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Pathomechanism

There are two toxicological approaches to explain the pathomechanism of MCS: the model of the neurogenic inflammation and the model pf the chemical inflammation.

Neurogenic inflammation

Chemical exposure can occur in patients without them perceiving an unpleasant odor. This leads to changes in brain functions: There is a reduced blood flow to the temporal lobe, the two temporal regions and the prefortal areas of the cerebral cortex. This disorder is permanent in chronically ill patients. Further exposure to triggering substances leads to an additional reduced blood flow to the olfactory brain in the right and left hippocampus, in the right Parahippocampal gyrus, in the right amygdala, in the right thalamus and in the right lower cerebral cortex. In healthy patients, other regions are affected by decreased blood flow.

Volatile, organic compounds also lead to prolonged reaction and reflex times, a disturbed sense of balance, a decline in the ability to differentiate between colors and cognitive performance.

A direct transport of chemicals via the olfactory system has been demonstrated in rats. There, Harmful substance act directly on the brain, since the blood–brain barrier is circumvented: from the olfactory mucosa to the olfactory bulb / 1. Cranial nerve, on to the amygdala and finally into the limbic system and via the thalamus to the frontal cortex.

Repeated excitation of this nervous system leads to sensitization, especially in the limbic system, as a result of which the threshold for subsequent reactions to chemicals is lowered. This in turn leads to an unspecific readiness to react to substances to which someone has not yet been exposed.

After exposure of MCS patients to volatile, organic compounds, the values of nerve growth factor and of vasoactive peptide rise above the already increased base value. This is not the case in patients with allergic eczema or allergic dermatitis. This enables the distinction between neurogenic inflammation and atopic or allergic forms.

TRP receptors

The binding of certain foreign substances or pollutants to chemo- or nociceptors of sensitive C-fibers in the skin, internal organs and mucous membranes of the airways leads to their excitation and the transmission of this signal to the central nervous system. The most important nociceptors are the vanilloid and the TRP receptors. These are activated by capsaicin, reactive oxygen compounds, volatile fungal toxins of the dialdehyde type (e.g. isovalleral) or volatile organic emissions. The receptors are therefore jointly responsible for the triggering in phase II and for the development of the symptoms in phase I. The C-fibers excited by the receptors send the signal to the spinal cord and the medulla oblongata. As a result,Glutamate is released and the NMDA receptor is activated. It is phosphorylated and thus permanently switched to an activated state, so that there is an increased sensitivity to stimuli with the same stimulus. Some of the nerve cells activated in this way release Substance P into the CNS and the periphery. Substance P is in turn responsible for triggering inflammatory and pain reactions.

The clinical picture of Fibromyalgia is partly caused by the same mechanism.

The TRPA1 receptor, a subgroup of the TRP receptors, is a chemoreceptor that is activated by substances such as allicin gingerol, mustard oil, cinnamaldehyde, allyl isothiocyanate and by isovalleral is irritated. In addition, it binds pollutants such as acrolein, isothiocyanates, other organic irritants in exhaust gases and various aldehyde components in cigarette smoke, but also metabolites of various drugs and 4-hydroxynonenal. It is assumed that the isocyanates evaporating from polyurethane foams act via the TRP receptor. Animal experiments have shown that the covalent bond to the TRPA1 receptor causes inflammation and pain reactions. The covalent bond comes about because electrophilic substances interact with a SH-group of a cysteine residue on the TRPA1 receptor. Such substances are increasingly found in cigarette smoke, smog but also fire smoke and are the cause of life-threatening shortness of breath in the case of smoke poisoning. This group of substances also includes all products of oxidative stress and lipid peroxidation. As a result of the covalent bond, the receptor remains in its activated state even after the substances have acted, which in turn leads to a lowering of the sensitivity threshold. The symptoms of this sensitivity reaction, especially to organic solvents and some pesticides, are due to the function of the TRP receptors and are reminiscent of rhinitis or asthma. Therefore one speaks of a "Reactive Airway Dysfunction Syndrome" (RADS). However, allergen-specific antibodies or T lymphocytes are missing in this form of asthma: activated effector cells of the immune system (e.g. mast cells) are detectable.

In addition to the TRPA1 receptor, chemical substances can also act directly in the brain on TRPV1. The resulting increased release of glutamate leads in turn to the activation of the NMD-receptors and thus ultimately to the development of inflammatory processes. Such chronic inflammations induce genes for synthesis new TRPV1 receptors on sensory nerve fibers of the airways and thus lead in turn to increased sensitivity to chemical substances.

