Cigarette smoke–induced neurogenic inflammation is mediated by α,β-unsaturated aldehydes and the TRPA1 receptor in rodents

Abstract

Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 α,β-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce neurogenic inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca 2+ in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. These responses were abolished by a TRPA1-selective antagonist and by the aldehyde scavenger glutathione but not by the TRPV1 antagonist capsazepine or by ROS scavengers. Treatment with CSE or aldehydes increased Ca 2+ influx in TRPA1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE and aldehydes on Ca 2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify α,β-unsaturated aldehydes as the main causative agents in CS that via TRPA1 stimulation mediate airway neurogenic inflammation and suggest a role for TRPA1 in the pathogenesis of CS-induced diseases.

A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma

“…TRPA1-antagonists showed efficacy in animal models of acute and inflammatory pain and diminished the noxious effects of TRPA1 agonists known to cause asthma-related conditions (17,19,20,28,29). We asked whether a TRPA1 antagonist would prevent or diminish airway inflammation when administered to OVAsensitized Balb/C mice during the airway challenge phase of the OVA protocol.…”

“…Agonists of TRPV1 and TRPA1, such as capsaicin, acrolein, or chlorine, are potent tussive agents and have been associated with allergic and occupational asthma and reactive airway dysfunction syndrome (RADS) (12,(17)(18)(19)(20)(21)(22)(23). Potential endogenous TRPA1 agonists include reactive oxygen species, hypochlorite, and lipid peroxidation products (18,(24)(25)(26).…”

“…Similar to TRPV1, TRPA1 is activated or sensitized downstream of inflammatory PLC-coupled receptor pathways and mediates inflammatory pain sensitization (12)(13)(14)27). In animal models, TRPA1 antagonists block chemically induced inflammatory thermal and mechanical hyperalgesia, neuropathic pain, and diminish acute airway responses to chemical exposures (17,19,28).…”

Gabapentin Attenuates the Activation of Transient Receptor Potential A1 by Cinnamaldehyde

“…Agonists of TRPA1 have been found in the components in natural plants, environmental irradiants and inflammatory compounds (Macpherson et al, 2007;McNamara et al, 2007;Materazzi et al, 2008;Taylor-Clark et al, 2008). For example, isothiocyanates (the pungent component in horseradish and wasabi), allicin (a component of garlic), cinnamaldehyde (an active compound in cinnamon oil), tetrahydrocannabinol (the psychoactive compound in marijuana), acetaldehyde (an ethanol metabolite), 4-hydroxy-2-nonenal (HNE) and prostaglandin J2 (an inflammatory mediator containing reactive α, β -unsaturated aldehydes), which elicit acute pain or neurogenic inflammation by activating TRPA1 expressed in the sensory neurons (Story et al, 2003;Bandell et al, 2004;Jordt et al, 2004;Bautista et al, 2005;Macpherson et al, 2005;Trevisani et al, 2007;Andersson et al, 2008;Andrè et al, 2008;Taylor-Clark et al, 2008). Because of such polymodal nature of TRPA1 in nociception, negative modulation of the TRPA1 activity using antagonists may be beneficial for suppressing diverse types of pain.…”

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…In fact, TRPA1 is activated by a wide range of pungent and irritant compounds [125], including ingredients of various spicy foods, such as allyl isothiocyanate (mustard oil, wasabi and horseradish) [73], allicin and diallyldisulfide (garlic derivatives) [126], cinnamaldehyde (cinnamon), and environmental irritants and industry pollutants, such as acetaldehyde [127], formalin [128], hypochlorite, isocyanates [129], ozone [130], carbon dioxide [131], and acrolein [117], a highly reactive , -unsaturated aldehyde present in tear gas, and cigarette smoke [132]. Moreover, isofluorane [133], nicotine [134], NO donors [135], and cyclophosphamide [117] have been reported to activate TRPA1.…”