergara, P., Di Marzo, D., Pierantoni, M. G. G., Napolitano, M., Russo, T., and Cimino, F. (2006). p53 suppresses the nrf2-dependent transcription of antioxidant response genes. The Journal of biological chemistry, 281(52):39776-39784. http://www.citeulike.org/user/HEIRS/article/4364516?show_msg=already_posted
Culley, D. J., Raghavan, S. V., Waly, M., Baxter, M. G., Yukhananov, R., Deth, R. C., and Crosby, G. (2007). Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats. Anesth Analg, 105(1):83-88. http://www.citeulike.org/user/HEIRS/article/6557028
Bélanger, M., Asashima, T., Ohtsuki, S., Yamaguchi, H., Ito, S., and Terasaki, T. (2007). Hyperammonemia induces transport of taurine and creatine and suppresses claudin-12 gene expression in brain capillary endothelial cells in vitro. Neurochemistry international, 50(1):95-101.
http://www.citeulike.org/group/7833/article/6557716

Hydrogen Sulfide, Cigarette Smoke, Endotoxin and Particulate Matter -- The Toxic Effects They Have In Common!

Different chemicals have different modes of toxicity which can reduce, be additive or potentiate the effects of the others and alter other metabolic processes such as insulin release and activities of Nrf2 cell signaling.  Take four example, the four toxicants endotoxin, hydrogen sulfide (H2S), cigarette smoke and particulate matter. These pollutants are all common in the environment and can cause negative health effects in those that are susceptible, have certain chronic illnesses and/or multiple chemical sensitivity. Interestingly, one will note that all four are found in tobacco smoke and therefore, this probably makes cigarette more toxic at lower levels than each of the different agents on their own.

First of all, lets review a few important details about each of these toxicants. Cigarette smoke contains acrolein which is an aldehyde that has been implicated in the development of neurogenic inflammation. Cigarette smoke also has hundreds of chemicals. Some that have been identified and some that have not. The toxicity of many of the toxicants that have been identified are still unknown. Particulate matter (PM)are particles that are present in air pollution and reduce air quality. Their presence at higher levels are an irritant to almost anyone but at lower levels they may become irritants to individuals with special health conditions such as those patients with asthma and COPD. For PM, size matters! Finer particles are better able to travel down the windpipe and absorb into the lower lung tissue's protective layer and induce inflammation. Ultra-fine particles also have more surface area to bind chemicals which can elevate inflammatory responses even further. Exposures to hydrogen sulfide can be from endogenous sources such as intestinal bacteria or from production in the different cells. As we have noted, major sources of exogenous sources of H2S are from bacteria in contaminated drinking water from wells and groundwater and the waste of large animals feeding operations (CAFOS) that end up in rivers and streams. Of course, the source of endotoxin can be from those same sources but other sources include bacteria on food, smoke from wood and tobacco smoke, water-damaged buildings, animals, and from indoor contaminants like dust in the home and commercial and occupational settings. Contrary to popular belief, endotoxin is one of the most common pollutants in the environments because it can be found almost anywhere especially where there is water and is so small, that there is little, if any technology that is available to get rid of it. For instance, very few models of air filtration units have the ability to filter gram-negative bacteria which is the source of most endotoxin. 

Hydrogen sulfide has the ability to cause any number of health effects including death at high levels. As we noted above, it is produced endogenously by bacteria in the gut in addition to other cellulars sources including adipocytes (Fang) and the pancreas (Harrison). It has been shown that long-term exposure to endogenous hydrogen sulfide can impair the function of beta cells in the pancreas which may lead to insulin resistance and diabetes. Researcher's now believe that one way this occurs is through the generation of inflammatory processes from Il-1b that is produced by the liver may drive the inflammatory processes that effect the beta cells. Endotoxin has been associated with liver inflammation and inflammation in the liver has been associated with activation of neuroinflammation and sickness syndrome. Changes in Nrf2 signaling have been associated with insulin resistance and may be due to reductions in insulin secretion by damaged beta cells (Harrison) from H2S produced by pancreatic cells altering KATP channels and also from Il-1 production in the liver exerting a peripheral effect on pancreatic beta cells. Insulin has been shown to be an important signaler for HO-1 and Nrf2 under normal conditions. Harrison describes a five-fold increase in heme oxygenase -1 mRNA and a 4-fold increase expression in kidney epithelial cells by insulin induction. Long-term exposure to intestinal bacteria or other processes that produce copious amounts of H2S that activate cellular signal like nociceptors when detoxification is overwhelmed and cause pain, alter the microbiota and interact immunologically to cause inflammation that may contribute to autoimmune-type reactions. Also, the initiation of inflammatory processes in the liver and impaired insulin and Nrf2/HO-1 signaling and diabetes can generate long-lasting inflammatory processes in the brain and other peripheral complications may even be more detrimental. (Ehses)

