Airway Genetics and Ambient Combustion Aerosol

SPC 9 Veronesi: Sensory Nerve Insight

SPC 9 Veronesi: Sensory Nerve Insight

Links: 35 CAR Test SPC Questions
CAR Warm Up
SPC 1 Introduction: South Pole CAR (SPC) - A Character Test
SPC 2 South Pole CAR: ACA PM, Band Cell, and Monocyte Drop
SPC 3 ACA PM and ME/CFS: Do We Hear An Echo?
SPC 4 ACA UFPM: In the RBC - Through the BBB
SPC 5 ACA UFPM: IL-1 beta, RBC, BBB, - MCS and ME/CFS
SPC 6 ACA UFPM: Nerve Penetration
SPC 7 ACA UFPM: Olfactory, BBB, AD, PD, MCS, and ME/CFS
SPC 8 ACA PM: Gastro-Inflammation, Immunity, Vagal Circuitry
SPC 9 Veronesi: Sensory Nerve Insight
SPC 10 Kimata: Histamine Warning - Return to Masking
SPC 11 Central Sensitization: Intense, Repeated, and Sustained Inputs

On CAR
SPC 12 Disease Conditions Begin: Airway Epithelial Injury
SPC 13 Exposed Sensory Nerves - TRPA1
SPC 14 Exposed TRPA1: Central Sensitization
SPC 15 ACA: Loud and Clear
SPC 16 Airway Cytokine Release: Principle Mediator of Systemic Inflammation
SPC 17 Calderon-Garciduenas: Airway to Systemic: Putting It Together
SPC 18 Airway Gaps - Exposed Nerves - UFPM to the CNS
SPC 19 ACA PM: Months and Years Residence Time
SPC 20 Airway Gaps: Reduced Detox Enzyme Intervention
SPC 21 Solvents and Pesticides Primary: Shoe Fits Glove?
SPC 22 Veronesi and Roy: Genetic Difference in Airway Sensitivity

SPC 23 Jung Was Right Sort Of
SPC 24 Veronesi and Jung: A Perfect Match
SPC 25 Tailpipe and Chimney Emissions: Horizontal Coning
SPC 26 How Far Symptoms Travel: 25 Years, 500 Locations, 22 States
SPC 27 Not Into That Kind of Entertaining
SPC 28 Does it Cost More Than Money?
SPC 29 Airway to Systemic: Dysfunction of Detox Enzymes - Terlecky
SPC 30 Airway to systemic: Dysfunction of Detox Enzymes - Khatsenko
SPC 31 Gerde and Stadler: Benzo[a]pyrene Forever?
SPC 32 Phase I and II Detox Enzymes Defined

Lifestyle Change
SPC 33 ACA Catastrophic Consequences
SPC 34 Impossibly Good City Design
SPC 35 South Pole CAR Test: Satisfaction Guarantee

MCS 3 Definition and Concensus Criteria

MCS 3a Criteria Amendment Research Points (CAR)

MCS 3aa Etiology: Concensus Author CAR Test (SPC)

MCS 3b CAR References

SPC 9 Veronesi: Sensory Nerve Insight

Please choose the Incorrect Statement

SPC 9a)

Historically, inflammation has been described in immunological terms.
MERCK 1999:
"...the phagocytic system, whose function is to ingest and digest...Phagocytes include neutrophils and monocytes (in the blood) and macrophages (in the tissues). Widely distributed, macrophages are strategically situated at the interfaces of tissues with blood or cavitary spaces; eg, alveolar macrophages (lungs), Kupffer cells (liver sinusoids), synovial cells (joint cavities), perivascular microglial cells (lining of CNS), mesangial phagocytes (kidneys)...

...Cytokines affect the magnitude of inflammatory or immune responses...

...Specific immunity has the haulmarks of learning, adaptability, and memory. The cellular component is the lymphocyte...Lymphocytes are divided into two subsets: thymus-derived (T cell) and bone marrow-derived (B cell)...Although intimate cell contact is necessary for optimal T-cell responses, T-cells and monocytes secrete cytokines, which can influence close or distant events...

...Resolution...An immune response can be associated with massive lymphocyte proliferation and differentiation (eg, enlarged tonsils with strep throat). What happens to lymphocytes when the infection is controlled? As mentioned above, an immune response is associated with the secretion of several cytokines. When the infection is controlled and the Ags are removed, cytokine secretion turns off. When cytokine secretion ceases, the lymphocytes undergo apoptosis (programmed cell death)..."

SPC 9b)

In recent years, the role of the sensory nerve receptors in determining the inflammatory immune response has been highlighted.

VERONESI 2001:

"...these studies (Veronesi 1999a, 1999b) indicated that human tracheal-bronchial epithelial cells (i.e. BEAS-2B) housed irritant receptors and acid sensitive pathways, which when triggered released inflammatory cytokines...When these receptors are activated by irritants, they respond with a rapid increase in CA2+, and the subsequent release of inflammatory cytokines (i.e. IL-6) and neuropeptides from their cell bodies (Marz 1998, Murphy 1995)...

