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

Abstract

BackgroundInhaled 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.MethodsWe 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.ResultsBiopsies 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.ConclusionsFuture 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.

An endothelial microRNA-1–regulated network controls eosinophil trafficking in asthma and chronic rhinosinusitis

“…119 All these signaling pathways have been implicated in asthma and mediate critical functions within the airway structural cells. [120][121][122][123][124][125] It is of note that even though the elucidated targets of miR-1 provide a coherent molecular mechanism for its effect on tissue eosinophilia, these findings do not rule out a direct effect of miR-1 on the intrinsic signaling events within eosinophils. There are limitations to our investigation.…”

Novel Inhaled Pan-JAK Inhibitor, LAS194046, Reduces Allergen-Induced Airway Inflammation, Late Asthmatic Response, and pSTAT Activation in Brown Norway Rats

“…Dose-response studies to explore the effect of lower doses of LAS194046 on pSTAT6 showed that 0.3 and 1 mg/kg had similar significant effects. Increase of several pSTATs has been reported in the literature in human airway of patients with asthma and COPD (Christodoulopoulos et al, 2001;Mullings et al, 2001; Yew-Booth et al, 2015), proving relevance Profile of the New Inhaled Pan-JAK Inhibitor LAS194046 of the JAK-STAT pathway in those diseases and the potential for these proteins to be used as target engagement markers in clinical studies (Southworth et al, 2018).…”

Identification of pAKT as a pharmacodynamic marker for MER kinase in human melanoma G361 cells

“…pAKT is an important biomarker for human cancer [22][23][24][25]. To establish pAKT as a direct phosphorylation target of MER kinase, we developed a MER cellular assay and compared the inhibition of MER activation and AKT phosphorylation.…”