It is interesting to note that both high levels and low levels of H2S are associated with diabetes. Dr. Whiteman from the Northcott Devon Medical Foundation reports reduced levels of H2S in the blood of patients with diabetes. Lower levels of H2S were found to be important clinical markers for microvessel functioning which is an important complication of diabetes (ScienceDaily). Considering that Nrf2 modulates the effects of H2S from HO-1,this has important implications for the role of Nrf2. Maybe homeostasis becomes unbalanced at both high and low H2S levels which may be a consequence of impaired Nrf2 signaling. Oh describes that H2S and Ho-1 can inhibit the damaging effects of NO and NF-kappaB from LPS endotoxin and that down-regulation of H2S/CSE in lung injury pathology includes down-regulation of NO/iNOS and upregulation of CO/HO-1 (Zhou). (Jee whiz, I feel like I am on a roller coaster ride - up, down, up, down! Just kidding!) The point here is how we see the modulation of two neurogasotransmitters.

Recently it has been reported that antagonizing TRPA1 channels for a prolonged period reduces some of the symptoms associated with diabetic hypersensitivity (Wei). Hyperglycemia is an important consequence of insulin resistance and diabetes which produces alterations in mitochondrial function and as Bonnard shows from his findings the mitochondrial dysfunction is a consequence of insulin resistance and result of ROS generation in diet-induced diabetic mice. Diet is an important source for the ingestion and propagation of intestinal bacteria in the intestinal tract. Mitochondrial dysfunction generates reactive species especially H2O2 from NADPH which can alter cell signaling and cause further damage to cells.

Fibromyalgia is suspected to be at least in part, a condition associated with neuropathic pain in which nociception plays an important role. Ro presents evidence that both TRPV1 and TRPA1 contribute to muscle nociception and hyperalgesia and elevations inflammatory mediators, H2O2 and other ROS increase their expression as well as, sensitize them. In addtion, chronic and consistent activation of TRP channels may lead to endoplasmic reticulum stress and the effects of ER stress are usually attenuated through HO-1 (Liu) but Fallahi shows in his presentation that Nrf2 signal decline following activation of the ER stress response. Andre explains aldehydes, which acrolein is one in cigarette smoke and also present in cooking oil and combustive products, are the main cause of neurogenic inflammation mediated through TRPA1 and suggests this channel may add to smoking pathologies. Acrolein also triggers endoplasmic reticulum stress. Haberzetti writes acrolein is also produced from the metabolism of numerous drugs, in addition to be a major irritant in cigarette smoke and through his observations, he determined that exposure to acrolein induces ER stress including the unfolding response and implicates NF-kappaB and production of cytokines as important factors in the process. Zhang demonstrated that acrolein up-regulates HO-1 through the gene promoter Nrf2 and silencing Nrf2 attenuated significantly the response of HO-1 to acrolein. The result of which could include an increase in the toxic effects of smoking. From this study one can see that Nrf2 knock-out would increase sensitivity in the respiratory tract to cigarette smoke.  Roy reveals further details in showing that acrolein can either lead to an adaptive response at low doses, presumably through the up-regulation of HO-1 through Nrf2 or lead to death processes. At higher doses, mitochondrial-induced apoptotic processes are more apt to ensue. This is also the case if the adaptive process can not mitigate the effects of the toxicant.

