TOPIC: MCS as an Irritant Hypersensitivity
MCS as an Irritant Hypersensitivity 4 years 11 months ago #1
One compelling hypothesis for MCS is an irritant hypersensitivity. It explains reactions to low levels of diverse chemicals and the cross-sensitization that occurs in MCS.
We have sensory nerves that alert us to a variety of noxious mechanical, thermal, and chemical stimuli. A subset of sensory nerves can be directly activated by diverse chemical stimuli via their irritant receptors TRPA1 & TRPV1, which induces release of inflammatory neuropeptides such as CGRP and substance P. This is called neurogenic inflammation.
These sensory nerves can also activate mast cells resulting in even more inflammation. Mast cells and other inflammatory cells can then further sensitize sensory nerves, partly by releasing nerve growth factor. This neuroimmune cycle may perpetuate and progress irritant hypersensitivity.
Since these few irritant receptors can be activated by diverse chemicals, then further sensitization also results in cross-sensitization, where symptomatic reactions begin to occur to smaller exposures and milder irritants.
More recently, solitary chemosensory cells (SCCs) with bitter taste receptors have been discovered in human nasal tissue and are suspected to maybe function as an irritant-inflammatory pathway as it does in mice where SCCs, activated by diverse "bitter" irritants, in turn activate the aforementioned sensory nerves which then degranulate mast cells. [1,2]
Symptoms are partly determined by which sensory nerves are sensitized and activated, but one of the most common MCS symptoms: headache, is one of the most common complaints from exposures to environmental irritants and pollution. Hypersensitive trigeminal sensory nerves activated via TRPA1 by airborne irritants are implicated in migraines and headaches.
Many possible contributors to chemosensory nerve hypersensitivity have been hypothesized such as a defective nasal epithelial barrier, an increased density/quantity of sensory nerve fibers, their irritant receptors, their inflammatory neuropeptide content, or reduced levels of neuropeptide-degrading enzymes, or a lowered activation threshold, or increased neuropeptide receptors. Sensitized mast cells can also be degranulated by some neuropeptides such as substance P. These changes could increase sensory nerve contact with inhaled irritants and/or increase neurogenic inflammatory capacity. [4,5]
This irritant hypersensitivity process has some support from MCS studies. In one study, the MCS group had elevated plasma levels of nerve growth factor and the neuropeptides substance P and VIP. After VOC exposure, the levels of all those, and histamine, rose.  Several studies of people with MCS and chemical airway hypersensitivity had a lowered threshold for cough reflex to the TRPV1 agonist capsaicin.[7-11] People with allergic and non-allergic rhinitis often report hypersensitivity to diverse chemicals such as smoke and perfume, and have been found to have mucosal hyperinnervation with increased expression of the neuropeptides CGRP and substance P.  Exposure to high levels of TRPA1-activating chemical irritants, including chlorine and aldehydes, often induce airway hypersensitivity to chemical irritants. A study in mice showed an increasing reactivity from repeated chemical irritant exposures of the same dose. Another mouse study showed that acrolein, a TRPA1 agonist found in smoke and car exhaust, potentiated reactions to subsequent TRPA1 and TRPV1 agonists.  Although some studies have also shown desensitization from some types of irritant exposures. Depleted glutathione levels in the respiratory tissues could also increase sensitivity to reactive electrophilic irritants since the less glutathione they can react with to become neutralized, the more of the irritant molecules are available to react with sensory nerves.  There are other supporting studies too.
Irritant chemicals are ubiquitous. Reactive chemicals are used in the production of so many products, such as aldehydes like formaldehyde. Smoke and vehicle exhaust contains acrolein and other irritants. Natural irritants are also common and many of us react to the smell of ozone, chlorine, fresh cut grass, mint plants, onions, garlic, and cinnamon as well. And menthol is in so many mint flavored products such as toothpaste, mouthwash, floss, gum, breath mints, candies etc. Citric acid is a common preservative. All of those can activate TRPA1.
People with mast cell activation disorders (MCAD) often have hypersensitivities to diverse chemicals, foods etc. too. Along with chemosensory nerves, mast cell activation could play a major role in many cases of MCS. There are many potential treatment targets regarding activation of sensory nerves and mast cells.
I've read up on this in quite a lot of scientific publications and textbooks and it is very fascinating. There's so much more I'd love to add but I don't have the cognitive energy to provide a comprehensive summary yet.
Nice Explanation of some TRPA1 Activation Mechanisms
Sensory Detection and Responses to Toxic Gases
A Scientific Review of Multiple Chemical Sensitivity: Identifying Key Research Needs (Nov 2010)
1: Solitary chemosensory cells and bitter taste receptor signaling in human sinonasal mucosa
2: Cholinergic neurotransmission links solitary chemosensory cells to nasal inflammation
3: Intraganglionic Signaling as a Novel Nasal-Meningeal Pathway for TRPA1-Dependent Trigeminovascular Activation by Inhaled Environmental Irritants
4: Neurogenic inflammation: with additional discussion of central and perceptual integration of nonneurogenic inflammation.
5: Hypothesis for induction and propagation of chemical sensitivity based on biopsy studies
6: Effect of VOC exposure on plasma levels of neuropeptides, nerve growth factor and histamine in MCS
7: Increased capsaicin cough sensitivity in MCS
8: Relationship of airway symptoms from chemicals to capsaicin cough sensitivity in atopic subjects.
9: The capsaicin cough reflex in patients with symptoms elicited by odorous chemicals.
10: The capsaicin cough reflex in eczema patients with respiratory symptoms elicited by perfume.
11: Quality of life and capsaicin sensitivity in patients with sensory airway hyperreactivity
12: Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control
13: Sensory irritation and multiple chemical sensitivity
14: Sensitization of the trigeminovascular system following environmental irritant exposure.
Last Edit: 4 years 8 months ago by Bruce Hart. Reason: Deleted broken link
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