Multiple Chemical Sensitivity Etiology
Airway Genetics and Ambient Combustion Aerosol
Appendix: Added Splash I-VI
Appendix: Added Splash I-VI
I. Safdar 2011: To Run or Not to Run
II. MCS 2ab Etiology: Nasal Cytokines in Context
III. MCS 3ac: Belpomme 2020, Lull 2010 - Ambient PM and Reactive Microgliosis
IV. MCS 2ac Etiology: Belpomme 2015 - Formula or Reality?
V. MCS 3ad: MCS Genetics - Likely a Neural Portrait
VI. MCS 3ae Treatments Unsafe? Fermented Papaya (FPP) and Ginkgo Biloba
I. Safdar 2011: To Run or Not to Run
McMaster Daily News 2011:
"...Endurance exercise can stop you from looking and feeling old and may even help you live longer, a study by McMaster University researchers has found.
The study, published in the prestigious science journal Proceedings of the National Academy of Sciences, found that premature aging in nearly every organ in the body was completely prevented in mice that ran on a treadmill three times a week for five months [45 minutes each time].
...Mitochondria are unique in that they have their own DNA. It has been thought that lifelong accumulation of mitochondrial DNA mutations leads to an energy crisis that results in a progressive decline in tissue and organ function, ultimately resulting in aging. But the study on genetically-disadvantaged mice found those who had endurance exercise training [running on a treadmill] three times a week looked as young as healthy mice while their sedentery siblings were balding, greying, physically inactive, socially isolated and less fertile..."
Safdar A. et al. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. PNAS 108;10:4135-4140 2011
II. MCS 2ab Etiology: Nasal Cytokines in Context
Bascom 1992 observation that the airway can release cytokines is not necessarily reflected as an increase of cytokines and chemokines in MCS nasal secretions: found the same in controls at baseline, and after exposure to n-butanol (Dantoft 2015) - despite the altered systemic cytokine profile confirmed previously (Dantoft 2014).
Primary to MCS is usually genetic sensitivity (Veronesi 2001, 2000, Roy 2000, Jung 1921) together with cumulative exposure including ambient combustion aerosol (ACA) particulate matter (PM) resulting in altered structure and function of the neuro-inflammatory system (Bascom 1997): exposed and multiplied nerves confirmed in the nasal epithelium (Meggs 1997); nerve growth factor (NGF) elevated in MCS nasal secretions (Milqvist 2005); greater cough upon exposure to capsaicin (Nogami 2004); NGF, vasoactive intestinal peptide (VIP), and substance P (SP) increased systemically both at baseline and after exposure to paint (Kimata 2004); and the initiating role of TRPA1 and TRPV1 receptors on peptidergic airway nerve terminals has been elucidated by many well qualified and credible contributors as outlined in MCS 2a Etiology: TRPA1 Precision (Deering-Rice 2011, Hazari 2011, Costa 2010, Taylor-Clark 2010, Caceres 2009, Latremoliere 2009, Anand 2008, Bessac 2008, Nassenstein 2008, Bautista 2006, Inoue 2005, Kobayashi 2005, Veronesi 2001). Symptoms of MCS are often of a flu like pattern (Dantoft 2014, Bascom 1992); with increased nasal congestion (Doty 1994); hyperalgesia (Tran 2013, Holst 2011, Latremoliere 2009); neurocognitive impairment, and lightheaded aspects of cerebral hypoperfusion (Belpomme 2015, Orriols 2009).
Systemic elevation of cytokines involves alveolar macrophages, epithelial, sensory nerve, and other cells - and is relative to inflammatory exudation of fluid and cells into both large and small bronchi, bronchioles, and gas exchanging tissue (Hogg 2009, Veronesi 2001).