Nociceptive behavior seems to be an important part of many of the environmental illnesses including fibromyalgia, airway hypersensitivity and other lung disease, degenerative diseases and multiple chemical sensitivity(MCS), just to name a few. One symptom often reported by those who suffer from MCS is a chronic and annoying cough from cigarette smoke and air pollution. Birrell recently showed that activation of TRPA1 by its agonists can lead to chronic cough and incidentally the "agent" he used in his experiment was acrolein which activated both TRPA1 and vagal nerves. The author points out that current cold remedy treatments are usually not effective for this kind of cough and there a number of TRPA1 ligands, and therefore are number of TRPA1 triggers that can generate a cough. This study might help to explain the persistant cough in many MCS patients. Of course, many chemicals can bind to particulate matter and therefore activate TRPA1 receptor and stimulate chronic cough. Caterina notes that TRPA1 can be activated in a different manner than just binding and this is achieved by TRPA1 ligands attaching themselves to cysteine residues on the channel which may change the structure and lengthen the time of activation. Bang explains that activators of TRPA1 are reactive eletrophile species. Meaning they are all able to effect gene expression by reacting with nucleic acids, proteins and other small molecules (Farmer) and include acrolein, mustard oil, iodoacetamide etc.  In addition, there are also non-electrophile activators which include menthol, THC, camphor and others. (Bang) TRPA1 also reacts to the ROS, H2O2. In addition, these compounds induce the expression of the enzymes of the Nrf2 detoxification system. Caterina explains, "there may be a so-far unexplained mechanism of cooperation between Nrf2 and TRPA1 that has not been identified". He could be referring to the now understood role of nociception and the ER stress response which involves PERK/Nrf2 or may be referring to some other mechanism. Madeira demonstrates that H2S is protective against gastic damage and in a similar study this is achieved by the down-regulation of NO and the up-regulation of CO/HO-1. He also suggests that TRPV1, at least in this case, plays some part in this protection. The similarities between Caterina's and Madiera's study are worth noting and may suggest interaction between TRP receptors and Nrf2 is important for the protective benefits of the gasoneurotransmitters.

The aryl hydrocarbon (AhR) may be another important factor in multiple chemical sensitivity. In addition to smoke mediated COX-2 and prostaglandin production and contributing to inflammation induced lung disease, the AhR is involved in the detoxification of polyaromatic and polyhalogenic hydrocarbons. Both classes include a number of chemicals that are present in the environment and used in manufacturing and agriculture. Also, abherrant functioning of the AhR is believed to be responsible for mediating the toxicity of dioxins which is also in cigarette smoke. In addition, to the ER stress response activation from cigarette smoke. Cigarette smokes also activates the AhR and also alters adipocyte differentiation and down-regulated the expression of adiponectin, PPAR-gamma and other markers and elevated MCP-1(Shimada) . There may be some negative control of the Nrf2/HO-1 pathway by cigarette smoke which can elevate levels of adiponectin and suppress levels cytokine levels (Kim). The absence of the aryl hydrocarbon is responsible for toxicities of other chemicals as well. It was reported last week that endotoxin which has been shown to be a trigger for chronic fatigue syndrome, is detoxified by the activities of the aryl hydrocarbon. Any dysfunction in this protein could lead to unexpected consequences and an increased sensitivity to endotoxin. It is important to remember here that Nrf2 is both modulated and modulates the AhR. Abnormal signaling by either one could lead to consequences related to toxicity. In addition, the beneficial activities of the AhR are inhibited by Tnf-a. Impaired Nrf2 which modulates the inflammatory mediator will only add to toxic effects in a negative way. Recent studies show endotoxin  causes endoplasmic reticulum failure "possibly by actions of the mitochondria" which would lead again, to reduction of Nrf2 (Koslov).   Endotoxin is extremely common in the environment in air and water pollution and therefore, it should be of particular concern for those with multiple chemical sensitivities as well as other conditions including those with dysfunction in immune regulation.

Related Reference:

• Slide Presentation: Loss of nrf2 dependant signaling following induction of endoplasmic reticulum stress.

