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TOPIC: MCS ae Etiology: Airway Reactivity

MCS ae Etiology: Airway Reactivity 8 years 11 months ago #1

TRPA1 and TRPV1 may go in hand.


"...Both TRPA1 and TRPV1 may contribute to the development of hypersensitivity to noxious stimulations (i.e. hyperalgesia) (Lamotte 1992, Obata 2005, Bautista 2006, Kwan 2006, Dhaka 2006). In addition TRPA1 is activated by certain environmental irritants such as acrolein (Bautista 2006) that fail to activate TRPV1..."


"...The airways are densely innervated by sensory nerves, the majority of which are afferent C-fibres adapted to detect noxious stimuli (Carr & Undem 2003)...

...transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankryin 1 (TRPA1) are ion channels responsible for the action potential initiation in nociceptive nerves in response to a wide range of inflammatory mediators and noxious irritants (Bessac 2008)...

...ozone evokes high-frequency action potential discharge in broncho-pulmonary C-fibres, and this is a direct effect that occurs via the gating of TRPA1 channels within the C-fibre membranes..."


"...the transient receptor potential vanilloid receptor (TRPV1) formerly known as vanilloid receptor VR1 was thought to be confined to sensory C nerve cell bodies and fiber terminals...TRPV1 is now known to be broadly expressed in all "port of entry" tissues (e.g., skin, gut, airways, conjunctiva) and the various cell types lining such tissues (i.e., keratinocytes, epithelia, endothelia, etc.)...

...The TRPV1 is activated by various ligand-like agents and a plethora of seemingly unrelated stimuli such as chemical irritants, inflammatory mediators, and tissue damaging stimuli. These include capsaicinoids such as capsaicin, RTX, and olvanil; endogenous ligands such as anandamide (which also activates the cannabinoid 1 receptor); and inflammatory mediators (e.g., phorbol-12-myristate 13-acetate, lipoxygenase products, leukotriene B4, phorbol-12-phenylacetate 13 acetate 20-homovanillate). TRPV1 is also activated by nonselective stimuli: such as high temperature (>43 degrees C), acidic pH (<5.3), intracellular redox states, and electric charge. The precise mechanisms of receptor activation by such agents have not been fully established although such stimuli appear to alter protein conformation and stability through specific amino acid residues on the receptor, which results in ion influx and disruptions of structural gating..."

Returning to VERONESI 2001 reminds - that although TRP channels have been found to express more widely than on sensory c fiber nerves only - there is much higher inflammatory release from receptors on the nerves than of the epithelial cell population - and deenervation hugely reduces inflammatory response.


...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...

...BALB/c mice were deenervated of polymodal sensory c fibers by neonatal capsaicin treatment. Sensory neurons , dissected from the DGR (dorsal root ganglia) of these deenervated animals and exposed to various PM (50mg/ml) or prototype irritants failed to release IL-6 in response - implicating the sensory c fibers as critical to cytokine release in response to PM...

(Gavett 1998, Scheerens 1996, Satoh 1993, Yeadon 1992, Nielsen 1991, Prior 1990, Hayes 1981)..."

It appears that TRPA1 may be a most principle receptor - channel activation may closely match chemical reactivity of MCS - they have been shown indispensable for producing head pain.


"...TRPV1 is unlikely to represent the major reactive irritant receptor. TRPV1-deficient mice showed normal respiratory sensitivity to electrophilic agents (acrolein) and solvents (styrene)...(Symanowicz 2004)...TRPV1 lacked responsiveness to acrolein (Dinis 2004)...electrophilic irritants activated only a subset of capsaicin-sensitive neurons (Inoue 2005)...

...TRPA1 (transient receptor potential ankyrin 1) is expressed in a subpopulation of TRPV1-expressing c-fiber neurons...

...acrolein (aldehyde in smog and smoke)...is a potent agonist of...TRPA1 channels (Bautista 2006)...cultured sensory neurons from TRPA1-deficient mice lacked any responsiveness to this irritant suggesting that TRPA1 is the sole chemosensory receptor for acrolein (Bautista 2006)...

...TRPA1 is activated by (smoke constituents) methacrolein, methyl vinyl ketone, and croton aldehyde (Andre 2008, Escalera 2008)...oxidizing agents...hypochlorite (chlorine gas)...(Bessac 2008a)...formaldehyde, acetaldehyde, tear gas agents, and industrial isocyanates (Bang 2007, Bessac 2009, Brone 2008, McNamara 2007)...almost all oxidizing and electrophilic chemicals will affect TRPA1 function...endogenous agonists include reactive oxygen species (ROS), hypochlorite, lipid peroxidation products, cyclopentenone prostaglandins, and isoprostanes...

...a potential explanation for the diversity of TRPA1 agonists (Hinman 2006, Macpherson 2007)...TRPA1 is activated through covalent modification of the channel protein (agreement with Veronesi 2006)...

...aldehydes such as acrolein are strong electropliles and react with cysteine residues (amino acid component of protein)...Hypochlorite, hydrogen peroxide, and other reactive oxygen species directly oxidize cysteine thiols to sulfinic and sulfonic groups (Pereire 1973)...

...TRPA1 can be locked into a constitutively active state, indicating saturation of a reactive site (Hinman 2006)...