...Sensory neurons and BEAS-2B were exposed to equal numbers of ROFA or SPM particles. Biological activation (i.e. increase in Ca2+, IL-6 release) occurred in both cell types in response to either ROFA or SPM...

...BEAS-2B epithelial cells and DRG neurons were exposed at equivalent concentrations and exposure times to PM from industrial, ambient, residential, and volcanic sources. In all instances, sensory neurons released 10-200 fold higher levels of IL-6 relative to epithelial cells...This disproportionate inflammatory response of two critical airway target cells may be relevant to the susceptible population component of PM 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... Found elevated in MCS patients (Dantoft 2014)...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..."

SPC 9c)

Receptors on airway epithelial cells, sensory neurons, and immune cells both respond to - and secrete cytokines and neuropeptides - but the key ingredient of MCS is continuous exposure of sensory nerves in damaged and remodeled airway epithelium - with greater release of inflammatory cytokines and neuropeptides compared to intact epithelial cells.

SPC 9d)

In defiance of the old medical model which has cytokines turn off and lymphocytes undergo apoptosis when the infection is removed - instead continuous exposure to the ACA and other chemicals perpetuate neuroimmune inflammatory response by activation of exposed sensory receptors. Meggs 1997 discovered lymphocytic infiltrates in the damaged airway epithelium shown in MCS biopsies.

SPC 9e)

Airway defects resulting in an altered cytokine profile and subsequent systemic inflammation are also likely in CFS and ME/CFS (myalgic/ encephalomyelitis, chronic fatigue syndrome) (Maes 2012).

SPC 9f)

An additional complication concerns more particles reaching the lower airway to be involved with alveolar macrophages because of the less than intact respiratory nasal mucosa that Meggs 1997, Calderon-Garciduenas 2001, and Veronesi 2001 have described - resulting in still more cytokine production greater release of polymorphonuclear leukocytes (PMN) from the bone marrow and still more cytokine production.

MEGGS 1997:

Biopsy of MCS subjects

"...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..."

CALDERON-GARCIDUENAS 2001:
"...PM clearance from the nose depends largely on intact mucociliary mechanisms, and whereas deposition of particles larger than 3 microns (um) takes place in the anterior part of the nose (devoid of ciliated epithelium), particles beween 0.5 and 3 um are filtered by an intact respiratory nasal mucosa and transported by ciliary propulsion to the nasopharynx (Fry 1973)...
...Chronic exposures to air pollutants pose significant public health concerns for healthy individuals as well as those at higher risk, such as asthmatics and patients with compromised cardiorespiratory function. A compromised nasal epithelium has a diminished ability to protect itself and the lower respiratory tract..."

MUKAE 2001:

"...We conclude that repeated exposure to PM-10 (particulate matter less than 10 microns in diameter) stimulates the bone marrow to increase the production of polymorphonuclear leukocytes (PMN) in the marrow and accelerate the release of more immature PMN into the circulation. The magnitude of these changes was related to the amount of particles phagocytosed by alveolar macrophages..."

HOGG 2009:

"...alveolar macrophages, epithelial and other cells interact with the particles to produce a wide variety of cytokines and chemokines that generate a local inflammatory immune response. These mediators spill over into the blood to stimulate the bone marrow to increase the release of leukocytes from the marrow, and the liver to increase the production of a variety of acute phase proteins. This systemic response is associated with vascular activation and the progression of the atherosclerotic process..."

Baldwin 1998 found increased cardiopulmonary disease risk in a community based sample having odor intolerance.

It is cause, effect, and catastrophe - illness and premature death - perpetuated by the use of combustion based transportation and woodstoves.

HOGG 2009:

"...elevation in the levels of circulating leukocytes is an important predictor of both an excessive decline in lung function (Chan-Yeung 1988) and increased all cause mortality (Weiss 1995)..."

SAKAI 2004:

"...The results in this study show that a low level of atmospheric PM is associated with a decrease in bone marrow stimulation, which results in decreased circulating segmented PMN, band formed PMN, and monocyte counts...IL-6 levels were parallel with band formed counts...

...It is considered that the atmospheric PM level is one of the important factors affecting circulating leukocyte counts and basal inflammatory status...

...Multiple regression test showed that PM levels had more significant effects on segmented PMN, band formed PMN, and monocyte counts than cigarette smoking and type of work..."

HIRAIWA 2013:

"...Of all the pollutants, inhalable particles (PM-10) showed the strongest association with adverse respiratory health effects (Schwartz 1995)...data from large population cohorts have indicated an association between exposure to PM and cardiovascular morbidity and mortality (Brook 2010, Eftim 2008, Miller 2007, Pope 2004)...due to the systemic inflammatory response induced by exposure to PM air pollution (Hogg 2009)..."

