VALIDATION AND COMPARISON OF OZONE-INDUCED HYPERTUSSIVE RESPONSES IN THE RABBIT AND GUINEA-PIG

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

The thesis investigates establishing a hypertussive model of cough primarily in
the rabbit and with comparative experiments conducted in the guinea pig.
These models were then used to investigate the effectiveness of various
antitussives such as codeine and levodropropizine, as well as, putative
antitussives such as anticholinergics, PDE inhibitors, bronchodilators and drugs
affecting targets on sensory nerves. “Hypertussive” is a poorly recognised term
and it is defined in the context of this thesis to describe an inappropriately
frequent and/or loud cough response when compared to normative cough
responses for the same given dose and route of a given tussive stimuli.
A novel model of hypertussive cough responses was established and
validated in the rabbit and guinea pig using ozone as a sensitising agent.
Primary measures include cough frequency, cough magnitude, time to first
cough and cough duration. In further experiments lung function parameters
such as dynamic compliance and total lung resistance, and total and differential
cell counts, as well as pilot experiments involving analyzing categories of cough
“sounds” were measured. The thesis was also concerned with the measurement
and classification of cough events and in particular the discrimination of cough
events from sneeze events. Two commercially available systems and ad hoc
approaches were used to evaluate how best to describe, count and classify the
cough response and qualitative and quantitative judgement have been made to
assess a best approach.
In summary, the data in this thesis suggests that ozone is a particularly
effective acutely-acting non-allergic sensitising agent capable of shifting the
dose response curve of the cough response to citric acid leftward by 0.5 to 1 log
units. Sensitization of the cough reflex overcame desensitization of rabbits and
guinea pigs to citric acid, allowing cross-over designs to be employed. Ozone
appears to act via sensitization of the peripheral airway sensory input, but I
found no evidence that this was via an action on Transient Receptor Potential
Ankyrin 1 (TRPA1), which has previously been suggested to be an important
target for ozone. Codeine and levodropropizine were effective against
hypertussive responses, but did not block the normotussive cough.
Anticholinergic drugs were not effective against ozone sensitised cough nor
normotussive cough responses in the rabbit, but significantly inhibited
sensitised cough responses and normotussive cough responses in guinea pigs.
However, salbutamol demonstrated a similar treatment profile to the
anticholinergic drugs implying that bronchodilation is an important
mechanism to reduce the cough response in guinea pigs. Thus, these data
suggest that drug candidates that cause bronchodilation may falsely identify as
antitussives in the guinea pig model. Phosphodiesterase inhibitors were
effective at blocking the infiltration of leukocytes in both guinea pigs and
rabbits, but did not effect the acutely sensitised cough, suggesting that in this
model ozone is inducing hypertussive responses independently of leukocyte
infiltration.
Date of Award2015
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorClive Page (Supervisor) & Domenico Spina (Supervisor)

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