MCS 13 Deluca 2010: Severe Oxidative Stress

[michael edward badolato jr]

DELUCA C. ET AL BIOLOGICAL DEFINITION OF MULTIPLE CHEMICAL SENSITIVITY FROM REDOX STATE AND CYTOKINE PROFILING AND NOT FROM POLYMORPHISMS OF XENOBIOTIC-METABOLIZING ENZYMES TOX AND APPLIED PHARM 248;285-92 2010 -

measured consequences of defective airway epithelia: elevated cytokines, chemokines, growth factors, and nitric oxide,  glutathione depletion,  a dysfunction of the glutathione-s-transferases(GST) - metabolizing and antioxidant enzymes involved in chemical defense, decreased catalase activity, altered lipid composition of blood cells indicating accelerated lipid peroxidation, and indicated by these measurements - cytokine mediated inhibition of cytochrome P450 (CYP) and aryl hydrocarbon, increased peroxynitrite formation, and severe oxidative stress.

 

The Deluca study - along with Kimata 2004 (described in MCS 7) has measured altered plasma levels in MCS - laying further to rest any question as to whether MCS is a physical disease - a grim picture of pain, loss of detoxification enzyme effectiveness, and destructive levels of inflammatory cytokines, chemokines, growth factors, and nitric oxide.

However, they did not acknowledge the inflammatory situation has occurred due to sensory nerves in defective airway epithelium. 

The genotypes that underly enzymes relating to chemical defense were found the same in control and MCS groups despite the altered expression and activity in MCS. But if the study had integrated the defective airway as primary cause there would have been a different genetic finding.

 

Recall in MCS 15 VERONESI B. AND OORTGIESEN M. NEUROGENIC INFLAMMATION AND PARTICULATE MATTER (PM) AIR POLLUTANTS NEUROTOX 22; 795-810 2001:

"...taken together, the above in vivo and in vitro studies suggested that the variable inflammatory sensitivity to PM observed in different mouse strains (i.e. Balb/C, B6) relate to quantitative differences in the neuropeptide, VRI (TRP) receptors, and acid-sensitive pathways found on sensory neurons that innervate the nasal and upper pulmonary airway. Such data showed how genetically determined differances in sensory neural pathways could influence expressions of PM - induced airway inflammation...genetic differences are thought  to underly these variations and have been experimentally demonstrated for ozone (Kleeberger 1995, Zhang et al 1995), nitrogen dioxide (Holroyd et al 1997), and diesel exhaust (Ichinose et al 1997, Miyabara et al 1998)..."

 

And a reminder (also from MCS 15) - MCS usually occurs among those having a genetically determined intuitive cast of mind with hypersensitivity of the sense organs and hypochondriacal symptoms (known as MCS). JUNG C.G. PSYCHOLOGICAL TYPES 1921 PRINCETON UNIVERSITY PRESS AND IN THE PORTABLE JUNG VIKING PRESS.

 

Instead of acknowledging the genetically vulnerable airway - the Deluca study correctly states that elevated cytokines can inhibit P450 enzyme effectiveness (CYPs) but does not give credit to the defective airway and sensory nerves as cause of the elevated cytokines and mistakenly state - or at least give the impression - that the disease is non genetic as in the following -

DELUCA C. ET AL TOX AND APPLIED PHARMAKOL 248; 285-92 2010:

"...Notwithstanding the absence of genetic defects in CYPs, recent studies have increasingly implicated various inflammatory stimuli, first of all, pro-inflammatory cytokines (Chun 2002, Nadin 1995, Tapner 1996, Tinel 1999) to cause changes in the activities and expression levels of CYPs through nitric oxide signalling (Chun 2002, Stadler 1994). For example, drug metabolizing CYPs such as CYP3A4 and CYP2B6, which are constitutively expressed in human mono nuclear cells, have been significantly repressed by IFN Gamma or IL-2 (Liptrott 2009)...