Sensory nerves - including TRPA1 expressing peptidergic terminals - exposed in a damaged airway epithelium of tight junction defects and focal desquamation (Meggs 1997) - in contact with ACA PM and other chemicals - are activated to excessive release of neurotransmitters (Veronesi 2001, Meggs 1997). MCS people suffer intense, repeated, and sustained input - changes in neural plasticity referred to as central sensitization ( Latremoliere 2009) - and evidence electroencephalographic alterations (Bell 1998, 1996) and SPECT hypoactivity strongly suggestive of UFPM to the CNS (Calderon-Garciduenas 2010, 2008, Orriols 2009, Elder 2006).

SPC 9g)

Because MCS people have airway defects there may be a sharing of at least some aspects of the following description (Block 2009, Calderon-Garciduenas 2008).

Airway breakdown occurs universally beginning in childhood among non-smoking residents of ACA PM 2.5, UFPM, and PM LPS - highly polluted Mexico City (MC) (Calderon-Garciduenas 2008, 2001) - and is accompanied by a closely investigated CNS pathology of neuroinflammation - subclinical early - but associated with eventual neurodegeneration due to ACA PM, adsorbed compounds, byproducts of ozone exposure (photochemical smog resulting principally from vehicle exhaust), and cytokines reaching the brain.

The CNS condition includes increased inflammatory markers iNOS (inducible nitric oxide synthase), TNF alpha, Il-1beta, COX-2 (cyclooxygenase-2), and NFkB (nuclear factor kB) especially in frontal cortex, substantia nigrae, and vagus nerves (found systemically elevated in ME/CFS [Maes 2012]),

neuron damage or loss, microglial activation (innate immune system macrophages of the brain - their job to engulf and digest but with cumulative collateral damage) indicated by increase of HLA-DR surface antigen positive cells and CD-14 lipopolysaccharide (LPS) receptors - LPS a potent inflammatory cell wall component of gram negative bacteria (endotoxin) commonly adsorbed on DEP (diesel exhaust particles) (Block 2004) - with resulting ROS (reactive oxygen species) and cytokine production, blood-brain barrier (BBB) dysfunction - changes in inflammatory , tight junction, and transport proteins of the cerebral vascular microvessels (3 to 8 micron diameter) that comprise the BBB - endothelial cell damage with increase in leukocyte adhesion molecules - and confirmed using Positive Emission Tomography - activated microglia and astrocytes evidencing brain neuroinflammation in ME/CFS patients - found to correlate with degree of cognitive impairment (Nakatomi 2014) - and two markers of BBB opening - nitrotyrosin and protein S100B - elevated in a subset of MCS and EHS (electrohypersensitivity) subjects (Belpomme 2015).

accumulation of Abeta-42 (42 amino acid form of amyloid beta) as neuronal, vascular and diffuse plaques, Abeta and alpha synuclein aggregation (associated with Alzheimers and Parkinsons Disease respectively) - CALDERON-GARCIDUENAS 2008:"...Both Abeta42 (42 amino acid-isoform of beta amyloid associated with Alzheimer's) and alpha synuclein ( an abundant brain 140-residue-protein linked to Parkinson's disease) are proteins capable of aggregation and misfolding (shown to occur more rapidly in conditions of PM exposure), leading to progressive neurodegeneration that develops insidiously over the lifetime of the individual (McGeer 2006, Jellinger 2003, Nguyen 2002, Selkoe 2002, 2001)...",

lipid peroxidation (systemically confirmed in MCS people [Deluca 2010]), astrogliosis evidenced by enhanced glial fibrilliary acid protein (GFAP) expression, and DNA damage (Block 2009, Calderon-Garciduenas 2008).

In contrast, non-smoking residents of less polluted cities Veracruz and Tlaxcala - upon the same examination appeared in good shape during childhood - but four of the five oldest subjects age 27 and above - 27, 36, 40, and 45 demonstrated either dysruption of the BBB (blood-brain barrier) by confocal microscopy for tight junction abnormalities (Zonula Occlulens ZO-1) or Abeta42 (42 amino acid-isoform of beta amyloid) immunoreactivity by immunohistochemistry in olfactory bulb and cortical neurons of one subject - and in diffuse and mature senile plaques in another - a preAlzheimer's-like indicator of brain neuroinflammation (Calderon-Garciduenas 2008).

Although more is worse - there is no safe level of chronic and repeated exposure to combustion byproducts including vehicle exhaust.

SPC 9h)
Damage to the barrier that lines the airways and proliferation of exposed sensory nerve fibers found in MCS people (Meggs 1997) does not result in a neuroimmune inflammatory response to ACA PM and other chemicals with systemic multi-organ implications.