Citations and Original Document

CiteULike: ENDOTOXIN-MEDIATED DISTURBANCE OF HEPATIC CYTOCHROME P450 FUNCTION AND DEVELOPMENT OF ENDOTOXIN TOLERANCE IN THE RAT MODEL OF DEXTRAN SULFATE SODIUM-INDUCED EXPERIMENTAL COLITIS

CiteULike: ENDOTOXIN-MEDIATED DISTURBANCE OF HEPATIC CYTOCHROME P450 FUNCTION AND DEVELOPMENT OF ENDOTOXIN TOLERANCE IN THE RAT MODEL OF DEXTRAN SULFATE SODIUM-INDUCED EXPERIMENTAL COLITIS: "Masubuchi, Y. and Horie, T. (2004). Endotoxin-mediated disturbance of hepatic cytochrome p450 function and development of endotoxin tolerance in the rat model of dextran sulfate sodium-induced experimental colitis. Drug Metabolism and Disposition, 32(4):437-441."

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.

Endotoxin and Loss of Tolerance via Reduced HO-1: Potential Mechanism in CFS and MCS?

It has been suggested that chemical sensitivity and possibly other environmental illness conditions can be the result of a "loss of tolerance".  Notably, this "loss of tolerance" may be the result of altered signaling of the immune response and contrbuting factors may include the presence of endotoxin which can 1) activate inflammatory responses, 2) reduce the threshold of reactions to allergens and 3) alter gene expression from ROS and alterations in methylation. In addition, endotoxin through activtion of GSK3b provides a mechanism to "deactivate" the antioxidant system, Nrf2. High fat diets and hyperglycemia may also promote the translocation of bacteria in the respiratory and intestinal tract. This may further increase inflammation and promote neuroinflammation in the brain as a consequence of cytokine activity in the intestinal tract and liver. At some point, the break down of the blood brain barrier may increase the likelihood of brain inflammation and changes in behavior and neurotransmission.

A recent study provides support for the hypothesis of "loss of tolerance" in environmental illness because of the role of Nrf2 as a master regulator of detoxification.  Heme oxygease is an antioxidant that is regulated by Nrf2. Naidu explains that past research has demonstrated that HO-1 deficient animals are highly susceptable to toxicity from endotoxin. Further " the potential significance of HO-1 in the adaptive immune system has been implied by a recent report, in which genetic deficiency of HO-1 decreased the suppressive activity of regulatory T cells (8)." This loss of supression could suggest a possible explanation of some symptoms related to environmental illness, especially chemical sensitivity and to some extent chronic fatigue syndrome.  There is debate on the benefits and potential harmful effects of  exercise on the latter and there are now a number of reports that demonstrate that exercise elevates HO-1 expression. On the other hand, it also can lead to an increase of translocation of bacteria that are alway present in the gut, even though the balance of gut may be different at one point vs another. In any event, the effect of exercise on bacteria translocation and HO-1 levels offer an explanation why some patients improve with exercise while others do not. As Naidu explains, there may be multiple pathways for the expession of HO-1 and may be species specific. Interestingly, he does point out that inhibition of the P38 pathway contributes to HO-1 expression at least in this study and this expression occurs via regulation by Nrf2 and reactive species are involved with this activation. This supports other research that blockade of the P38 pathway increases the expression of NO by endotoxin.


Naidu, S., Vijayan, V., Santoso, S., Kietzmann, T., and Immenschuh, S. (2009). Inhibition and genetic deficiency of p38 mapk up-rregulates heme oxygenase-1 gene expression via nrf2. Journal of Immunology, 182:7048-7057.  http://www.citeulike.org/user/HEIRS/article/7586285

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

Why Endotoxin Can Increase Pain,Chemical and Mold Sensitivity and Causes Sickness Behavior!

