Complex Regulatory Role of the TRPA1 Receptor in Acute and Chronic Airway Inflammation Mouse Models

Abstract

The Transient Receptor Potential Ankyrin 1 (TRPA1) cation channel expressed on capsaicin-sensitive afferents, immune and endothelial cells is activated by inflammatory mediators and exogenous irritants, e.g., endotoxins, nicotine, crotonaldehyde and acrolein. We investigated its involvement in acute and chronic pulmonary inflammation using Trpa1 gene-deleted (Trpa1−/−) mice. Acute pneumonitis was evoked by intranasal Escherichia coli endotoxin (lipopolysaccharide: LPS) administration, chronic bronchitis by daily cigarette smoke exposure (CSE) for 4 months. Frequency, peak inspiratory/expiratory flows, minute ventilation determined by unrestrained whole-body plethysmography were significantly greater, while tidal volume, inspiratory/expiratory/relaxation times were smaller in Trpa1−/− mice. LPS-induced bronchial hyperreactivity, myeloperoxidase activity, frequency-decrease were significantly greater in Trpa1−/− mice. CSE significantly decreased tidal volume, minute ventilation, peak inspiratory/expiratory flows in wildtypes, but not in Trpa1−/− mice. CSE remarkably increased the mean linear intercept (histopathology), as an emphysema indicator after 2 months in wildtypes, but only after 4 months in Trpa1−/− mice. Semiquantitative histopathological scores were not different between strains in either models. TRPA1 has a complex role in basal airway function regulation and inflammatory mechanisms. It protects against LPS-induced acute pneumonitis and hyperresponsiveness, but is required for CSE-evoked emphysema and respiratory deterioration. Further research is needed to determine TRPA1 as a potential pharmacological target in the lung.

Effects of Thymus vulgaris L., Cinnamomum verum J.Presl and Cymbopogon nardus (L.) Rendle Essential Oils in the Endotoxin-induced Acute Airway Inflammation Mouse Model

“…TRPA1 and TRPV1 are expressed and often co-localized on the capsaicin-sensitive peptidergic afferents densely innervating the lung [41], as well as on pulmonary epithelial cells lymphocytes and bronchial smooth muscle cells [42,43]. TRPA1 and TRPV1 have been reported to be protective against the LPS-induced acute lung injury model [44][45][46]. The potential interactions of these essential oil components with the TRP ion channels in the LPS-induced acute lung injury model might open future drug developmental perspectives worth investigating.…”

Lung Epithelial TRPA1 Mediates Lipopolysaccharide-Induced Lung Inflammation in Bronchial Epithelial Cells and Mice

“…Previous findings regarding the role of TRPA1 in LPS-induced inflammation have been equivocal. By comparing the responses between wild-type and trpa1 –/– mice, Hajna et al (2020) demonstrated that TRPA1 protects against LPS-induced acute pneumonitis and hyperresponsiveness. Kamei et al (2018) , however, reported that TRPA1 plays no role, because TRPA1 knockout does not alter LPS-induced bladder inflammation in mice.…”

“…However, studies on the functional importance of TRPA1 in LPS-induced consequences have reported equivocal findings. TRPA1 protects against LPS-induced pneumonitis ( Hajna et al, 2020 ) and does not contribute to LPS-induced bladder inflammation ( Kamei et al, 2018 ) in mice. However, TRPA1 mediates LPS-induced lung inflammation in mice ( Liu et al, 2020 ) or inflammatory responses to LPS in vitro ( Prandini et al, 2016 ; Yin et al, 2018 ).…”

TRP Channels as Cellular Targets of Particulate Matter

“…LPS molecules on the surface of bacterial particles increase activity of TRPV4 in a matrix stiffness-dependent manner [ 57 ]. Of note, multiple TRP channels, including TRPV1 [ 58 , 59 , 60 ], TRPV4 [ 23 , 61 ], TRPA1 [ 60 , 62 , 63 , 64 , 65 ], TRPM3 [ 60 ] and TRPM8 [ 60 ] have been described as targets of LPS, probably via the induction of modifications in the plasma membrane [ 66 , 67 ]. Therefore, these TRP channels may mediate the action of PM contaminated with this bacterial component.…”

“…These components can activate TRP channels and cause deleterious effects associated with cancers, heart attack, vascular abnormalities and other pathological processes. TRPA1 is a remarkable airway chemical sensor with roles in both protective reflexes (sneezing, coughing) and pathophysiological responses (inflammation, bronchial hyperreactivity) [ 40 , 58 ]. The components found in CS can activate TRPA1 channels in the plasma membrane of cells located along the respiratory tract.…”