RT Journal Article
SR Electronic
T1 New inhaled JAK inhibitor LAS194046 inhibits allergen-induced airway inflammation in Brown Norway rats
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 3412
VO 44
IS Suppl 58
A1 Isabel Ramis
A1 Elena Calama
A1 Anna Domènech
A1 Cristina Carreño
A1 Elena Calaf
A1 Mònica Cordoba
A1 Joan Alberti
A1 Jorge De Alba
A1 Jordi Bach
A1 Neus Prats
A1 Montserrat Miralpeix
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/3412.abstract
AB Introduction: Janus kinase (JAK) is an emerging target for the treatment of asthma and COPD. We have identified a potent and selective pan-JAK inhibitor with excellent lung retention by inhaled administration.Aim: To describe the efficacy of the new JAK inhibitor LAS194046 in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration.Methods: Plasma and lung concentrations of LAS194046 were measured after intratracheal (i.t.) administration in Wistar rats. In OVA-sensitized Brown Norway rats, LAS194046 was administered by aerosol 1 h prior to the OVA challenge. BAL and lung tissue were obtained 24 h post challenge. Total and differential BAL cells counting was performed by Sysmex. Cytokines in BAL were measured by Luminex technology. Phosphorylated STAT3 (pSTAT3 Y701) was assessed in lungs by ELISA and IHC.Results: Sustained lung levels were observed whereas plasma levels dropped very fast after i.t. administration. In the OVA model, aerosolized JAK inhibitor A dose-dependently inhibited eosinophil and neutrophil counts as well as IL-6, MIP1α, MCP1 and IL1-β levels in BAL. In lung tissue, the compound inhibited OVA-induced pSTAT3 in bronchial epithelium, vascular smooth muscle and parenchyma. Alveolar inflammation, alveolar hemorrhages and interstitial edema were also reduced.Conclusions: LAS194046 by inhaled route is efficacious at reducing airway inflammation and pSTAT3 in lung. These findings confirm that JAK is involved in allergen-induced inflammation and suggest that JAK inhibition by inhaled route might be a potential therapeutic option for asthma treatment.