For example, inflammatory cytokine IL-6, rising in proportion to the amount of ACA PM reaching alveolar macrophages (Hiraiwa 2014, 2013, Hogg 2009, Goto 2004, Mukae 2001) - is nearly double among residents of Japan compared to living on the South Pole - due largely to ACA PM (Sakai 2004) - which also supports MCS disease process because many ACA components activate TRPA1 receptors (Deering-Rice 2011, Hazari 2011, Costa 2010, Taylor-Clark 2010, Caceres 2009, Anand 2008, Bessac 2008, Nassenstein 2008, Bautista 2006, Inoue 2005, Kobayashi 2005, Veronesi 2001). There is no proven safe level of chronic and repeated exposure to ACA PM - consequences include an insidious neuro-degeneration throughout the lifetime (Calderon-Garciduenas 2008, McGeer 2006, Jellinger 2003, Nguyen 2002, Selkoe 2002, 2001).
At baseline - without study provocation - MCS often includes neurocognitive impairment, SPECT hypoactivity (Orriols 2009), electroencephalographic alterations (Bell 1998, 1996), central sensitization - a functional synaptic plasticity resulting in pain hypersensitivity (Tran 2013, Holst 2011, Latremoliere 2009) - Orriols 2009 suggested that permanent neuronal damage and reduced inhibitory neuronal activity in the olfactory pathways to the orbito-frontal cortex and the limbic system may be due to penetration of UFPM, and Belpomme 2015 - in measurement of reduced brain blood flow in the temporal lobes reported cerebral capsulothalamic hypoperfusion - a potentially lightheaded hypoxia in approx 50% of MCS cases - further confirming involvement of the limbic system and thalamus in the inflammatory process - and two markers of blood brain barrier disruption (protein S100B and nitrotyrosin) elevated in 15 and 28%.
The major components of PM 2.5 and UFPM - ultrafine particulate matter less than 0.1 micron median aerodynamic diameter (Hiraiwa 2013) - an ambient exposure of 24/7/365 proportions - include transition metals, sulfate and nitrate ions, organics, minerals, adsorbed gases, and biocontaminants (endotoxins, mold, pollen) attached to a core of carbonaceous material (Gillespie 2013) acting as a vector (Bonvallot 2001, 2000, Boland 2000, 1999, Baeza-Squiban 1999, Bayram 1998, Kumagai 1997, Thomas 1997) with prolonged tissue residence time (Gerde 2001, 1997, 1991, Burtscher 1986, Adamson 1982, Natusch 1978) - most from vehicle exhaust, wood burning, and coal burning (Bernstein 2004) - and to a lesser but significant extent from oil refineries, metal processing facilities, smelters, and wildfires (Block 2009, Muhlfeld 2008, Rothen-Rutishauser 2008, Valavanidis 2008).
The Sakai 2004 study comparing exposure in Japan to the South Pole, average of all on the expedition, measured tissue damaging immature PMN (band cells) 2.37 to 1.18; monocytes were also nearly halved 3.04 to 1.46; and inflammatory cytokine IL-6 1.45 down to 0.67 day 271 in Antarctica, and back up to 1.25 day 576 on return to Japan.
Multiple regression test showed that ACA PM had more affect on segmented PMN, band PMN, and monocyte counts than cigarette smoking and type of work - demonstrated in results of the separately accomodated smokers and those with toxic occupational exposure on the voyage (Sakai 2004).
Consistent with studies (Hiraiwa 2014, 2013, Sakai 2004, Goto 2004, Mukae 2001); Hogg 2009 concluded: "...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.
With respect to the role ACA PM has in supporting disease conditions such as MCS and the physiological consequences of increased systemic inflammation and CNS neurodegenerative process - it is not realistic to dismiss MCS as a psychological syndrome or disease of unknown etiology. In this context - psychological inquiry not requested by the patient is inappropriate because it has no utility in the diagnosis, treatment, or cure of the disease.
III. MCS 3ac: Belpomme 2020, Lull 2010 - Ambient PM and Reactive Microgliosis
Outline
A. Lull 2010: Ambient PM Supports Reactive Microgliosis
B. Belpomme 2020 EHS/MCS Model - Activated Microglia
C. EHS/MCS, ME/CFS, AD, PD Data Support Microglial activation
D. UFPM Olfactory and Trigeminal Nerve Pathways
E. PM Defined - Loss of Life Expectancy
A. Lull 2010: Ambient PM Supports Reactive Microgliosis
"Microglia reside in the CNS, comprise approximately 12% of the brain (depending on brain region, health, or pathology), and serve as the brain’s immune defense...
