scholarly journals A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Alessia Balestrini ◽  
Victory Joseph ◽  
Michelle Dourado ◽  
Rebecca M. Reese ◽  
Shannon D. Shields ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Transient Receptor Potential ◽  
Phase 1 ◽  
Allergic Airway Inflammation ◽  
Receptor Potential ◽  
Airflow Limitation ◽  
Phase 1 Study ◽  
Preclinical Species ◽  
Orally Bioavailable ◽  
Transient Receptor

Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.

A role for transient receptor potential ankyrin 1 cation channel (TRPA1) in airway hyper-responsiveness?

2015 ◽  
Vol 93 (3) ◽  
pp. 171-176 ◽  
Author(s):  
Aruni Jha ◽  
Pawan Sharma ◽  
Vidyanand Anaparti ◽  
Min H. Ryu ◽  
Andrew J. Halayko
Keyword(s):  
Airway Inflammation ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cation Channel ◽  
Chronic Obstructive ◽  
Airway Narrowing ◽  
Airway Caliber ◽  
Transient Receptor

Airway smooth muscle (ASM) contraction controls the airway caliber. Airway narrowing is exaggerated in obstructive lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The mechanism by which ASM tone is dysregulated in disease is not clearly understood. Recent research on ion channels, particularly transient receptor potential cation channel, subfamily A, member 1 (TRPA1), is uncovering new understanding of altered airway function. TRPA1, a member of the TRP channel superfamily, is a chemo-sensitive cation channel that can be activated by a variety of external and internal stimuli, leading to the influx of Ca2+. Functional TRPA1 channels have been identified in neuronal and non-neuronal tissues of the lung, including ASM. In the airways, these channels can regulate the release of mediators that are markers of airway inflammation in asthma and COPD. For, example, TRPA1 controls cigarette-smoke-induced inflammatory mediator release and Ca2+ mobilization in vitro and in vivo, a response tied to disease pathology in COPD. Recent work has revealed that pharmacological or genetic inhibition of TRPA1 inhibits the allergen-induced airway inflammation in vitro and airway hyper-responsiveness (AHR) in vivo. Collectively, it appears that TRPA1 channels may be determinants of ASM contractility and local inflammation control, positioning them as part of novel mechanisms that control (patho)physiological function of airways and ASM.

Role of transient receptor potential vanilloid 1 receptors in endotoxin-induced airway inflammation in the mouse

2007 ◽  
Vol 292 (5) ◽  
pp. L1173-L1181 ◽  
Author(s):  
Zsuzsanna Helyes ◽  
Krisztián Elekes ◽  
József Németh ◽  
Gábor Pozsgai ◽  
Katalin Sándor ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Bronchial Hyperreactivity ◽  
Whole Body ◽  
Transient Receptor Potential Vanilloid ◽  
Wild Type ◽  
Trpv1 Receptors ◽  
Transient Receptor

Airways are densely innervated by capsaicin-sensitive sensory neurons expressing transient receptor potential vanilloid 1 (TRPV1) receptors/ion channels, which play an important regulatory role in inflammatory processes via the release of sensory neuropeptides. The aim of the present study was to investigate the role of TRPV1 receptors in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity with functional, morphological, and biochemical techniques using receptor gene-deficient mice. Inflammation was evoked by intranasal administration of Escherichia coli lipopolysaccharide (60 μl, 167 μg/ml) in TRPV1 knockout (TRPV1−/−) mice and their wild-type counterparts (TRPV1+/+) 24 h before measurement. Airway reactivity was assessed by unrestrained whole body plethysmography, and its quantitative indicator, enhanced pause (Penh), was calculated after inhalation of the bronchoconstrictor carbachol. Histological examination and spectrophotometric myeloperoxidase measurement was performed from the lung. Somatostatin concentration was measured in the lung and plasma with radioimmunoassay. Bronchial hyperreactivity, histological lesions (perivascular/peribronchial edema, neutrophil/macrophage infiltration, goblet cell hyperplasia), and myeloperoxidase activity were significantly greater in TRPV−/− mice. Inflammation markedly elevated lung and plasma somatostatin concentrations in TRPV1+/+ but not TRPV1−/− animals. In TRPV1−/− mice, exogenous administration of somatostatin-14 (4 × 100 μg/kg ip) diminished inflammation and hyperreactivity. Furthermore, in wild-type mice, antagonizing somatostatin receptors by cyclo-somatostatin (4 × 250 μg/kg ip) increased these parameters. This study provides the first evidence for a novel counterregulatory mechanism during endotoxin-induced airway inflammation, which is mediated by somatostatin released from sensory nerve terminals in response to activation of TRPV1 receptors of the lung. It reaches the systemic circulation and inhibits inflammation and consequent bronchial hyperreactivity.

scholarly journals A TRiP Through the Roles of Transient Receptor Potential Cation Channels in Type 2 Upper Airway Inflammation

2021 ◽  
Vol 21 (3) ◽  
Author(s):  
Wout Backaert ◽  
Brecht Steelant ◽  
Peter W. Hellings ◽  
Karel Talavera ◽  
Laura Van Gerven
Keyword(s):  
Airway Inflammation ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Upper Airway ◽  
Receptor Potential ◽  
Cation Channels ◽  
Cellular Functions ◽  
Upper Airways ◽  
Transient Receptor

Abstract Purpose of Review Despite their high prevalence, the pathophysiology of allergic rhinitis (AR) and chronic rhinosinusitis (CRS) remains unclear. Recently, transient receptor potential (TRP) cation channels emerged as important players in type 2 upper airway inflammatory disorders. In this review, we aim to discuss known and yet to be explored roles of TRP channels in the pathophysiology of AR and CRS with nasal polyps. Recent Findings TRP channels participate in a plethora of cellular functions and are expressed on T cells, mast cells, respiratory epithelial cells, and sensory neurons of the upper airways. In chronic upper airway inflammation, TRP vanilloid 1 is mostly studied in relation to nasal hyperreactivity. Several other TRP channels such as TRP vanilloid 4, TRP ankyrin 1, TRP melastatin channels, and TRP canonical channels also have important functions, rendering them potential targets for therapy. Summary The role of TRP channels in type 2 inflammatory upper airway diseases is steadily being uncovered and increasingly recognized. Modulation of TRP channels may offer therapeutic perspectives.

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