Toll-like receptors: are a class of proteins that play a key role in the innate immune system. (Wipedia)

Background: Binding to toll-like receptors may initiate inflammatory responses including the production of chemokines. They mainly signal through NF-kappaB and increase transcription of inflammatory proteins Il-1b, Tnf-a, CCL2 (MCP-1) etc. (Devaraj) These are receptors that are highly expressed and are considered to be a link between diet and metabolism and are implicated as important factors in a number of health conditions including lupus, atherosclerosis and diabetes. (Dasu) We have noted in other blogs that they may play an important role in conditions that are most often considered "environmental illnesses" including chronic fatigue syndrome and/or contribute to symptoms of chemical sensitivity. To put it simply, toll-like receptors are considered signal transducers that initiate inflammatory processes and two common ligands are LPS endotoxin (which has been implicated in CFS) and saturated fatty acids. The ligands that bind TLR contain a "molecular pattern" the TLR recognizes and may be present in microbial and non-microbial agents or may be responsive to signals generated at the site of inflammation or from endogenously-produced proteins like heat shock proteins. Thus, their activites become a concern when ever pathogenic exposure or inflammation may be present.

The distribution of the toll-like receptors is different in different tissues but include epithelia and endothelia in the intestinal tract, the respiratory tract, the blood-brain barrier, etc. It is now believed that there is a commensal relationship that exists between the gut microbiota and TLR to maintain gut integrity (Hopkins) and may involve epigenetic influences and down-regulation of TLR gene transcription. (Takahashi)    It has been determined that TLR2 and TLR4 bind to gram positive and negative bacteria respectively. However, the production of one type of TL receptor may induce the induction of the other. Devaraj demonstrated that type-1 diabetes and increased levels of IL-1b and TNF-a is correlated with expression of TLR and also endotoxin "contribute to the inflammatory burden by activating TLR receptors" and suggests their instrumental in diabetes pathology. In addition, it has also been determined that high glucose levels can stimulate the expression of these receptors in monocytes. While toll-like cells are involved in cytokine production and cell activation, the inflammatory responses initiated by activation of receptors may last long after the initial stimulus is gone or may potentiate the inflammatory responses of other insults. It may seem beneficial to blunt the responses of TLR, but it may be more harmful by making the organism more susceptible to infection.(Hopkins) On the other hand, aberrant signaling from TLR can lead to autoimmune-type conditions as we noted above.

Other studies demonstrate that the expression of TLR are widespread are can activate microglia and astocytes and play a role in neuroinflammatory responses. Microglia are sensory-type cells that are the main source of inflammatory mediators in the nervous system.  Some studies show that TLR activation of microglia leads to an increase in NO, superoxide and other cytokines and that TLR-deficient microglia demonstrated a significant reduction in several types of inflammatory responses. Obata confirmed TLR3 has an important role in the development of tactile allodynia after nerve injury and blocking these receptors may provide effective treatment for neuropathic pain which has been linked to fibromyalgia. Recent findings are suggestive of the notion that fibromyalgia is a "disorder of central processing with neuroregulation/
transmission dysfunction" (NFA) and TLR4 may initiate an inflammatory profile through NF-kappaB at least in a subset of fibromyalgia patients. In one model of neuropathic pain, tactile allodynia was "abrogated" in CCR2 mice which is the receptor for CCL2 (MCP-1), the inflammatory cytokines activated by NF-kappaB and has been suggested as a possible marker for fibromyalgia. It also plays a very important role in the development of neuroinflammation via the TNF-a/CCL2/CCR2 pathway. From this, it has been suggested that activation of immune cells and microglia peripherally and in neurons may contribute to inflammatory and neuropathic pain states and (Abbadie) importantly, it is now understood that TLR agonists modulates CCR2 expression and CCL2 responsiveness. (Souto, Parker) Jo et al explains peripheral injuries that lead to neuropathic states causes pathology not only in the damaged nerves but also causes changes in the central processing of sensory information and glial activation may facilitate "noxious signal transduction" even after the initial injury has healed. Therefore, TLR may not only initiate neuropathic pain but also maintain it.  Experts believe nociceptive behavior may influence symptoms of MCS (Pall) and it has been demonstrated pain caused by bacterial infection may be generated through activation of nociceptors via the TLR in neurons. (Wabachi) In addition, TLR responses play a role in viral and parasitic infections, multiple sclerosis, exacerbate injury in ischemia (Kielian) and chronic activation of TLR is associated with anxiety, avoidance and sickness behavior (Hudson) and increased sensitivity to other toxicants (Pestka).

