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

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

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

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

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

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

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

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

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

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

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

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

Chemical Sensitivity and Th2 Autoimmune Disease: The Loss of Treg Cells As Referee!

I recently discussed how IL-10 determines the severity and length of sickness syndrome. At that time, I suggested chemical sensitivity is a loss of tolerance caused by an imbalance of T regulator cells and dysfunction of Nrf2 and based this assumption on a recent study showing environmental pollutants may lead to a decrease in the expression of Tregs whereas, normally chronic exposure increases them. In previous animal studies, the loss of Tregs results in the development of "immediate autoimmune-type disease."

The paragraphs below will provide more support for the idea that Nrf2 does indeed play a role in environmental illness including MCS in particular. First of all, it is important to review that environmental illnesses usually include allergy, asthma, inflammatory bowel disease, diabetes, lyme disease, heavy metal disease, chemical sensitivity, just to name a few. Generally, environmental illnesses may be categorized as Th1 or Th2 according to their T cell pathway subset which is either considered to be cell-mediated or humoral , respectively. Vodjani provides a graphical representation of environmental illnesses in relation to autism in his article and classifies them as Th1 or Th2. He classifies chemical sensitivity as a Th2 humorally- regulated autoimmune disease along with allergy and asthma. Tregs, as he describes, are cells that try to negotiate a balance between cells that suppress and ones that maintain homeostasis. More simply, they are T cells with specific markers. Personally, I have dubbed them to be immune cell referees!

This is how he classifies the autoimmune diseases:

Th1 Autoimmune Disease

• mulptiple sclerosis
• diabetes
• arthritis
• uveitis
• lyme disease
• mercury-induced autoimmunity
• atopic dermatitis (initiation phase)
• inflammatory bowel disease
• bacterial infection
• mold infection

Th2 Autoimmune Disease

• lupus erythematosis
• lead-induced autoimmune disease
• allergy
• asthma
• chemical sensitivity
• parasitic infection
• atopic dermatitis (acute phase)
• inflammatory bowel disease
• bacterial infection
• malignancy

This author also describes the steps involved when conditions in the intestinal tract initiate autoimmune disease and brain disfunction/ neurodegeneration. These steps are as follows:

1. mucosal immune abnormalities
2. imbalanced gut flora
3. intestinal barrier diysfunction
4. systemic inflammation
5. neuroinflammation
6. neuroinvasion
7. neurodegeneration

In support of the idea of chemical sensitivity as an autoimmune disease one needs to understand the concept of loss of tolerance which include loss of Tregs and loss of suppression of inflammatory initiators. This loss may depend on other proteins such as Il-10 and HO-1 which are ultimately directed or indirectly regulated by Nrf2. For instance, it has been demonstrated Nrf2 -/- cells express lower HO-1 which is necessary for Treg suppression.  Tregs levels also are negatively influenced by high-fat (Ma), age, mental stress, are differentially regulated by different AhR ligands (Quintana) and vitamin D levels. The last of which also decreases with age.

Williams and his team provides more insight into how the expression of Nrf2 is different with exposure to environmental pollutants. This article is long and the author makes several points worth discussion that support the notion of the possible involvement of Nrf2 in chemical intolerance. Initially the researcher describes how Nrf2 deficiency may stimulate a Th2 response according to the type of pollutant such as particulate matter. He admits even after presenting his findings, exposures to mixed pollutants are hard to analyze but he believes he uses an approach to match a "real-world" setting. His findings provide a mechanism for how certain environments tend to be more reactive to certain people and why these reactions do not always "appear" to be allergenically-mediated. Through this study, the researcher demonstrates Nrf2 positive and Nrf2 deficient animals show different immune profiles when exposed to different pollutants. For example, he found IL-18 was increased in Nrf2 positive but decreased in Nrf2 deficiency. This suggests Nrf2 regulates Il-18 which plays a role in inhibiting IgE in B cells. Typically, IL-18  is associated with some types of allergy, most often bacterial or viral and curiously, it is elevated in chronic autoimmune urticaria (itchy rash). (Ibrahim) Also, Nrf2-/- show lower protein CD40 that regulate IgE response which may include mild allergy-type responses like in hay fever to life threatening symptoms of anaphylactic shock. Nrf2 levels can fluctuate and if alterations of CD40 and IgE reflect this, it may explain why IgE profiles are often "scewed" in MCS patients. Williams also demonstrated that NAC, a common antioxidant used in MCS therapy has both positive and negative immune effects depending on the type of exposure to the point it may influence the Th1 or Th2 subtypes and may explain why some patients have good luck with NAC therapy and others do not.  It also makes it evident that MCS treatments need to be medically-focused and individualized, why control of environmental stressors are critical and at least for the present, no "recipe" is going to be a "fix" for every MCS patient.