NMDA receptors

The activation of the NMDA receptor caused by glutamate leads to the increased formation of nitrogen monoxide (NO), a trigger of inflammatory reactions. Therefore, with MCS or also CFS, increased parameters of the NO metabolism such as Citrulline, citrulline-bound peptides or increased NO concentrations in the exhaled air.

Three Nitric oxide synthases are involved in the development of MCS: the neutral NOS (nNOS), the endothelial NOS (eNOS) and the inducible NOS (iNOS). They are all activated, among other things, by calcium that has flowed into the cell through the activated NMDA receptor. In particular the iNOS shows a much increased activity in inflammation.

Nitric oxide reacts with superoxide radicals and other reactive oxygen compounds to form peroxynitrite, a strong oxidant that inhibits superoxide dismutase (SOD) in particular. As a result, the enrichment of the ROS leads to an increased formation of nitric oxide. Functionally restricted Mitochondria as well as structural damage and inflammation in the brain and nervous system arise. The increased chemical sensitivity in the limbic system is limited to the brain regions in which NMDA receptors occur. The disturbance of the energy metabolism caused by the NO peroxynitrite cycle causes the NMDA receptors to be over-sensitive to other stimuli. This is done by lowering the membrane potential.

The SH group of cysteine is the main target of nitric oxide; the formation of these nitrosyl compounds is mostly reversible. Peroxynitrite, on the other hand, reacts with the OH group from tyrosine to nitrotyrosine in an irreversible process. The blockade of tyrosine leads to functional disorders of the thyroid and thus to the blockage of the formation of thyroid hormones. In many chronic, inflammatory diseases such as arteriosclerosis, multiple sclerosis, amyotropic lateral sclerosis or Parkinson's disease, the nitro and nitrotyrosine concentrations are increased. Melatonin is also nitrosated. Furthermore, peroxynitrite SH group oxidizes enzymes. The activated NMDA receptor and the iNOS induced thereby lead to an increased formation of Peroxynitrite with the associated nitration of tyrosine and oxidation of SH groups in proteins. An example of this would be Glutathione S-transferase, the active center of which is inhibited by nitration of the tyrosine. As a result, detoxification reactions can only take place to a reduced extent. Furthermore, enzymes for the biosynthesis of dopamine, serotonin, tyrosine hydroxylase and tryptophan hydroxylase are inhibited. The resulting lack of dopamine and serotonin causes key symptoms of MCS and CFS, such as depression and chronic fatigue. The lack of melatonin caused by the inhibited synthesis of serotonin leads to sleep disorders.

Peroxynitrite plays a central role in a number of cell-damaging processes in acute and chronic diseases such as stroke, myocardial infarction, chronic heart failure, diabetes, cancer, neurodegenerative diseases and chronic inflammatory diseases. It oxidizes important metabolic substances such as vitamin C, glutathione,unsaturated fatty acids, cholesterol, tocopherol, lycopene, coenzyme Q10 and makes them ineffective. This leads to oxidative stress. When the brain is still in the stage of development and differentiation, the maturation of the nerve cells and their growth are inhibited. This can lead to permanent impairment of mental performance in children.

The binding of glutamate to the NMDA receptor increases the formation of ROS, nitric oxide, peroxynitrite and damages the cell membrane through lipid peroxidation, which leads to the triggering of apoptosis. The result is functional disorders in the brain, muscles, the retina of the eyes, intestinal mucosa and immune system.

Both nitric oxide and peroxynitrite inhibit respiratory metabolism and energy balance in the mitochondria. Nitric oxide inhibits the iron-sulfur centers of complexes I, II and IV of the respiratory chain and thus their function in electron transport. Due to the lack of Adenosine triphosphate leads to the "energy deficiency syndrome" or "mitochondrial disease", because ATP-dependent ion pumps (e. g. Na-K-ATPase) of the nerve cells can only work to a limited extent or are even completely inhibited. There can also be disturbances in the transmission of nerve impulses along the axon fibers. This results in the symptoms of peripheral and central polineuropathy and encephalopathy. The energy deficiency syndrome itself manifests itself in symptoms such as extreme tiredness, short-term, coma-like deep sleep after meals in connection with uncontrolled salivation and heavy snoring, rapid exhaustion during mental and physical activity and muscle weakness with lactic acidosis. The syndrome is characterized by aerobic glycolysis: Damage to the mitochondrial enzymes means that the hydrogen split off from the glucose can no longer be oxidized. The electron is therefore transferred directly to oxygen without the participation of NADH, so that more oxygen radicals and superoxides are formed. This leads to genotoxic and inflammatory reactions such as radical chain reactions with unsaturated fatty acids in the membrane (lipid peroxidation). Parkinson and Huntington's disease are typical representatives of diseases as a result of the energy deficiency syndrome.