Other reports show in epithelial cells, TLR mediate immune cells production from exposure to particulate matter and contribute to airway hypersensitivity from exposure to ozone. (Williams) More recently, it has been shown that the aryl hydrocarbon receptor (AhR), which plays a role in the detoxification of polyaromatic hydrocarbons and halogenated hydrocarbons, negatively regulates TLR signaling. Animals that are deficient in the AhR exhibit exaggerated inflammatory responses including significant elevations in TNF-a and IL-6 and are highly susceptible to septic shock. (Ogawa, Kimura) We have expressed the belief that the abnormal functioning of the AhR may contribute to environmental illnesses including multiple chemical sensitivity because of its role in detoxification and its relationship to the antioxidant system regulator Nrf2. The Nrf2 protects neurons and other cells against oxidative and environmental insults in primary and secondary injury. TLR activates NF-kappaB through the universale adaptor protein MyD88 and it has been shown that Nrf2 has a "global influence" on MyD88-dependant and independant signaling. Deficiency of Nrf2 dysregulated expression of genes that encode molecular components of innate immunity (e.g., peptidoglycan-recognition proteins, proinflammatory cytokines, chemokines, and adhesion molecules and receptors." (Thimmulappa)

Study Highlight: Pestka provides evidence that the preexposure of a TLR agonist such as LPS endotoxin increases the inflammatory response of DON, a mycotoxin. This response which included production of IL-1b, Il-6, and TNF-a was at levels higher than either produced alone. During the study, preexposure to other TLR agonists, also increased the pro-inflammatory responses of DON in a similar manner as LPS. In addition, similar heightened responses occured from LPS preexposure of TLR and subsequent effects of microbial and non-microbial "agents" including satratoxin, Shiga toxin, zearalenone and toxicants such as nickel chloride, triphenyltin, dinitrochlorobenzene (a known irritant) and dioxin. It has been concluded from this study that prior exposure to TLR agonists (ie endotoxin, saturated fat and others) "might render macrophages highly sensitive to subsequent induction of proinflammatory gene expression by xenobiotics with diverse mechanisms of action." (Pestka)

Notes:

• An important source of bacterial and endotoxin contamination is from our drinking water. Find out more about the importance of healthy water with a clip from the Dr. Oz Show. Other main sources include from the air we breath.
• IRAK-1 is necessary for LPS-mediated suppression of PPARalpha and PGC-1alpha, nuclear factors essential for the expression of anti-oxidative enzymes such as GPX3 and catalase (Maitra) "ROS trafficking(NADPH oxidase) mediates LPS/TLR signals in neutraphils and downstream targets including IRAK-1. Deficiency of Nrf2 predisposes neutraphils to greater responsiveness to LPS which is mediated by increased ROS generation. (Thimmulappa)

Reference Resource:

• Toll-like receptor (TLR)-mediated biology (Hopkins)
  

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Original document and citations can be accessed here.

MDA, NO and endotoxin associated with circulatory changes in cirrhotic livers

Title: Increased plasma malondialdehyde in patients with viral cirrhosis and its relationships to plasma nitric oxide, endotoxin, and portal pressure.

Summary: "strongest factors to predict HVPG, WHVP, and HSR are plasma levels of NOx, MDA, and endotoxin, respectively. Conclusion "

Citation: Lee, K.-C., Yang, Y.-Y., Wang, Y.-W., Lee, F.-Y., Loong, C.-C., Hou, M.-C., Lin, H.-C., and Lee, S.-D. Increased plasma malondialdehyde in patients with viral cirrhosis and its relationships to plasma nitric oxide, endotoxin, and portal pressure. Digestive Diseases and Sciences.

Airborne endotoxin concentrations in homes burning... [Environ Health Perspect. 2010] - PubMed result

"airborne endotoxin concentrations in homes burning biomass fuels are orders of magnitude higher than those found in homes in developed countries where endotoxin exposure has been linked to respiratory illness in children"

Airborne endotoxin concentrations in homes burning... [Environ Health Perspect. 2010] - PubMed result:

SphK1 regulates proinflammatory responses associated with endotoxin and polymicrobial sepsis.