Our results suggest that serious and multiple dysfunctions of chemical defense systems found in MCS patients may mainly not depend on genetic defects, but instead may rely on non-genetic modifications of metabolizing/antioxidant enzyme expression and/or activity, mediated by redox active agents such as NO and inflammatory cytokines..."Found elevated in MCS patients (Dantoft 2014, Deluca 2010)

 

Recall BASCOM, R. (MCS 6) previously at the Environmental and Airway Disease Research Facility, University of Maryland School of Medicine, Baltimore MD and more recently a lead investigator into cardio-pulmonary effects among World Trade Center responders: MULTIPLE CHEMICAL SENSITIVITY: A RESPIRATORY DISORDER TOX IND H VOL 8(4); 221-28 1992:

"...multiple chemical sensitivity represents an amplification of the non-specific immune response to low level irritants. This alteration may occur through altered function of the c-fiber neurons, an altered function of the respiratory epithelium, or an altered neuro-epithelial interaction...the airway epithelium and the airway surface fluid it produces and regulates are the first line of defense against the multiple, "non-self" constituents in the 10-20,000 liters of air inhaled each day. The airway epithelium is not an inert barrier, as was once thought, but contains a great capacity for xenobiotic metabolism...the observation that the airway can release cytokines...flu-like symptoms, low grade fever, and fatigue that...usually begins several hours after the exposure and last up to 48 hours...a type of acute phase response. Cytokines are now recognized as responsible..."

 

And (also in MCS 6) MOHANKUMAR, S.M.J. ET AL. PARTICULATE MATTER, OXIDATIVE STRESS, AND NEUROTOXICITY 29;479-88 2008:

"...PM exposure is associated with...the release of inflammatory cytokines and mediators from respiratory epithelia into the systemic circulation...Recent studies indicate that micoglia can activate in response to circulating cytokines from the periphery and endogenous transmitters. Microglia located in proximity to fenestrated or "leaky" blood brain barriers can be signalled by circulating PM particles themselves or by inflammatory cytokines/chemokines being released systemically from the chronically inflamed airways...IL-1 is produced by respiratory epithelia in response to PM exposure...can cross the blood brain barrier...prolonged increases in IL-1 levels causes the blood brain barrier to become leaky providing access to IL-1 and other circulating cytokines..."

 

And (from MCS 5) VERONESI B. AND OORTGIESEN M. of the National Health Effects and Research Laboratory, Cellular and Molecular Branch, Neurotoxicology Division, US Environmental Protection Agency, and Cato Research LTD. NEUROGENIC INFLAMMATION AND PARTICULATE MATTER (PM) AIR POLLUTANTS. NEUROTOX  22;795-810 2001:

"...neurogenic inflammation. In this process, a cascade of cellular and sub-cellular events...the sensory nervous system and its peptidenergic transmitters (i.e. SP, CGRP, NKA) initiate and sustain this inflammation...In normal physiological settings, the respiratory epithelial population and its sensory innervation act reciprocally to influence the growth, differentiation, and homeostasis of each other...These relationships are especially critical to the organism's inflammatory response...In all instances, sensory neurons release 10-200 fold higher levels of IL-6 (pro-inflammatory cytokine) relative to epithelial cells...conditions associated with chemical pollutants are characterized by damage to the epithelial barrier that lines the airways. Such damage not only results in the loss of critical neuropeptide deactivating enzymes (e.g. NEP) but allows the sensory fiber to physically extend closer to the airway lumen and in closer proximity to the inhaled PM particles...enhanced and prolonged inflammatory events...increased inflammatory response..."

 

And again (from MCS 5) MEGGS W.J. HYPOTHESIS FOR THE INDUCTION AND PROPAGATION OF CHEMICAL SENSITIVITY BASED ON BIOPSY STUDIES. ENV H PERSPECT (SUPPL 2) 473-78 1997:

"...There are defects in the tight junctions between respiratory epithelial cells, focal desquamation of the epithelial cells in places, hypertrophy of glandular structures, lymphocytic infiltrates, and proliferation of sensory nerve fibers...tumor necrosis factor is produced by lymphocytes..."

 

And MEGGS W.J. ARCH ENV H 54(5); 309-11 1999:

"...The mechanism by which inflammatory conditions are provoked by chemicals is via chemoreceptors on sensory nerve c-fibers with the release of substance P and other mediators of neurogenic inflammation...progression of inflammation to organ damage is possible to those who continue to be exposed..."