Ppesticides of organophosphates have a neurotoxic effect and inhibit the enzyme acetylcholinesterase in the nervous system and brain. As a result, the neurotransmitter acetylcholine is no longer broken down, so that acetylcholine increases muscarinic and nicotinic receptors in the nervous system and the brain. This leads to increased glutamate release and NMDA receptor activation. Organophosphates are also contained in plasticizers, flame retardants, or plastic building materials such as soundproofing and thermal insulation panels, in upholstery and assembly foams and in electronic devices. As a result of this broad application, the pollutants get into the indoor air, accumulate in house dust and from there finally get into the human organism.

Pesticides of the group of pyrethroids attack the sodium ion channels in the membranes of nerve cells in the brain, which also carry the NMDA receptor. After the cell has been excited, they slow down the closing of the sodium channels, so that the NMDA receptors are strengthened.

GABA receptors

Nerve toxins, especially chlorinated hydrocarbon insecticides such as hexachlorocyclohexane, lindane, chlordane, deildrin, aldrin and toxaphene, but also various active ingredients ensure non-competitive inhibition at the GABAa receptors. With repeated exposure to low concentrations, neurotoxic insecticides such as Endosulfan, Chlordimeform, Amitraz, Chlorpyrifos and Lindane it can cause epilepsy-like seizures. The concentration threshold of a new seizure falls with each exposure. By administering NMDA antagonists, this can be reduced or completely prevented.

Binding to the picrotoxin binding site of the GABA receptor by pesticides such as lindane or dieldrin leads to an influx of chloride and thus to the functional inhibition of the GABA receptor.

By inhibiting the GABA receptors, the regulation of nerve activity is blocked by negative feedback, so that there is increased nerve activity and thus the release of glutamate.

Chemical ignition

When people with MCS are exposed to chemicals - especially fragrances - basophils release increased amounts of histamine. The basophilic granulocytes have the above-mentioned TRPV1 receptors and other TRP receptors.

Furthermore, after exposure to volatile chemicals, MCS sufferers developed symptoms of severe rhinitis with increased mucus secretion. In this nasal wash, in contrast to healthy test persons, histamine and some inflammation markers such as cytokines, interferons and nitric oxide could be detected. Similar reactions could be demonstrated in cell cultures through exposure to substances from fungi and microorganisms.

Reactive Oxygen Species (ROS)

Reactive oxygen species can arise from the effects of foreign substances and pollutants. For example, there is a connection between the effect of 7,12-Dimethylbenz(a)anthracene and an increase in the ROS in rat follicle cells before they lead to apoptosis. Adding glutathione can prevent apoptosis in the cell cultures.

In the lung tissue, particulate matter can cause the formation of reactive oxygen species. In particular, inhalation of dust containing heavy metals leads to a significantly increased formation of oxygen radicals in the immune cells of the lungs compared to the control group. Substances bound to the surface of the particles, such as quinones, can cause oxidative stress further promote. In animal experiments with rats, these fine dust particles could be detected in the liver, heart and brain. Through the action of cyclooxygenases as a result of fine dust such as diesel soot or carbon particles, eventually reactive oxygen species arise. This is done by activating the gene for the cyclooxigenase-2 in macrophages in the tissue of the alveoli. The increased formation of ROS now intensifies inflammatory reactions in the lungs via the induction factor NF-κB.

In the immune system, the physiological function of the ROS is to kill pathogens and trigger inflammation via NF-κB. If the inflammation is chronic, however, ROS attacks cells and tissues in your own body.

In animal models it was shown that a reduction in ROS led to a decrease in 8-hydroxyguanine, an indicator of oxidative damage to DNA. Furthermore, compared to the control group, there was less heart damage or arteriosclerotic vascular changes - even in advanced age. Membrane proteins accumulate due to the oxidation of SH groups under the action of ROS. Because of the now existing covalent disulfide bridges, the membrane proteins are restricted in their mobility. The lipid molecules of the lipid bilayer now have a less ordered arrangement, so the membrane is more permeable to ions such as hydrogen or potassium.