"critical role for SphK1 in endotoxin signaling and sepsis-induced inflammatory responses and suggest that inhibition of SphK1 is a potential therapy for septic shock."

CiteULike: SphK1 regulates proinflammatory responses associated with endotoxin and polymicrobial sepsis.:

Effect of SRT2104 on Endotoxin-induced Inflammation

Effect of SRT2104 on Endotoxin-induced Inflammation: "URL: Effect of SRT2104 on Endotoxin-induced Inflammation

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Inflammation-Induced Anhedonia: Endotoxin Reduces ... [Biol Psychiatry. 2010] - PubMed result

Inflammation-Induced Anhedonia: Endotoxin Reduces ... [Biol Psychiatry. 2010] - PubMed result: "Inflammation-Induced Anhedonia: Endotoxin Reduces Ventral Striatum Responses to Reward."

Blunting the response to endotoxin in healthy subjects: effects of various doses of intravenous fish oil. Intensive care medicine.

HEIRS Environmental Illness Research Blog: Why Endotoxin Can Increase Pain,Chemical and Mold Sensitivity and Causes Sickness Behavior!

Pittet, Y. K., Berger, M. M., Pluess, T.-T. T., Voirol, P., Revelly, J.-P. P., Tappy, L., and Chioléro, R. L. (2009). Blunting the response to endotoxin in healthy subjects: effects of various doses of intravenous fish oil. Intensive care medicine. http://www.citeulike.org/user/HEIRS/article/6007905

TLR as Inflammatory Mediators: Why Ozone and MCS Do Not Mix

Several recent observations have revealed possible routes of physiological consequences of toxicant exposure (ie ozone) that may be related to symptoms of MCS. It has been suggested activation of TRP channels may play an important role causal in MCS. (Pall) Bessac and Jordt write, "that both the TRPA1 and TRPV1 receptor may contribute to chemical hypersensitivity, chronic cough, and airway inflammation in asthma, COPD, and reactive airway dysfunction syndrome" and other reports link TRPA1 to asthma.(Drug Disovery) Activations of these receptors will increase their expression, therefore, increasing the likelihood of activation (and symptoms) by exposures that activate them. Or on the other hand, Bessac writes, cross-desensitization exists by one chemical may desensitize it to another. As we noted over a year ago, changes in these receptors can occur by interactions with other proteins including IGF-1 and inflammatory cytokines that may alter these receptors functioning which may cause "aberrant signaling".

Recently it has been demonstrated that ozone activates TRPA1 channels and TRPA1 channels have been shown to be upregulated by the inflammatory cytokine MCP-1/ pathway which has been discussed at length in other blogs. Ozone and smoking promote a process called oxidation of phospholipids (oxPL) that generates ROS from NADPH oxidase activation, increase MCP-1, negatively regulate Nrf2 and are associated with autoimmune diseases such as lupus, RA and Parkinson's disease. OxPL are generated during inflammatory conditions and inhibit the full differention of dendritic cells and therefore restrict normal adaptive immune response. (Bluml) Recently other research has provided evidence that additional ozone reactions can be caused from abnormal enzymatic actions of glutathione which, by he way, is also regulated by Nrf2 through other proteins. In addition, ozone contributes to airway hypersensitivity and hyperresponsiveness through the modulation of TLR receptors and other green house gases may play a part in the "learned response" tied possibly to physiological response in MCS, may  potentiate the effects of lead-based paint and increase related health risks and cause panic-like behavior.

Just in case you have heard that ozone generators are physiologically calming...well, according to the research, quite the opposite seems to be true. For instance, as new study shows there is a sensor in the brain for CO2, another greenhouse gas, that will cause panic-attacks. Such behaviors are crucial for animals for survival to be able to "sense" and prevent biological suffocation and "aberrant signaling" of TLR receptor may decrease the threshold of activation of these sensors. Keely explains that "epithelial hypoxia" in the gut results in a 40-fold increase in translocation of gram-negative bacteria, regardless of intestinal barriar function. In the gut, hypoxia is associated with acute and chronic inflammation (ie IBD) and its presence initiates factors that exploits the intestinal environment to achieve the translocation process. One can assume that similar sensory processes that activate panic or flight response may be present in other tissues including the lungs and gut. Additionally, it has been demonstrated that viruses activate TLR receptors but the mechanism is slightly different.