Analogous to the role of macrophages and lymphocytes in the periphery, one role of microglia is to act as the brain’s immune defense against disease and injury. In addition to these duties, however, microglia are involved in a number of processes in the normal, healthy CNS. In a normal brain, microglia are said to be resting, and can be distinguished by both their morphology and pattern of gene expression. In this state, microglia take on a ramified appearance, in which long, thin processes extend from the cell body into the surrounding milieu...
Despite the fact that these ramified microglia are referred to as resting, they are constantly surveying the surrounding environment by extending and retracting their processes (Davalos 2005, Nimmerjahn 2005). In doing this, microglia are able to sample the microenvironment, maintain homeostasis, and identify signals that require a response. When reacting to extracellular signals, such as the presence of pathogens, foreign material, and dead or dying cells, microglia may undergo a morphological change into an ameboid shape with short or nonexistent processes (Krentzberg 1996). This morphological change is also accompanied by changes in signaling and gene expression that can result in changes in surface receptor expression, the release of pro- or anti-inflammatory factors, recruitment molecules, and ROS, among others (Si 2002, Hurley 1999, Graeber 1988, Colton 1987). The cumulative effect of these changes in morphology and phenotype is a shift from resting to activated microglia...
Reactive microgliosis drives chronic neuron damage. Both stimulation of microglia with pro-inflammatory triggers (e.g., lipopolysaccharide [LPS]), PM, paraquat, rotenone, deildren, ameloid beta), and direct neuron damage (e.g., glutamate excitability) result in microglial activation causing the release of neurotoxic factors, such as IL-1beta, nitric oxide (NO), TNF alpha, peroxynitrite (NOO-), superoxide (O2), and hydrogen peroxide (H2O2). Subsequently, after damage with either a pro-inflammatory trigger or a direct neurotoxin, the neuron releases microglial activators (soluble neuron-injury signals), such as u calpain, MMP3, alpha-synuclein, and neuromelanin, which activate microglial cells and propagate the cycle. This self-perpetuating cycle of neurotoxicity is known as reactive microgliosis. LPS = lipopolysaccharide; MMP3 = matrix metalloproteinase 3; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP = 1-methyl-4-phenylpyridinium ion; 6-OHDA = 6-hydroxydopamine; PGE2 = prostaglandin E2; PM = particulate matter. This figure was slightly modified from Block and Hong 2007...
The phenomenon of microglial priming offers valuable insight into why microglia continue to respond to additional stimuli in the chronic cycle of neuro-inflammation...In the case of priming, microglia are not just exhibiting an enhanced toxic microglial response. Rather, in the case of priming, the microglial phenotype shifts, in which a much lower stimulus is needed to exact a toxic microglial response, which enhances the probability that the chronic cycle of toxic reactive microgliosis will continue.
Microglia can be continuously activated to produce toxic factors (cytokines and reactive oxygen species) by either single or chronic exposure to disease proteins, environmental toxins, cytokines, and neuronal damage (reactive microgliosis), resulting in the progressive loss of neurons with time, a fundamental component of neurodegenerative disease..."
B. Belpomme 2020 EHS/MCS Model - Activated Microglia
Belpomme 2020 proposed an EHS/MCS specific model similar to that of Lull 2010 but without identifying the "environmental stressors".
"...In a first step, there could be an initial local inflammatory response to environmental stressors, whatever they may be. Resident microglia cells, astrocytes, and mastocytes could be the first cells in the brain locally involved in the inflammatory process, releasing inflammatory mediators such as histamine.
On the basis of our data [Belpomme 2018, 2015, Irigaray 2018a, 2018b, 2018c], it is speculated that histamine is a key mediator contributing to the induction of oxidative/nitrosative stress and, consequently, to cerebral hypoperfusion, thereby leading to some local cerebral hypoxia.
