Cleaning products as indoor air pollutants: role of alkylphenols in airway sensory irritation
File(s)
Author(s)
Baxter, Billy Peter
Type
Thesis or dissertation
Abstract
A growing body of epidemiological evidence suggests that cleaning product exposure has deleterious effects on respiratory health, which could be attributed to the activation of airway sensory nerves. 4-tert-octylphenol (4-t-OP), an alkylphenol that results from the rapid breakdown of non-ionic surfactants in cleaning products, was identified as a possible cause of cleaning-related airway symptoms and the aim of this thesis was to investigate whether 4-t-OP can activate airway sensory nerves. In vitro, 4-t-OP caused depolarisation of guinea pig vagus nerve segments and calcium influx in airway-specific neurons, indicating that 4-t-OP can activate airway sensory nerves. In vivo, 4-t-OP triggered guinea pig vagus single fibre firing and also increased tracheal pressure, the latter suggesting that 4-t-OP can induce bronchoconstriction. Various pharmacological tools were used in vitro and in vivo to characterise the mechanism driving 4-t-OP-induced airway sensory nerve activation. A novel mechanism was identified with two independently stimulated pathways: the first involving activation of GPER and downstream activation of the ion channel TRPM3; and the second involving activation of the ion channel TRPV4, leading to the release of ATP and subsequent activation of P2X2/3 purinoceptors. In vitro organ bath experiments demonstrated that 4-t-OP can cause airway smooth muscle contraction and that this effect is also driven through GPER, TRPM3 and TRPV4. Although the data suggested that 4-t-OP was likely to evoke cough, no cough was observed in conscious guinea pigs when tested. It was hypothesised that inhalation was affected by the complex nasal geometry of guinea pigs, so a method of nasal cavity occlusion was therefore developed. The TRPM3-selective agonist CIM0216 was then demonstrated to evoke cough in nasally-occluded guinea pigs. To summarise, this thesis provides direct pre-clinical evidence that 4-tert-octlyphenol can activate airway sensory nerves and cause airway smooth muscle contraction, which may contribute towards cleaning-related airway symptoms.
Version
Open Access
Date Issued
2024-01-02
Date Awarded
2024-06-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
Advisor
Belvisi, Maria
Tetley, Teresa
Sponsor
Biotechnology and Biological Sciences Research Council (Great Britain)
AstraZeneca (Firm)
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)