Nitric oxide synthases induced by ROS form increasingly nitrogen monoxide and, together with ROS, peroxynitrite. Peroxynitrite triggers the chain reaction of lipid peroxidation. This process is known as nitrosative stress. In addition to peroxynitrite, other oxygen radical formers such as adriamycin, paraquat, nitrufurantoin or paracetamol trigger lipid peroxidation. During the metabolism of paracetamol to N-acetyl-p-benzoquinone imine the superoxide anion O₂ is formed. When carbon tetrachloride is metabolized, the trichloromethyl radical (CCl₂) or the trichloromethyl peroxy radical (CCl₂OO).

Lipid peroxidation can cause great damage, especially in the brain. This is because the brain has a relatively low antioxidant capacity and has a high oxygen demand. This need is associated with a higher production of oxygen radicals in the mitochondria. The polyunsaturated fatty acids present in the membranes of the nerve cells of the brain are particularly susceptible to lipid peroxidation. If this mechanism of oxidative stress is no longer prevented with glutathione, this contributes to degenerative processes, which can ultimately lead to dementia and Alzheimer's disease.

A protein domain of the p66Shc protein produces hydrogen peroxide with the help of copper. In addition, in the event of cellular stress, four p66Shc molecules combine via cysteine-cysteine interactions to form a stable complex, which causes the mitochondria to burst and thus triggers apoptosis. Both glutathione and thioredoxin can inhibit the activity of p66Shc.

The apoptosis of a nerve cell in the brain also ensures the apoptosis of the presynaptic (upstream) nerve cell. The reason for this is that the life-sustaining reaction of the postsynaptic cell on the presynaptic cell is no longer given by growth hormones. As a result, degeneration processes spread far beyond the once affected cell.

In the human organism there is a delicate relationship between reducing and oxidizing substances. Oxidative stress shifts this redox equilibrium in the direction of oxidation, which leads to a reversal in the direction of pathogenic processes. Due to an excess of oxidizing substances, about lymphocytes are more easily attached to the endothelial cells of the blood vessels and promote inflammatory processes there. The cellular redox potential shifts from about −0.24 V on the mitochondrial membrane to positive values. The value in blood plasma saturated with oxygen is 0.22 V. Due to the close connection with inflammation, this is also referred to as inflammation syndrome.

In order to compensate for the lack of reducing SH groups as in cysteine or glutathione, the cell metabolism tries to compensate for the cysteine deficiency through new synthesis from methionine. However, since the mitochondrial function is disturbed, there is too little NADH, so that methyl-tetrahydrofolic acid cannot be regenerated from folic acid. Due to the lack of methyl tetrahydrofolic acid, homocysteine cannot be converted to methionine; homocysteine accumulates and is therefore a sign of chronic inflammatory processes or oxidative stress. ROS are considered to be the trigger for the formation of factors such as heat shock proteins. Pollutants and foreign substances induce the HSP group 60/65, which normally act as a protective system against physical and chemical stress stimuli. In mononuclear cells of the peripheral blood of MCS patients, a strong increase in HSP-60-expression was demonstrated.

NF-κB and cytokines

Oxidative and nitrosative stress, especially ROS, activate the transcription factor NF-κB, which sets numerous inflammatory mechanisms in motion. In animal experiments it could be proven that - after 6 hours of administration of coal dust with a concentration of 300 µg/m³ via the breath - the oxidative stress increased and the migration of the NF-κB subunits B50 and B65 into the cell nucleus began. These subunits ensure an increased synthesis of mRNA at the sites in the DNA that code for pro-inflammatory cytokines (Interferon-γ, TNF-α, Interleukin-6).

The synthesis of NF-κB is up to 10 times higher in the cells of the immune system in MCS patients compared to control persons. In addition, NF-κB remains permanently active due to the ROS leads to an excess of proinflammatory cytokines. Interferon-γ-values are already increased in MCS patients before a provocation load; there is a further increase upon exposure. The secretion of Interleukin-10 by peripheral lymphocytes, however, is reduced by more than half both before and after a challenge. Interleukin-10 normally reduces inflammatory responses via negative feedback.

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