In a second step, amplification of inflammation could occur, including oxidative/nitrosative stress-related BBB disruption, allowing transmigration of circulating inflammatory cells from the blood to the brain. Finally, neuroinflammation in the brain would occur, mainly involving the capsulo-thalamic area of temporal lobes, i.e., the limbic system and the thalamus..."
C. EHS/MCS, ME/CFS, AD, PD Data Support Microglial Activation
"...cerebral hypoperfusion in one or two of the hemisphere in 50.5% of the cases...
Near 40% had a increase in histaminemia (especially when both conditions were present), indicating a chronic inflammatory response can be detected in these patients.
Nitrotyrosin, a marker of both peroxynitrite (ONOO°-) production and opening of the blood-brain barrier (BBB), was increased in 28% the cases. Protein S100B, another marker of BBB opening was increased in 15%.
Circulating autoantibodies against O-myelin were detected in 23%, indicating EHS and MCS may be associated with autoimmune response.,
We found increased Hsp27 and/or Hsp70 in 33% of the patients.
We serially measured the brain blood flow (BBF) in the temporal lobes of each case with pulsed cerebral ultrasound computed tomosphygmography (UCTS). Both disorders were associated with hypoperfusion in the capsulothalamic area, suggesting that the inflammatory process involve the limbic system and the thalamus. Our data strongly suggest that EHS and MCS can be objectively characterized and routinely diagnosed by commercially available simple tests. Both disorders appear to involve inflammation-related hyper-histaminemia, oxidative stress, autoimmune response, capsulothalamic hypoperfusion and BBB opening, and a deficit in melatonin metabolic availability; suggesting a risk of chronic neurodegenerative disease..."
Belpomme 2015 reported elevated markers of oxidative and nitrosative stress occurring in nearly identical frequency among MCS and EHS subjects - and in Belpomme 2020, Irigaray 2018a results involving EHS only - elevation of thiobarbituric acid reactive substances (TBARS), oxidized glutathione (GSSG), and NTT occurred 1 of the 3 markers in 43%, 2 of the 3 in 21%, and all 3 in 15% of the EHS subjects. Considering nearly identical occurrence of the Belpomme 2015 markers among MCS and EHS subjects it might be expected the latter findings reported in EHS subjects would be similar for MCS.
Again using UCTS, Irigaray 2018b found below normal pulsometric index (PI) indicating cerebral hypoperfusion - reduced brain blood flow (BBF) in the middle cerebral artery dependent areas iof the temporal lobes, especially the capsulo-thalamic area which corresponds to the limbic system and thalamus.
Note on Testing
The proposed routine diagnostic markers are not specific to MCS and are only elevated in the minority at any given time, 15% S100B, 28% NTT, 23% auto-antibodies against myelin, 33% Hsp27/Hsp70, and less than 40% histamine. While valuable in disease understanding at group level, they cannot be recommended as diagnostic tools - nor should anyone be pressured into such blood tests. And recall the near 40% histamine result is likely tilted upward by the improper MCS subject group inclusion criteria requiring acute respiratory symptoms.
It is malpractice to require testing for a disability claim - or any time not agreed upon by the patient as having utility in the diagnosis, treatment, or cure of the disease. There are no close correlations between these markers and level of symptom severity and functional limitations. And unless willing to risk anti-inflammatory medications - testing may have no utility for the patient.
So that no one is left out - an environmental illness disability claim process is case by case - real life detail - in determining if claimant symptoms, signs, and affect on ability are of a severe impairment such as to be unable to engage in substantial gainful employment.
ME/CFS
Nakatomi 2014 found brain neuroinflammation using positive emission tomography (PET) including activated microglia and astrocytes in correlation with the degree of cognitive impairment.
CALDERON-GARCIDUENAS 2008:
"...air pollutants including UFPM, PM 2.5, and PM-LPS produce brain neuroinflammation and neurodegeneration through at least 4 pathways...Induction of upper respiratory, lung epithelial, and endothelial injury leading to persistent chronic inflammation in the respiratory tract and systemic inflammation...
The systemic inflammation is accompanied by the production of proinflammatory cytokines such as TNFalpha, IL-6, and IL-1beta...for which brain blood vessels exhibit constitutive and induced expression of receptors...
