2-butenal and Neurogenic-Inflammation

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 alpha,beta-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 Ca2+ 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 Ca2+ 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 Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify alpha,beta-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.

Topics: Acrolein; Aldehydes; Animals; Ankyrins; Calcitonin Gene-Related Peptide; Calcium Channels; Calcium Signaling; Cell Line; Ganglia, Spinal; Guinea Pigs; Humans; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurogenic Inflammation; Neurons, Afferent; Nicotiana; Rats; Smoke; Substance P; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPC Cation Channels

Airway irritants cause a variety of lung pathologies. Two separate studies, the first recently reported in the JCI by Bessac et al. and the second reported by Andrè et al. in the current issue of the JCI (see the related article beginning on page 2574), have identified irritants that activate transient receptor potential cation channel, subfamily A, member 1 (TRPA1) receptors in airway sensory neurons, resulting in neurogenic inflammation and respiratory hypersensitivity. The identification of TRPA1 activation by toxicants from cigarette smoke and polluted air, such as crotonaldehyde, acrolein, and oxidizing agents such as hydrogen peroxide, is an important finding. These two studies enhance our understanding of how pollution and cigarette smoke can damage airway function and will hopefully pave the way for the development of rational alternative therapeutics for such airway injury.

Topics: Acrolein; Air Pollutants; Aldehydes; Animals; Calcium Channels; Guinea Pigs; Mice; Models, Biological; Neurogenic Inflammation; Neurons, Afferent; Nicotiana; Oxidants; Respiratory Hypersensitivity; Respiratory System; Respiratory Tract Diseases; Smoke; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels