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A1416 - Effects of a Potent and Selective p38α MAPK Inhibitor (CHF6297) in a Novel Model of Corticosteroid-Resistant Allergic Asthma
Author Block: L. Ravanetti1, A. Dijkhuis2, T. Dekker2, F. Facchinetti3, G. Villetti3, R. Lutter1; 1Respiratory Medicine, Academic Medical Centre/University of Amsterdam, Amsterdam, Netherlands, 2Experimental Immunology, Academic Medical Centre/University of Amsterdam, Amsterdam, Netherlands, 3Chiesi Farmaceutici, Parma, Italy.
Rationale. Steroid-resistant asthma is a major unmet need in asthma therapy. Disease heterogeneity and lack of representative animal models underlie the poor understanding of pathogenic mechanisms and hampers the identification of therapeutic targets. Inhibition of p38 MAPK is considered a new possible intervention for the treatment of inhaled corticosteroids (ICS)-resistant asthma. Contributions of p38 MAPK to pathogenesis, mechanisms involved and potential for therapeutic targeting remain elusive. We aimed to develop a robust chronic asthma model ICS-resistant and therefore to investigate the roles and therapeutic targeting of the p38 signaling. Methods. Mice were sensitized i.n. 5 days a week for 5 weeks to HDM extract and LPS simultaneously. During the 4th and 5th week of sensitization experimental groups have been treated with Fluticasone Propionate (FP) or a highly selective p38α MAPK inhibitor designed for inhalation delivery (CHF6297). Cellular influx was assessed by FACS analysis in BAL, lungs, draining lymph nodes (mLNs) and blood; cytokines were measured by ELISA and luminex (Milliplex) in BAL and lung by ex vivo intracellular staining. PenH was determined as a measure of airway hyperresponsiveness (AHR). Results. Exposure to HDM/LPS enhanced AHR, lymphoid and myeloid cells influx into the airways, increased Th1 and Th2 cytokines, IL1- and IL17-family cytokines, leukocytes chemoattractant molecules and the neutrophil activation marker MPO in BAL and lung. None of these inflammatory parameters were attenuated by FP treatment in HDM/LPS-treated mice, while FP dampens inflammation in mice treated with HDM or with LPS only. On the contrary, CHF6297 significantly reduced total cells number, eosinophils, neutrophils, alveolar macrophages, dendritic cells and innate lymphocytes in BAL of HDM-LPS sensitized mice. Conclusions. Exposure to HDM combined with LPS aggravates airway inflammation, causes enhanced AHR and worsens a broad inflammatory response in airways that are not sensitive to FP treatment. In this corticosteroid-resistant asthma model, the selective p38α MAPK inhibitor CHF6297 resulted in broad suppression of myeloid and lymphoid cells infiltrate in the airways. The study is supported by Chiesi Farmaceutici S.p.A. and the U-BIOPRED consortium that receives funding from the European Community and from the European Federation of Pharmaceutical Industries and Associations as an IMI JU funded project.