These cytokines can activate endothelial cells in the BBB, disrupt the BBB...upregulate COX-2...and trigger cascades leading to activation of mapkinases/NFkB (nuclear transduction of NFkB in endothelial brain cells of exposed subjects). A high level of activation of NFkB in astrocytes results in increased expression of nitric oxide production that opens the BBB...once the BBB is disrupted, significant leaking of RBC and protein such as prothrombin may follow...Concomitantly with the increment in CD 163, immunoreactivity for CD68 and HLA-DR in microglia, perivascular macrophages, and endothelial cells were observed, in keeping with the inflammatory response..."
MAES 2012:
"...Inflammatory and oxidative and nitrosative stress (IO & NS) pathways play a key role in the pathophysiology of ME/CFS (Maes 2010). The findings encompass a low grade inflammation, as indicated by an increased production of nuclear factor kB (NFkB), and cyclooxygenase (COX-2), and inducible nitric oxide synthase (iNOS) (Maes 2007a, 2007b); immune activation with increased expression of activation markers, e.g. CD8+ and CD38+ and HLA-DR+ markers (Lorusso 2009); increased levels of cytokines including interleukin(IL) 1 alpha, IL-1beta, IL-4, IL-5, IL-6 and lowered IL-8, IL-13, and IL-15 levels (Fletcher 2009, Lorusso 2009)..."
AD and PD
GILLESPIE 2013:
"...Numerous clinical and experimental studies have...identified the brain to be neurochemically and neuropathologically affected by various types and sizes of PM air pollution (Gerlofs-Nijland 2010, Campbell 2009, 2005, Calderon-Garciduenas 2008, 2007, Sunyer 2008, Zanchi 2008, Sirivelu 2006, Block 2004)...
In the central nervous system (CNS), oxidative stress is largely mediated by microglia, which are macrophage-like, phagocytic cells that are activated by a broad range of stimuli, including PM (Sama 2007, Block 2004) and nanoparticles (Long 2006). Once activated, the microglia produce multiple reactive oxygen species (ROS) such as hydrogen peroxide, hydroxyl radicals and peroxynitrites (Block 2007, Fariss 2005) that can diffuse from their plasma membrane and damage nearby neurons...
The nasal olfactory pathway is believed to be a key portal of entry, where inhaled nanoparticles have been shown to reach trigeminal nerves, brainstem, and hippocampus (Wang 2008, 2007)...particulate matter has been observed in human olfactory bulb periglomerular neurons and particles smaller than 100nm were observed in intraluminal erythrocytes from frontal lobe and trigeminal ganglia capillaries (Calderon-Garciduenas 2008)...air pollution components reach the brain (Peters 2006), even penetrating deep into the parenchyma...
Alzheimer's (AD) and Parkinsons Disease Disease (PD) share early pathology in the olfactory bulb, nuclei, and pathways, with olfactory deficits being one of the earliest findings in both diseases (Doty 2008)..."
"...Parkinson's disease (PD) is a progressive neurodegenerative disease affecting about 1.6% of the general population aged over 65 (deRijk 1997)...
The clinical symptoms of PD, manifest as the loss of initiation and control of movement and appear only after a substantial loss of dopaminergic neurons (50-60%) in the substantia nigra pars compacta (SNpc) in the midbrain (Pakkenberg 1991)..."
BLOCK 2004:
"...DEP (diesel exhaust particles) are selectively toxic to DA (dopaminergic) neurons through microglia-mediated ROS production...
A predominant pathology of PD is the specific degeneration of DA neurons, while other neuronal subtypes remain generally unaffected. The neuron-glia culture model used in this study demonstrates that DEP neurotoxicity is selective to DA neurons...
DA neurons possess reduced antioxidant capacity, as evidenced by low intracellular glutathione that render DA neurons more vulnerable to oxidative stress and microglial activation, relative to other cell types (Loeffler 1994). Additionally, the mesencephalon houses the SN and contains 4.5 times as many microglia when compared with the cortex (Kim 2000)...
our data show that DEP activate microglia, that microglia are crucial to DEP-induced DA neurotoxity, that DEP stimulated microglia to produce free radicals (superoxide), and that NADPH oxidase is the source of DEP-induced microglial ROS responsible for DA neurotoxicity...
