Mechanisms and Consequences of Variable TRPA1 Expression by Airway Epithelial Cells: Effects of TRPV1 Genotype and Environmental Agonists on Cellular Responses to Pollutants in Vitro and Asthma

Abstract

Background: Transient receptor potential ankyrin-1 [transient receptor potential cation channel subfamily A member 1 (TRPA1)] and vanilloid-1 [transient receptor potential cation channel subfamily V member 1 (TRPV1)] detect inhaled irritants, including air pollutants and have roles in the development and exacerbation of asthma. Objectives: This study tested the hypothesis that increased expression of TRPA1, stemming from expression of the loss-of-function TRPV1 (I585V; rs8065080) polymorphic variant by airway epithelial cells may explain prior observations of worse asthma symptom control among children with the TRPV1 I585I/V genotype, by virtue of sensitizing epithelial cells to particulate materials and other TRPA1 agonists. Methods: TRP agonists, antagonists, small interfering RNA (siRNA), a nuclear factor kappa light chain enhancer of activated B cells (NF- ) pathway inhibitor, and kinase activators and inhibitors were used to modulate TRPA1 and TRPV1 expression and function. Treatment of genotyped airway epithelial cells with particulate materials and analysis of asthma control data were used to assess consequences of TRPV1 genotype and variable TRPA1 expression on cellular responses in vitro and asthma symptom control among children as a function of voluntarily reported tobacco smoke exposure. Results: A relationship between higher TRPA1 expression and function and lower TRPV1 expression and function was revealed. Findings of this study pointed to a mechanism whereby NF- promoted TRPA1 expression, whereas NF- –regulated nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 2 (NLRP2) limited expression. Roles for protein kinase C and p38 mitogen activated protein kinase were also demonstrated. Finally, the TRPV1 I585I/V genotype was associated with increased TRPA1 expression by primary airway epithelial cells and amplified responses to selected air pollution particles in vitro . However, the TRPV1 I585I/V genotype was not associated with worse asthma symptom control among children exposed to tobacco smoke, whereas other TRPA1 and TRPV1 variants were. Discussion: This study provides insights on how airway epithelial cells regulate TRPA1 expression, how TRPV1 genetics can affect TRPA1 expression, and that TRPA1 and TRPV1 polymorphisms differentially affect asthma symptom control. https://doi.org/10.1289/EHP11076

The Cytochrome P450 2C8*3 Variant (rs11572080) Is Associated with Improved Asthma Symptom Control in Children and Altered Lipid Mediator Production and Inflammatory Response in Human Bronchial Epithelial Cells

“…Data were deidentified before genotype analysis. Characteristics of the patient population have been previously described ( Stockmann et al, 2013 ; Deering-Rice et al, 2016 ; Rapp et al, 2023 ). Saliva (2 mL) samples were collected using Oragene DNA kits (DNA Genotek Inc., Ottawa, ON, Canada), and genomic DNA was extracted for SNP genotyping following supplier protocols.…”

Lysophosphatidic acid and itsreceptors: Role in bronchial asthma pathogenesis

“…Например, С-волокна, ненейрональные клетки, клетки дыхательных путей, клетки гладкой мускулатуры, эпителиальные клетки и фибробласты экспрессируют TRPA1 [36]. Сигаретный дым, выхлопные газы автомобилей, загрязнение воздуха, активные формы кислорода, различные температурные условия входят в число известных агонистов TRPA1 [37,38]. Активация сенсорных нервов через TRPA1 инициирует кашель, секрецию слизи, гиперреактивность дыхательных путей, воспаление и развитие бронхообструкции [15,17,37,39].…”

Dual role of transient receptor potential ankyrin 1 in respiratory and gastrointestinal physiology: From molecular mechanisms to therapeutic targets

“…Inhaled irritants and environmental challenges trigger TRPA1 ( Buch et al, 2013 ; Kunkler et al, 2014 ; Rapp et al, 2023 ). Activation of TRPA1 in epithelial cells triggers immediate protective responses, initiating reflexes aimed at preserving airway integrity ( Mukhopadhyay et al, 2011 ).…”