...three cysteine residues were crucial for channel activation (Macpherson 2007)...activation of TRPA1 by covalent modification through reactive irritants...dose response relationships and activation kinetics of TRPA1 do not conform to standard pharmacological paradigms and are highly dependent on the chemical status of the cellular and tissue environment...

...TRPA1 agonists show wide divergence, sometimes one or two orders of magnitude...TRPA1 agonist activity will depend on the reversible or irreversible nature of the chemical bonds formed and on agonist membrane permeability...

...since most TRPA1 agonist can react with thiols, cellular and extracellular reduced glutathione levels will affect the reach and potency of inhaled airway irritants. Once glutathione is depleted, either as a consequence of disease or during extended exposures, TRPA1 may respond more strongly (Deluca 2010 found MCS people have severe glutathione depletion). With each breath more reactive agonist is delivered, leading to an increase in covalent modifications and heightened TRPA1 activity...robust TRPA1 induced irritation even at low subacute exposure levels...once irreversibly modified channels may remain active for extended periods of time even when the irritant stimulus is removed...(Bessac 2008a)...

...The multiple chemical sensitivity of TRPA1...tissue injury may sensitize TRPA1 channels through inflammatory signaling pathways, thereby establishing prolonged hypersensitivity to multiple reactive chemicals (Bandell 2004, Bautista 2006, Dai 2007, Jordt 2004)..."


"...the site of action of air-borne environmental irritants is TRPA1 receptor on trigeminal nerve terminals in the epithelium of nasal mucosa. The expression of TRPV1 receptors in trigeminal neurons innervating the nasal mucosa has been demonstrated by receptor binding (Rinder 1996) and immunocytochemical studies (Damann 2006, Dinh 2003)...

...Although the initial exposure to air-borne environmental pollutants is the nasal and respiratory epithelium, it is not certain how this leads to meningeal blood vessel dilatation.

As topical (dural) administration of CGRP antagonist blocks the effects of nasally administered TRPA1 agonists on blood flow we presume that the vasodilatation is mediated by CGRP release from perivascular nerve terminals within the meninges.

Activation of trigeminal neurons innervating the nasal mucosa may propagate the signal to the meninges via trigeminal nerve collaterals as trigeminal neurons innervating the nasal cavity have collaterals projecting back into the cranium (Finger 1993).

Intraganglionic transmission (Ulrich-Lai 2001) may transmit the signal from nasal innervating neurons to nearby trigeminal neurons which innervate the meninges...

...In summary, our results demonstrate that TRPA1 receptor activation by environmental irritants stimulates CGRP release from trigeminal neurons and increases cerebral blood flow and may contribute to headache associated with environmental irritants..."


"...The California bay laurel...the 'headache tree'...inhalation...can cause severe headache crises...

...monoterpene ketone umbellone, the major volatile constituent...

...umbellone stimulates the transient receptor potential ankryin 1 (TRPA1) channel in a subset of peptidergic nocioceptive neurons (recall Bessac 2008 above), activating the trigeminovascular system...

...in wild-type mice, umbellone elicited excitation of trigeminal neurons and released calcitonin gene-related peptide from sensory nerve terminals. These two responses were absent in TRPA1 deficient mice. Umbellone caused nocioceptive behaviour after stimulation of trigeminal nerve terminals in wild-type, but not TRPA1 deficient mice...

...TRPA1 activation may either be caused directly by umbellone, which diffuses from the nasal mucosa to perivascular nerve terminals in meningeal vessels, or by stimulation of trigeminal endings within the nasal mucosa and activation of reflex pathways...

...present data also strengthen the hypothesis that a series of agents, including chlorine, cigarette smoke, formaldehyde, and others that are known to be headache triggers and recently identified as TRPA1 agonists, utilize the activation of this channel on trigeminal nerves to produce head pain...

...our observations identify umbellone, via its selective TRPA1-agonism, as a trigeminovascular stimulator...for the headache-inducing properties of California bay laurel...a similar pathway may represent the underlying mechanism responsible for headache crises triggered in sensitive people by a series of compounds present in environmental pollutants and botanical perfumes/odours (Blau and Solomon 1985, Kelman 2007, Friedman 2009)..."


"...This case suggests that the trigeminal system can play a major role in headache, probably associated with increased trigeminal afferent activity from the nasal mucosa (Ottaviani 1995)..."

The experience of sore eyeballs - whether eyes closed or not during exposure - may indicate transmission via nerve pathways - interaction of opthalmic, trigeminal, and olfactory.


"...the peripheral branches of the ophtalmic branch of the trigeminal nerve enter the olfactory bulb along with the olfactory nerve and terminate in the glomerular layer along with the olfactory neurons..."

TRPA1 may also be major in asthma.


"...TRPA1-activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma. Endogenous TRPA1 agonists, including reactive oxygen species and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma...

...Our data suggest that TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways, driving asthmatic airway inflammation following inhaled allergen challenge...

...We show that genetic deletion of TRPA1 or pharmacological channel inhibition diminishes allergen-induced inflammatory leukocyte infiltration, mucus production, cytokine and chemokine levels, and airway hyperreactivity. Trpa1 -/- mice also showed impaired acute and inflammatory neuropeptide release in the airways. In contrast, all aspects of asthmatic airway inflammation were normal in Trpv1 -/- mice..."


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Tags: MCS, TRPA1, TRPV1, afferent, c-fiber, chemical, etiology, multiple, nerves, receptors, More…
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