The toxicity and immune-stimulating characteristics of DEP in the lung have been linked to both the adsorbed chemicals on the outside of the carbon particle and the physical characteristics of the particle itself (Ma 2002)...
several compounds known to be toxic to DA neurons (polyaromatic hydrocarbons, quinones, and transition metals) are also found on DEP (Ma 2002). However, most of the potentially neurotoxic compounds adsorbed to DEP induce oxidative stress through redox-cycling with cytochrome P450 activity (Ma 2002, Kumagai 1995) and not through NADPH oxidase activation...
carbon black particles, which lack all chemical and biological adsorbed compounds, have been shown to produce oxidative stress in cells through the NADPH oxidase pathway (Ma 2002). Together this supports that physiochemical factors of DEP are culpable in microglia activation..."
"...Long term exposure to air pollution should be considered a risk factor for both Alzheimer's and Parkinsons diseases and APOE 4 allele carriers could have a higher risk of developing AD..."
D. UFPM Olfactory and Trigeminal Nerve Pathways
While Belpomme 2015 focused on BBB disruption associated with cerebral hypoperfusion - Orriols 2009 referred to the penetration of UFPM directly to the CNS via the olfactory nerves (Gillespie 2013, Pedata 2010, Araujo 2009, Phalen 2009, Schmid 2009, Valavanidis 2008, Calderon-Garciduenas 2008, deHaar 2006, Kreyling 2006, 2004, Donaldson 2003, Oberdorster 1996). Researchers have confirmed that UFPM of the ACA have pathways to the CNS through both the olfactory and trigeminal sensory innervation - especially in damaged nasal and upper pulmonary airway epithelium (Calderon-Garciduenas 2010, 2008, Orriols 2009, Genter 2009, Matsui 2009, Elder 2006, Lewis 2005).
"...Breakdown of the nasal respiratory and olfactory epithelium and the BBB facilitates the access of systemic inflammatory mediators and components of air pollution to the central nervous system (CNS) (Calderon- Garciduenas 2004)..."
"...MCS patients present brain signal photon emission computed tomography (SPECT) and psychometric scale changes...
In comparison to controls, cases presented basal brain SPECT hypoperfusion in small cortical areas of the right parietal and both temporal and fronto-orbital lobes. After chemical challenge, cases showed hypoperfusion in the olfactory, right and left hippocampus, right parahippocampus, right amygdala, right thalamus, right and left Rolandic and right temporal cortex regions (p<0.01)...
Neurologic dysfunction observed prior to chemical exposure could point to persistent subclinical neurologic changes. In fact, basal SPECT brain cortical hypoactivity was found in our patients. In animal models, inflammation and permanent damage of the olfactory neuronal pathways could result from translocation of inhaled ultrafine particles to the brain (Elder 2006)..."
"...The results obtained support that nano-sized DEPs (diesel exhaust particles) do in fact translocate to the central nervous system through the olfactory nerve..."
"...These data support the conclusion that a similar pattern of uptake may occur within the trigeminal system as has been observed in the olfactory system...
...into the CNS in concentrations greater than those found with systemic distribution and without penetrating the blood-brain barrier...
...These data underscore the importance of considering routes of toxicant entry that allow for bypassing of the protection afforded by the blood-brain barrier, and the importance of understanding the conditions under which these pathways are operative..."
E. PM Defined - Loss of Life Expectancy
During combustion particles are generated and PAHs (polycyclic aromatic hydrocarbons) form in the gas phase. When the exhaust cools - PAHs adsorb or condense on the particles (Burtscher 1998).
rapidly desorbed PAHs "...are deposited, slowly absorbed, and extensively metabolized in airway epithelium at prolonged elevation of the local tissue concentration (Gerde 1997)...
Over 5 months later particles in the lung and lymph nodes had only 37 and 59% of B[a]P desorbed - mostly during the initial rapid release - with the exception of more desorption from particles translocated to the lymph nodes - possibly due to environment within macrophages (Nyberg 1989, Harmsen 1985, Lundborg 1984)..."
