LAUSR

ABSTRACT Acrolein is a highly toxic, volatile, unsaturated aldehyde generated during incomplete combustion as in tobacco smoke and indoor fires. Because the transient receptor potential ankyrin 1 (TRPA1) channel mediates tobacco smoke‐induced lung injury, we assessed its role in high‐level acrolein‐induced toxicity in mice. Acrolein (100–275 ppm, 10–30 min) caused upper airway epithelial sloughing, bradypnea and oral gasping, hypothermia, cardiac depression and mortality. Male wild‐type mice (WT, C57BL/6; 5–52 weeks) were significantly more sensitive to high‐level acrolein than age‐matched, female WT mice. Both male and female TRPA1‐null mice were more sensitive to acrolein‐induced mortality than age‐ and sex‐matched WT mice. Acrolein exposure increased lung weight:body weight ratios and lung albumin and decreased plasma albumin to a greater extent in TRPA1‐null than in WT mice. Lung and plasma protein‐acrolein adducts were not increased in acrolein‐exposed TRPA1‐null mice compared with WT mice. To assess TRPA1‐dependent protective mechanisms, respiratory parameters were monitored by telemetry. TRPA1‐null mice had a slower onset of breathing rate suppression (‘respiratory braking’) than WT mice suggesting TRPA1 mediates this protective response. Surprisingly, WT male mice treated either with a TRPA1 antagonist (HC030031; 200 mg/kg) alone or with combined TRPA1 (100 mg/kg) and TRPV1 (capsazepine, 10 mg/kg) antagonists at 30 min post‐acrolein exposure (i.e., “real world” delay in treatment) were significantly protected from acrolein‐induced mortality. These data show TRPA1 protects against high‐level acrolein‐induced toxicity in a sex‐dependent manner. Post‐exposure TRPA1 antagonism also protected against acrolein‐induced mortality attesting to a complex role of TRPA1 in cardiopulmonary injury. HIGHLIGHTSTRPA1 protects mice against toxicity and mortality of inhaled high‐level acrolein.TRPA1 protection against inhaled high‐level acrolein is sex‐dependent in mice.Age (5–52 weeks old) was not a determinant of acrolein‐induced mortality in mice.TRPA1 antagonist is protective after inhaled high‐level acrolein in male mice.