TLR4 receptors recognize LPS endotoxin which is the a component of the wall of gram-negative bacteria. Several reports now suggest that a route of CFS is endotoxin exposure.Endotoxin is the result of lysis of bacteria from immune cells and therefore, will be present whereever there is inflammation. Of course, minimizing exposures that contain bacteria is one way to reduce TLR signaling. There are other TLR receptors that also initiate immune responses to other contaminants.   Recent evidence has demonstrated that saturated fat "angers" the immune system by interacting with TLR4 but the exact process of how saturated fat does this is unclear. Cani has noted that LPS in high-fat diets is 2 to 3 times greater and that LPS-containing  proportion is greater in the high-fat diet gut.  Other conditions may favor altered TLR4 signaling and because they initiate a variety of events inside the cell, the absence or dysregulation of the antioxidant system can lead to an exacerbation of inflammatory events because it modulates cytokines production such as pro-inflammatory Il-1 and Tnf-a and the anti-inflammatory cytokine Il-10 which modulates sickness syndrome. The antioxidant system Nrf2 supports other proteins in mitochondrial biogenesis which it has been reported that exposure to chemicals has an effect on cellular respiration and alters mitochondrial function.  Altered TLR signaling also may contribute to neuropathic pain. Other effects include alteration in neurotransmission such as dopamine which may contribute to Parkinson's disease and other neurodegenerative diseases.

I have written several essays on TLR receptors and how they interact with the immmune system from different environmental toxicants which can be read here. Also, to read citations for this article click here.

Dominant role of the MyD88-dependent signaling pathway in mediating early endotoxin-induced murine ileus.

CiteULike: Dominant role of the MyD88-dependent signaling pathway in mediating early endotoxin-induced murine ileus.: "Buchholz, B. M., Billiar, T. R., and Bauer, A. J. (2010). Dominant role of the myd88-dependent signaling pathway in mediating early endotoxin-induced murine ileus. American journal of physiology. Gastrointestinal and liver physiology."

Bench-to-bedside review: Endotoxin tolerance as a model of leukocyte reprogramming in sepsis

CiteULike: Bench-to-bedside review: Endotoxin tolerance as a model of leukocyte reprogramming in sepsis: "Cavaillon, J. M. and Conquy, M. A. (2006). Bench-to-bedside review: Endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Critical Care, 10(5):233+."

Nitro-Oleic Acid Protects Against Endotoxin-Induced Endotoxemia and Multi-Organ Injury in Mice.

Nitro-Oleic Acid Protects Against Endotoxin-Induced Endotoxemia and Multi-Organ Injury in Mice.: "URL: Nitro-Oleic Acid Protects Against Endotoxin-Induced Endotoxemia and Multi-Organ Injury in Mice.

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Astragalus, Intestinal Inflammation and Endotoxin

A new study has reported that Astragalus may prove an effective therapy against intestinal inflammation caused by LPS endotoxin. The study demonstrated that Tnf-a and Il-8 is significantly higher in LPS-induced damage in intestinal epithelial cells. Treatment with Astragalus mongholicus polysaccharide (APS) significantly abrogated LPS-endotoxin expression of Tnf-a and Il-8 and suggested this is achieved by blocking the P38Mapk pathway.




Yuan, Y., Sun, M., and Li, K.-S. S. (2009). Astragalus mongholicus polysaccharide inhibits lipopolysaccharide-induced production of tnf-alpha and interleukin-8. World journal of gastroenterology : WJG, 15(29):3676-3680. http://www.citeulike.org/user/HEIRS/article/5390452

Protein metabolism in leg muscle following an endotoxin injection in healthy volunteers

Protein metabolism in leg muscle following an endotoxin injection in healthy volunteers: "URL: Protein metabolism in leg muscle following an endotoxin injection in healthy volunteers

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