Title: Role of TRPA1 in acute cardiopulmonary toxicity of inhaled acrolein.

Authors: Conklin, Daniel J; Haberzettl, Petra; Jagatheesan, Ganapathy; Kong, Maiying; Hoyle, Gary W

Published In Toxicol Appl Pharmacol, (2017 Jun 01)

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 (100-275ppm, 10-30min) caused upper airway epithelial sloughing, bradypnea and oral gasping, hypothermia, cardiac depression and mortality. Male wild-type mice (WT, C57BL/6; 5-52weeks) 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; 200mg/kg) alone or with combined TRPA1 (100mg/kg) and TRPV1 (capsazepine, 10mg/kg) antagonists at 30min 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.

PubMed ID: 27592100

MeSH Terms: Acrolein/administration & dosage; Acrolein/toxicity*; Animals; Female; Inhalation Exposure/adverse effects*; Lung/drug effects*; Lung/pathology; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Organ Culture Techniques; Sex Factors; TRPA1 Cation Channel; Transient Receptor Potential Channels/physiology*