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

Abstract

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/mm2, 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