 

Despite the oversight - as though not knowing airway induced inflammation as cause with genetics and environment as co-factors, DELUCA 2010 is important for its measurement and discussion of serious and severe alterations as approximations from their graphical presentation show:

Cytokines, chemokines, and growth factors elevated

IFN-y controls 20 MCS 55, IL-8 controls 4 MCS 12, IL-10 controls 2 MCS 7, MCP-1 controls 10 MCS 20, PDGF controls 1500 MCS 3500, VEGF controls 2 MCS 16

Redox parameters - severe glutathione depletion and nitric oxide high

catalase activity controls 14 MCS 4, GST activity controls 3.6 MCS 2.0, GPX activity controls 24 MCS 27, GSH controls 370 MCS 275, GSSG controls 34 MCS 25, NO2/NO3 controls 15 MCS 30

Fatty acid profile altered indicating lipid peroxidation

SFA controls 33 MCS 37, PUFA controls 47 MCS 42, N-6 linoleic (c18;2w6) controls 12.4 MCS 11.2, N-3 linolenic (c18;3w6) controls 1.0 MCS .4, arachidonic acid (20;4w6) controls 20.8 MCS 19, Omega 3 (c22:6w3) controls 4.3 MCS 3.3 These alterations are in a pro-atherogenic direction.

 

DELUCA 2010 further state in their analysis:

"...Dysfunction of two major antioxidant enzymes and depletion of glutathione inevitably leads to severe oxidative stress and impaired elimination of phase 1 oxidation metabolites. Excessive amounts of hydrogen peroxide due to catalase deficiency will initiate a non enzymatic free radical driven chain reaction of lipid peroxidation implicated in a number of human pathologies..."

 

In the cleanest air and normalizing, upon re-exposure the disease starts in the airway and the systemic picture measured in the study can be felt to proceed secondarily as an almost immediate spontaneous progression.

Most MCS people are in enough continous exposure to be unaware of their airway as pathological - many only identifying downstream multi-organ symptoms. This was confirmed in airway biopsies and rhinoscopy by Meggs and others who found airway defects even in an MCS person unaware of airway symptoms (Meggs 1997).

In continuous exposure the airway performs a deceiving masking phenomena (Bessac 2008) - airway symptoms become sub acute - but the disease process of airway initiated inflammation continues. The airway may be noticed upon sudden change of exposure intensity and then goes into hiding again.

Upon emerging into clean air, often airway symptoms are part of  an acute hangover lasting 4 days with a peak of congestion at 24-48 hours. Once normalizing - if there is an exposure - the airway may momentarily tweak a symptom (as if a warning) such as a burning sensation or scratching of the throat - or it may change into a slightly nasal octave - and then may level as if no symptoms - but near immediate and delayed secondary symptoms manifest such as pain in the head and eventual congestion.

 

The ambient air consists of a combustion byproduct aerosol including solid particle agglomerates with adsorbed hydrocarbons, liquid condensed hydrocarbon particles, sulfate with hydratation, and vapor phase hydrocarbons (SOCIETY OF AUTOMOTIVE ENGINEERS. SCHEMATIC OF DIESEL PARTICLES AND VAPOR PHASE COMPOUNDS. SAE PAPER NO.940233 1994).

Cumulative exposure to these hydrocarbon laden particles is huge - and riding on genetic airway vulnerability - it drives MCS. Those reporting chemical sensitivity and referring to a specific high exposure event - such as a solvent or pesticide as causing MCS may be mistaken - more accurately it may have precipitated the disease - which had already existed as a predisposition or in a subjectively unrecognized chronic low grade form. In contrast, many people - such as those working in automotive repair with gasoline and solvents - may be exposed with identical severity but most don't come down with MCS.

Every census district within all counties of the US has enough ambient pollution to raise cancer risk (Woodruff (EPA) PUBLIC HEALTH IMPLICATIONS OF 1990 AIR TOXIC CONCEN... ACROSS THE UNITED STATES) and provoke the airway induced MCS disease process - so that almost everyone has exposure nearly 24/7 365 days of the year.

Breathing combustion derived particulate aerosol since birth - the gradual development of MCS due to continual exposure and a genetic airway predisposition is often unnoticed.

The biggest load of chemical is usually on fine particles and closer to source the more reaction. Vehicle exhaust is very potent arriving from 10 miles and 1 hour away - even involving just 1 or a few vehicles. Plumes that have mixed and at least several hours or a day old may provoke much less inflammation.

MCS is not the same for everyone - but in general it is incorrect to overlook the airway - in most cases it is cause. This acknowledgement - though there may be something that can be consumed to reduce suffering and inflammation - precludes drugs and nutraceuticals as a solution - because the only cure would be a new airway - and puts the moral imperative on cleaning up the environment - reducing population and consumption and changing chemical usage and combustion habits.