Williams states "oxidative stress is an important determinant of what path Th1 or Th2 autoimmunity takes and Nrf2 dysfunction may determine whether disease presentation is more of a Th1 or Th2 pattern." (This is an explanation for why patients with MCS have a long list of co-morbid health conditions and why they experience such a wide spectrum of symptoms.) Most importantly his findings demonstrate as he explains,  "In this elegant study it was shown that a change in the intracellular redox status of DCs upon activation by particulates such as diesel exhaust particulates disrupt the normal ability of TLR agonists to mature DCs and this perturbation of DC function was associated with dampened IFN- and augmented IL-10 secretion in Ag-specific T cells, agreeing with these Nrf2 findings. Our data supports the idea that restoring the oxidant/antioxidant balance in DCs may have a therapeutic benefit in Th2-dominant allergic diseases. Also, enhanced activation in Nrf2-/- exposure to PM may result from decreased expression of HO-1 which is a powerful immunosuppressive" which provides evidence of loss of Treg involvement. George et al findings indeed demonstrated that Treg suppression is dependant on HO-1. HO-1 defiency leads to abolished Treg cell suppression activity normally necessary for keeping the Th1 and Th2 immune balance responses "in check" .  Interestingly it seems, the contaminant and how effective the immune response to it ultimately may determine the development of MCS and how severe the symptoms if this author and the concept of "loss of tolerance" is attributable to the condition.  As we have noted, HO-1 regulates Il-10 which is involved in Treg regulation and with the loss of IL-10 and lower levels of Tregs, heightened reactions and inflammatory responses could occur. Supportively, the author explains, "Nrf2-disrupted DCs exhibit a heightened and constitutively proinflammatory state. These observations indicate an important role for Nrf2 in gauging an appropriate pattern of inflammatory activation of DCs, key regulators of the immune response, to danger signals such as environmental particulate matter or other allergens. Disruption of the Nrf2 gene may potentially enhance host susceptibility to various allergic or infectious diseases" and this he admits, "warrants further study."

 For further reading:

• Immunosuppression in Environmental Illness By High Fat and Cytokines: Ameliorated By Green Tea Compound!?
• T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.

Williams, M. A., Rangasamy, T., Bauer, S. M., Killedar, S., Karp, M., Kensler, T. W., Yamamoto, M., Breysse, P., Biswal, S., and Georas, S. N. (2008). Disruption of the transcription factor nrf2 promotes pro-oxidative dendritic cells that stimulate th2-like immunoresponsiveness upon activation by ambient particulate matter. J Immunol, 181(7):4545-4559. http://www.citeulike.org/user/HEIRS/article/3716629?show_msg=already_posted
Vojdani, A. and Lambert, J. (2009). A gut feeling for immune dysregulation & neuroinflammation in autism. http://www.citeulike.org/user/HEIRS/article/6498182
Definition of Dendritic Cell. MedicineNet.com. Retrieved January 7, 2009.
George, J. F., Braun, A., Brusko, T. M., Joseph, R., Bolisetty, S., Wasserfall, C. H., Atkinson, M. A., Agarwal, A., and Kapturczak, M. H. (2008). Suppression by cd4+cd25+ regulatory t cells is dependent on expression of heme oxygenase-1 in antigen-presenting cells. Am J Pathol, 173(1):154-160 http://www.citeulike.org/user/HEIRS/article/6477829?show_msg=already_posted
Ibrahim, S. A. and Khalifa, N. A. (2009). Interleukin-18 correlates with disease severity in chronic autoimmune urticaria. Egyptian Dermatology Online Journal, 5(1). http://www.citeulike.org/user/HEIRS/article/6509891
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/group/6096/article/6496762
Quintana, F. J., Basso, A. S., Iglesias, A. H., Korn, T., Farez, M. F., Bettelli, E., Caccamo, M., Oukka, M., and Weiner, H. L. (2008). Control of treg and th17 cell differentiation by the aryl hydrocarbon receptor. Nature, 453(7191):65-71. http://www.citeulike.org/group/5070/article/2578286

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

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

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

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

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

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


For further reading: