PI3Kγδ inhibition suppresses key disease features in a rat model of asthma.
Animals
Asthma
/ drug therapy
Disease Models, Animal
Rats
Male
Class Ib Phosphatidylinositol 3-Kinase
/ metabolism
Rats, Sprague-Dawley
Phosphoinositide-3 Kinase Inhibitors
/ pharmacology
Lung
/ drug effects
Dose-Response Relationship, Drug
Protein Kinase Inhibitors
/ pharmacology
Class I Phosphatidylinositol 3-Kinases
/ antagonists & inhibitors
Anti-Asthmatic Agents
/ pharmacology
Ovalbumin
/ toxicity
Phosphoinositide 3-kinase P110γδ asthma AZD8154
Journal
Respiratory research
ISSN: 1465-993X
Titre abrégé: Respir Res
Pays: England
ID NLM: 101090633
Informations de publication
Date de publication:
23 Apr 2024
23 Apr 2024
Historique:
received:
05
01
2024
accepted:
15
04
2024
medline:
24
4
2024
pubmed:
24
4
2024
entrez:
23
4
2024
Statut:
epublish
Résumé
Two isoforms of Phosphoinositide 3-kinase (PI3K), p110γ and p110δ, are predominantly expressed in leukocytes and represent attractive therapeutic targets for the treatment of allergic asthma. The study aim was to assess the impact of administration of an inhaled PI3Kγδ inhibitor (AZD8154) in a rat model of asthma. Firstly, we checked that the tool compound, AZD8154, inhibited rat PI3K γ & δ kinases using rat cell-based assays. Subsequently, a time-course study was conducted in a rat model of asthma to assess PI3K activity in the lung and how it is temporally associated with other key transcription pathways and asthma like features of the model. Finally, the impact on lung dosed AZD8154 on target engagement, pathway specificity, airway inflammation and lung function changes was assessed. Data showed that AZD8154 could inhibit rat PI3K γ & δ isoforms and, in a rat model of allergic asthma the PI3K pathway was activated in the lung. Intratracheal administration of AZD8154 caused a dose related suppression PI3K pathway activation (reduction in pAkt) and unlike after budesonide treatment, STAT and NF-κB pathways were not affected by AZD8154. The suppression of the PI3K pathway led to a marked inhibition of airway inflammation and reduction in changes in lung function. These data show that a dual PI3Kγδ inhibitor suppress key features of disease in a rat model of asthma to a similar degree as budesonide and indicate that dual PI3Kγδ inhibition may be an effective treatment for people suffering from allergic asthma.
Sections du résumé
BACKGROUND
BACKGROUND
Two isoforms of Phosphoinositide 3-kinase (PI3K), p110γ and p110δ, are predominantly expressed in leukocytes and represent attractive therapeutic targets for the treatment of allergic asthma. The study aim was to assess the impact of administration of an inhaled PI3Kγδ inhibitor (AZD8154) in a rat model of asthma.
METHODS
METHODS
Firstly, we checked that the tool compound, AZD8154, inhibited rat PI3K γ & δ kinases using rat cell-based assays. Subsequently, a time-course study was conducted in a rat model of asthma to assess PI3K activity in the lung and how it is temporally associated with other key transcription pathways and asthma like features of the model. Finally, the impact on lung dosed AZD8154 on target engagement, pathway specificity, airway inflammation and lung function changes was assessed.
RESULTS
RESULTS
Data showed that AZD8154 could inhibit rat PI3K γ & δ isoforms and, in a rat model of allergic asthma the PI3K pathway was activated in the lung. Intratracheal administration of AZD8154 caused a dose related suppression PI3K pathway activation (reduction in pAkt) and unlike after budesonide treatment, STAT and NF-κB pathways were not affected by AZD8154. The suppression of the PI3K pathway led to a marked inhibition of airway inflammation and reduction in changes in lung function.
CONCLUSION
CONCLUSIONS
These data show that a dual PI3Kγδ inhibitor suppress key features of disease in a rat model of asthma to a similar degree as budesonide and indicate that dual PI3Kγδ inhibition may be an effective treatment for people suffering from allergic asthma.
Identifiants
pubmed: 38654248
doi: 10.1186/s12931-024-02814-1
pii: 10.1186/s12931-024-02814-1
doi:
Substances chimiques
Class Ib Phosphatidylinositol 3-Kinase
EC 2.7.1.137
Phosphoinositide-3 Kinase Inhibitors
0
Protein Kinase Inhibitors
0
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Anti-Asthmatic Agents
0
Ovalbumin
9006-59-1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
175Informations de copyright
© 2024. The Author(s).
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