Investigating the role of extracellular ATP in Chronic Respiratory Diseases
File(s)
Author(s)
Issop, Sabina
Type
Thesis
Abstract
Chronic cough is a common symptom of respiratory diseases driven by activation of airway sensory nerves that express ion channels and receptors, including purinergic P2X3 channels, which are activated by ATP. A non-selective P2X3 receptor antagonist, Gefapixant, was one of the first drugs to show antitussive efficacy in clinical trials in treatment-refractory chronic cough patients. However, there are no data demonstrating levels of eATP in patients with refractory or unexplained chronic cough (RUCC) which is hypothesised to be increased in bronchoalveolar lavage fluid (BALF) and plasma samples.
Current methods used to measure eATP in biological samples are not always reliable or reproducible given that eATP rapidly degrades in the extracellular space. As such, a reliable and reproducible method for the collection and assessment of eATP in biological samples was developed.
In vitro and ex vivo experiments were used to show activation of vagal sensory nerves by the endogenous ATP ligand which could be blocked using P2X3 antagonists. However, in the clinic, P2X3 antagonists are commonly associated with taste disturbance side effects. Alternative strategies could include CD39, an ecto-nucleotidase enzyme that breaks down ATP and reduces activation of vagal sensory nerves by depleting levels of ATP. eATP levels were investigated in several airway disease models where decreases in eATP were measured in BALF samples. CD39 was also tested in an acute cigarette smoke model but had no impact on several key inflammatory markers, highlighting the need for alternative animal models with elevated eATP.
In patients with RUCC, the levels of eATP were reduced in BALF samples, but were increased in plasma samples. This increase supports the hypothesis that eATP is a driver in chronic cough and may have potential use as a clinical biomarker to select patient populations with elevated eATP who are more likely to respond to ATP-targeted therapies.
Current methods used to measure eATP in biological samples are not always reliable or reproducible given that eATP rapidly degrades in the extracellular space. As such, a reliable and reproducible method for the collection and assessment of eATP in biological samples was developed.
In vitro and ex vivo experiments were used to show activation of vagal sensory nerves by the endogenous ATP ligand which could be blocked using P2X3 antagonists. However, in the clinic, P2X3 antagonists are commonly associated with taste disturbance side effects. Alternative strategies could include CD39, an ecto-nucleotidase enzyme that breaks down ATP and reduces activation of vagal sensory nerves by depleting levels of ATP. eATP levels were investigated in several airway disease models where decreases in eATP were measured in BALF samples. CD39 was also tested in an acute cigarette smoke model but had no impact on several key inflammatory markers, highlighting the need for alternative animal models with elevated eATP.
In patients with RUCC, the levels of eATP were reduced in BALF samples, but were increased in plasma samples. This increase supports the hypothesis that eATP is a driver in chronic cough and may have potential use as a clinical biomarker to select patient populations with elevated eATP who are more likely to respond to ATP-targeted therapies.
Version
Open Access
Date Issued
2024-01-14
Date Awarded
01/08/2024
License URL
Advisor
Belvisi, Maria
Tetley, Terry
Birrell, Mark
Bonvini, Sara
Wortley, Michael
Dubuis, Eric
Sponsor
Wellcome Trust (London, England)
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)