GILLESPIE 2013:
"...The major components of PM include transition metals, sulfate and nitrate ions, organics, minerals, adsorbed gases, and biocontaminants (e.g., endotoxins, mold, pollen), attached to a core of carbonaceous material. The size of the particulates found in PM has been inversely related to its inflammatory damage (Pedata 2010, Valavanidis 2008, deHaar 2006, Oberdorster 1996) with smaller, ultra fine size particles being more toxic to the target tissue..."
HIRAIWA 2013:
"...PM-2.5 and UFPM (ultra fine particulate matter less than 0.1 micron median aerodynamic diameter) are primarily derived from direct emissions from combustion processes such as vehicle use of fossil fuel products, wood burning, and coal burning (Bernstein 2004)...several studies have shown that PM 2.5 and UFPM have the strongest association with adverse cardiovascular effects (Franck 2011, Stolzel 2007 ), which is a direct consequence of the systemic response induced by these particles (Nemmar 2002, Nemmar 2001)...
...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)..."
"...Collectively, these mediators generated by the deposition of fine particles in the lung contribute to the systemic inflammatory response by increasing circulating leukocytes, platelets and pro-inflammatory and pro-thrombotic proteins...
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..."
COPD
"...DEP injures respiratory epithelia via a luminal -apical unloading mechanism of DEP organics delivered by carbonaceous nanoparticles...
the particles' carbonaceous cores are coated with thousands of organics and heavy metals. Because large numbers of hazardous chemicals are present on DEP, its pathological effects on human airways are pleiotropic. We and others have found that DEP evokes the secretion of matrix metallo-proteinase-1 (MMP-1) from human bronchial epithelia (Li 2009, Amara 2007). Matrix metalloproteinase-1 (MMP-1) plays a role in tissue remodeling during development, inflammation, migration of inflammatory and malignant cells, and COPD and emphysema pathogenesis (Segura-Valdez 2000). It also has neurotropic effects, possibly enhancing sensitization of airway-innervating sensory neurons, contributing to airway hypersensitization and chronic cough (Conant 2004)...
TRPV4-p19s, a human genetic polymorphism previously identified as a COPD susceptibility locus (Zhu 2009), increases MMP-1 activation via increased Ca-2+ influx, providing a mechanistic link between human airway epithelia signaling, airway disease and air pollution...
TRPV4-p19s as a gain-of-function Ca-2+ permeable channel in a human respiratory epithelia cell line, in response to DEP, links COPD pathogenesis to pathologically increased Ca2+ influx into human respiratory epithelia elicited by a globally relevant air pollutant (DEP)...
our results imply that two human genetic polymorphisms are linked to respiratory health, TRPV4-p19s and MMP-1(-1607G/GG), thus highlighting the concept of disease susceptibility as a function of genetic "makeup" combined with environmental insults..."
"...a single exposure to particulate matter (PM) or gaseous air pollutants has the potential to "sensitize" the heart to subsequent arrhythmogenic stimuli, which is further worsened by the presence of underlying cardiovascular disease (Hazari 2009)...
the airways are innervated by sensory nerves bearing transient receptor potential (TRP) channels; namely, member A1 (TRPA1), and member V1 (TRPV1), which detect different types of noxious chemicals, including many of those found in the complex mixtures of common air pollutants such as DE. Activation of these nerves by airborne irritants such as ozone or acrolein causes centrally mediated autonomic "imbalance", which produces ventilatory, pulmonary, and cardiovascular function changes (Bessac 2008, Ghelfi 2008, Bautista 2006)..."
"...individuals with MCS had higher than normal pulse rate and lower than normal pulse rate variability...indicating abnormal regulation of the sympathetic branch of the autonomic nervous system during the exposure..."
USDOTFHA 2000:
"...Total social costs of air pollution associated with motor vehicle use are
estimated to range from $30 billion to $349 billion per year (Delucchi 1998). Most of those costs are associated with premature death and illness caused by particulate matter, including both direct particulate emissions and the secondary formation of particulates from other emissions. The wide range of air pollution cost estimates is indicative of the many uncertainties surrounding costs of motor-vehicle-related air pollution..."