Every year - not only has the plight of MCS sufferers worsened - but so has the environment of the World. In big ways and small we are responsible. What are you and I doing to make the World a better environment?

 

(abbreviations: IFN-y interferon gamma, IL-10 interleukin, MCP-1 macrophage chemotactic protein, PDGF platelet derived growth factor, VEGF vascular endothelial growth factor, catalase erythrocyte antioxidant activity, GST the glutathione family of conjugating biotransformative and anti-inflammatory enzymes, GPX glutathione peroxidase, GSSG glutathione oxidized form, NO2/NO3  Nitric Oxide, SFA saturated fatty acid, PUFA polyunsaturated fatty acid)

 

MCS is usually very high levels of neurogenic inflammation - including release of inflammatory neuropeptides, cytokines, chemokines, growth factors, nd nitric oxide - elevated plasma markers of inflammation -

arising from airway epithelial damage and exposed C-fiber nerves -

in a continuous environment of combustion byproduct aerosol -

with genetic vulnerability in the airway epithelial cell population and its sensory innervation usually a co-factor -

and resulting in disabling near immediate and secondary complications including increased nitric oxide and peroxynitrite formation, lipid peroxidation, dysfunction of metabolizing and anti-oxidant enzymes, central nervous system effects, and porphyrin abnormalities

.

What is MCS? (expanded) 

 

MCS is usually very high levels of neurogenic inflammation - including release of neuropeptides, cytokines, chemokines, growth factors, and nitric oxide (Mohankumar 2008, Veronesi 2001, Bascom 1992 MCS 6) - elevated plasma markers of inflammation (Badolato MCS 13, 7,  Deluca 2010,  Kimata 2004) -

arising from airway epithelial damage and exposed c fiber sensory nerves (Mohankumar 2008, Bessac 2008, Castranova 2002, Bonham 2001, Veronesi 2001, Meggs 1997, 1996,1993) -

reactive and measurable (Millquist 2005, Nogami 2004) -

in a continuous environment of combustion byproduct aerosol including particle agglomerates with adsorbed hydrocarbons and singlet nonagglomerated nanoparticles

Deering-Rice 2011, Hazari 2011, Li 2011, Taylor-Clark 2010,  Baulig 2009, 2003a,  Calderon-Garciduenas 2008, 2000, Veronesi 2003, 2002a, 2002b, 2001, 2000, 1999a, 1999b, Agopyan 2003, Bonvallot 2001, 2000, Gerde 2001, 1997, Oortgiesen 2000, Roy 2000, Miyabara 1998,1998a, Steerenberg 1998, Meggs 1997

OSHA 2012, Block 2009, Pakkanen 2003, Schauer 2002, 2001, 1999, US DOT FHA 2000, Society of Automotive Engineers SAE 940233 1994

Lucchini 2012, Mohankumar 2008,  Inoue 2005, Kittelson 1998, Cadle 1999, Kleeman 1999  

Fine particles expected to reach the CNS via trigeminal and olfactory nerve pathways

(Badolato MCS 11, Calderon-Garciduenas 2010, Genter 2009, Matsui 2009, Elder 2006, Lewis 2005)

with genetic vulnerability in the airway epithelial cell population and its sensory innervation usually a co-factor (MCS 15, Eberling 2009, Veronesi 2001, 2000, Roy 2000, Miyabara 1998, Jung 1921) - neuropeptides, TRP receptors, and acid sensitive pathways on c fiber sensory neurons lining the nasal and upper pulmonary airways critical to the homeostatic regulation of inflammatory response and activity of immune system cells -

resulting in disabling near immediate and secondary complications including increased nitric oxide and peroxynitrite (Deluca 2010), lipid peroxidation (Badolato MCS 13, Deluca 2010), dysfunction of chemical defense systems - metabolizing and antioxidant enzymes including decreased erythrocyte catalase and glutathione-s-transferase activity, severe glutathione depletion, and cytokine mediated suppression of cytochrome P450 and aryl hydrocarbon receptor activity (Deluca 2010) -

central nervous system effects (Tran 2012, Nassini 2011, Orriols 2009,  Calderon-Garciduenas 2008, Bell 1999, 1998)

and porphryrin abnormalities (Hahn 1997, Daniell 1997).

 

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