Transient receptor potential (TRP) A1 channels are cation channels found preferentially on nociceptive sensory neurones, including capsaicin-sensitive TRPV1-expressing vagal bronchopulmonary C-fibres, and are activated by electrophilic compounds such as mustard oil and cinnamaldehyde. Oxidative stress, a pathological feature of many respiratory diseases, causes the endogenous formation of a number of reactive electrophilic alkenals via lipid peroxidation. One such alkenal, 4-hydroxynonenal (4HNE), activates TRPA1 in cultured sensory neurones. However, our data demonstrate that 100 microm 4HNE was unable to evoke significant action potential discharge or tachykinin release from bronchopulmonary C-fibre terminals. Instead, another endogenously produced alkenal, 4-oxononenal (4ONE, 10 microm), which is far more electrophilic than 4HNE, caused substantial action potential discharge and tachykinin release from bronchopulmonary C-fibre terminals. The activation of mouse bronchopulmonary C-fibre terminals by 4ONE (10-100 microm) was mediated entirely by TRPA1 channels, based on the absence of responses in C-fibre terminals from TRPA1 knockout mice. Interestingly, although the robust increases in calcium caused by 4ONE (0.1-10 microm) in dissociated vagal neurones were essentially abolished in TRPA1 knockout mice, at 100 microm 4ONE caused a large TRPV1-dependent response. Furthermore, 4ONE (100 microm) was shown to activate TRPV1 channel-expressing HEK cells. In conclusion, the data support the hypothesis that 4-ONE is a relevant endogenous activator of vagal C-fibres via an interaction with TRPA1, and at less relevant concentrations, it may activate nerves via TRPV1.