The prostaglandin D2 pathway in rhinovirus-induced asthma exacerbations
File(s)
Author(s)
Farne, Hugo Andres
Type
Thesis
Abstract
Background: Despite currently available treatments, many asthma sufferers continue to experience exacerbations of their disease. This is driven by excess ‘type 2’ inflammation in a large proportion of these individuals. Antiviral interferon responses are also deficient in asthma, possibly as a consequence of excess type 2 inflammation.
The CRTH2 receptor is present on cells that are instrumental in promoting type 2 inflammation, and both CRTH2 and its ligand Prostaglandin D2 (PGD2) are upregulated in asthma, making it an attractive target. Trials to date have only shown that in mild asthma and stable disease, when presumably type 2 inflammation is quiescent, CRTH2 antagonism is relatively ineffective.
Methods: The effect of the CRTH2 antagonist OC459 on the type 2 inflammation induced by experimental rhinovirus infection in asthma was assessed in the placebo-controlled trial. A parallel mechanistic analysis was conducted to evaluate the effect of OC459 on CRTH2+ cell recruitment and activation to release type 2 cytokines, on antiviral immunity, and to understand the relative importance of PGD2-CRTH2 signalling in the pathophysiology of asthma exacerbations.
Results: Rhinovirus infection resulted in type 2 inflammation and associated worsening of asthma symptoms and lung function, which were unaffected by treatment with OC459. PGD2 was not induced by rhinovirus, with little change in CRTH2+ cell numbers in the lungs. Correlations with alternative proposed regulators of type 2 inflammation suggest IL-33 and TSLP are the predominant factors during asthma exacerbations. Antiviral immunity was not altered by OC459.
Conclusion: CRTH2 antagonism did not prevent the virally-induced worsening of asthma pathology and symptoms. Mechanistic analyses suggests PGD2-CRTH2 signalling is redundant in the recruitment of type 2 inflammatory cells and induction of type 2 cytokines in response to viral infection. Absent an effect on type 2 inflammation, it was not possible to test the hypothesis that this suppresses antiviral immunity.
The CRTH2 receptor is present on cells that are instrumental in promoting type 2 inflammation, and both CRTH2 and its ligand Prostaglandin D2 (PGD2) are upregulated in asthma, making it an attractive target. Trials to date have only shown that in mild asthma and stable disease, when presumably type 2 inflammation is quiescent, CRTH2 antagonism is relatively ineffective.
Methods: The effect of the CRTH2 antagonist OC459 on the type 2 inflammation induced by experimental rhinovirus infection in asthma was assessed in the placebo-controlled trial. A parallel mechanistic analysis was conducted to evaluate the effect of OC459 on CRTH2+ cell recruitment and activation to release type 2 cytokines, on antiviral immunity, and to understand the relative importance of PGD2-CRTH2 signalling in the pathophysiology of asthma exacerbations.
Results: Rhinovirus infection resulted in type 2 inflammation and associated worsening of asthma symptoms and lung function, which were unaffected by treatment with OC459. PGD2 was not induced by rhinovirus, with little change in CRTH2+ cell numbers in the lungs. Correlations with alternative proposed regulators of type 2 inflammation suggest IL-33 and TSLP are the predominant factors during asthma exacerbations. Antiviral immunity was not altered by OC459.
Conclusion: CRTH2 antagonism did not prevent the virally-induced worsening of asthma pathology and symptoms. Mechanistic analyses suggests PGD2-CRTH2 signalling is redundant in the recruitment of type 2 inflammatory cells and induction of type 2 cytokines in response to viral infection. Absent an effect on type 2 inflammation, it was not possible to test the hypothesis that this suppresses antiviral immunity.
Version
Open Access
Date Issued
2018-09
Date Awarded
2019-03
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Johnston, Sebastian
Jackson, David
Edwards, Michael
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)