title: Role of TRPA1 in acute cardiopulmonary toxicity of inhaled acrolein.
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.
authors: Diabetes and Obesity Center, Institute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, School of Medicine, University of Louisville, Louisville, KY 40292, United States. Electronic address: dj.conklin@louisville.edu.
authors: Daniel J
authors: DJ
authors: Conklin
authors: Diabetes and Obesity Center, Institute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, School of Medicine, University of Louisville, Louisville, KY 40292, United States.
authors: Petra
authors: P
authors: Haberzettl
authors: Diabetes and Obesity Center, Institute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, School of Medicine, University of Louisville, Louisville, KY 40292, United States.
authors: Ganapathy
authors: G
authors: Jagatheesan
authors: Department of Bioinformatics and Biostatistics, School of Public Health & Information Sciences, University of Louisville, Louisville, KY 40292, United States.
authors: Maiying
authors: M
authors: Kong
authors: Department of Environmental and Occupational Health Sciences, School of Public Health & Information Sciences, University of Louisville, Louisville, KY 40292, United States.
authors: Gary W
authors: GW
authors: Hoyle
mesh_terms: D000171:Acrolein / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D005260:Female; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D012737:Sex Factors; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000502:physiology*
chemical_list: D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D000171:Acrolein
keywords: Aldehydes; Cardiac dysfunction; Oxidative stress; Pulmonary injury