PI3K, p38 and JAK/STAT signalling in bronchial tissue from patients with asthma following allergen challenge

Thomas Southworth; Sarah Mason; Alan Bell; Isabel Ramis; Marta Calbet; Anna Domenech; Neus Prats; Montserrat Miralpeix; Dave Singh

doi:10.1186/s40364-018-0128-9

PI3K, p38 and JAK/STAT signalling in bronchial tissue from patients with asthma following allergen challenge

Biomark Res. 2018 Apr 11:6:14. doi: 10.1186/s40364-018-0128-9. eCollection 2018.

Authors

Thomas Southworth^{1

2}, Sarah Mason¹, Alan Bell¹, Isabel Ramis³, Marta Calbet³, Anna Domenech³, Neus Prats³, Montserrat Miralpeix³, Dave Singh¹

Affiliations

¹ 1Division of Infection, Immunity & Respiratory Medicine, The Medicines Evaluation Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
² 3The University of Manchester, 2nd Floor Education and Research Center, Wythenshawe Hospital, Southmoor Road, Manchester, M23 9LT UK.
³ Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain.

Abstract

Background: Inhaled allergen challenges are often used to evaluate novel asthma treatments in early phase clinical trials. Current novel therapeutic targets in asthma include phosphoinositide 3-kinases (PI3K) delta and gamma, p38 mitogen-activated protein kinase (p38) and Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling pathways. The activation of these pathways following allergen exposure in atopic asthma patients it is not known.

Methods: We collected bronchial biopsies from 11 atopic asthma patients at baseline and after allergen challenge to investigate biomarkers of PI3K, p38 MAPK and JAK/STAT activation by immunohistochemistry. Cell counts and levels of eosinophil cationic protein and interleukin-5 were also assessed in sputum and bronchoalvelar lavage.

Results: Biopsies collected post-allergen had an increased percentage of epithelial cells expressing phospho-p38 (17.5 vs 25.6%, p = 0.04), and increased numbers of sub-epithelial cells expressing phospho-STAT5 (122.2 vs 540.6 cells/mm², p = 0.01) and the PI3K marker phospho-ribosomal protein S6 (180.7 vs 777.3 cells/mm^2,p = 0.005). Type 2 inflammation was increased in the airways post allergen, with elevated levels of eosinophils, interleukin-5 and eosinophil cationic protein.

Conclusions: Future clinical trials of novel kinase inhibitors could use the allergen challenge model in proof of concept studies, while employing these biomarkers to investigate pharmacological inhibition in the lungs.

Keywords: Allergens; Asthma; Bronchoscopy; Immunohistochemistry; JAK-STAT signalling; Kinase; Phosphoinositide 3-kinase; p38 mitogen-activated protein kinase.