"...Moreover, ambient PM, including sulfates, nitrates, and organic aerosols, accounts for about 95% of the total damage cost, and mortality related to ambient PM accounts for about 70% of the total damage cost..."
"...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)..."
MERCK 1999:
"...Normal values for the total white blood cell (leukocyte) count range between 4,300 and 10,800/uL;
normal values for the differential WBC count are as follows: segmented neutrophils 34 to 75%; band neutrophils <8%; lymphocytes 12 to 50%; monocytes 3-15%; eosinophils <5%; and basophils <3%..."
Polymorphonuclear leukocytes (PMN) and neutrophils are terms used synonymously as are also immature granulocytes, immature polymorphonuclear leukocytes, band neutrophils, and band cells.
CALDERON-GARCIDUENAS 2001:
"...Every child in the Southwest Metropolitan Mexico City (SWMMC) group displayed an abnormal nasal biopsy. Major findings included lack of cohesion between cells, epithelial shedding, necrotic cells, PMN (polymorphonuclear leukocyte) epithelial infiltration, and short or absent cilia...
...A multinucleated PMN is seen infiltrating the nasal epithelium. Notice the wide intercellular spaces occupied by electron-dense granular material reflecting potential deficiencies in epithelial junction integrity...PMN epithelial infiltration was seen in every SWMMC biopsy...
...An unexpected finding was the presence of PM (particulate matter) in 5 of 15 SWMMC children...PM was localized in the widely abnormal intercellular spaces, in the cytoplasm of adjacent epithelial cells, and surrounding the abnormal cilia...deposition of dark osmiophilic granular material could be seen at the epithelial borders and inside large lysosomal bodies in neighboring epithelial cells...
...the electron microscopic findings observed in the nasal epithelium of children growing up in a polluted environment are likely a reflection of sustained airway epithelial injury...Because the children had no exposure to tobacco and had negative histories of upper and/or lower respiratory diseases (either acute or chronic), the findings described here may be attributed in large part to the chronic and sequential exposure to air pollutants..."
CALDERON-GARCIDUENAS 2008:
"...Olfactory bulb (OB) neurons in the glomerular region exhibit abundant particulate matter (PM) in their cytoplasm in a fourteen-year-old Mexico City (MC) boy...
...Peribronchial lymph node in a seventeen-year old male MC nonsmoker. There are numerous macrophages in the cortical zone with black particulate matter. The afferent lymphatics also exhibit abundant PM-loaded macrophages...
...Kuppffer cells (liver macrophages) loaded with PM in the liver of a thirty-two-year old MC resident...
...thirty-three-year old male MC resident. PMNs (polymorphonuclear leukocytes) are seen attached to endothelial cells in lung capillaries, in keeping with endothelial activation...
...twenty-four-year old female MC resident...The endothelial cell lining of the lung capillary exhibits elongated fronds that surround a luminal erythrocyte (red blood cell). The endothelial fronds completely embrace the erythrocyte (12,000Xmag)...close association between the cytoplasm of the endothelial cell and the erythrocyte with aggregation of particulate matter at the interface (25,000Xmag)...same lung capillary showing the relationship between the endothelial cell membrane-bound structure with ultrafine PM and the erythrocyte (RBC) surface (50,000Xmag)...An erythrocyte (RBC) in the lumen of a lung capillary exhibits numerous nanosized particulate material (50,000Xmag)...
...Ultrafine particles are not membrane bound which allows for direct access to intracellular proteins, organelles, and DNA, enhancing there toxic potential (Geiser 2005). Further, the passage of PM to the brain following the RBC-activated endothelial cell is likely to be increased in subjects exposed to pollutants owing to the disruption of the BBB (blood-brain barrier)...
"...brain oxidative stress starts in childhood and the teen years...in the scenario of air pollution exposure...progressive neurodegeneration that develops insidiously over the lifetime of the individual (McGeer 2006, Jellinger 2003, Nguyen 2002, Selkoe 2002, 2001)..."
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