TY - JOUR T1 - LSC 2014 abstract - Deciphering of the mechanism of the anti-asthmatic action of the CXCL12 neutraligand, chalcone 4 JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - 3415 AU - Francois Daubeuf AU - Dominique Bonnet AU - Virgile Beckaert AU - Ali Ouadi AU - Patrice Marchand AU - David Brasse AU - Patrick Gizzi AU - Marcel Hibert AU - Jean-Luc Galzi AU - Nelly Frossard Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/3415.abstract N2 - The chemokine receptor CXCR4 and its chemokine CXCL12 are involved in the recruitment of immune and inflammatory cells as successfully demonstrated in the airways using agents that block either CXCL12 or CXCR4 (Hachet-Haas et al JBC 2008). We here highlight the unique relationship between pharmacokinetics and anti-asthmatic activity of chalcone 4, a CXCL12 neutraligand. Balb/c mice were sensitized (OVA+alum) and challenged (OVA or solvent, i.n., D17-20). Chalc4 or vehicle were administered i.n. 2h before each challenge. Chalc4 reduces airway hyperresponsiveness measured by whole body plethysmography (45±7%) and Flexivent® (37±5%), as well as eosinophilia (54±2%), IL5 (75±6% ) and mucus (84±2%) in BAL and lung collagen (78±8%). IgE in plasma and IL4 in BALF are not changed, indicating a downstream effect on sensitization. In addition, chalc4 reduces recruitment of M1 macrophages (62±4%), and their production of TNFα in response to CXCL12 (98±4%). In parallel, chalc4 significantly reduces the levels of CXCL12 in the lung (20%). SPECT imaging performed with 123I-chalc4 and the pharmacokinetics (UHPLC-MS/MS) show that chalc4 rapidly leaves the lung (<5min) and blood stream (<10min) to be excreted in bile and urine. We show that this unusual pharmacokinetics is related to the activity of chalc4: the neutraligand binds CXCL12 in the lung to take it to the blood (1000-fold increase in plasma 5 min after chalc4 administration) where from it is gradually removed. In conclusion, we here demonstrate that reducing the local concentration of CXCL12 abolishes bronchial hyperresponsiveness, inflammation and remodeling in asthma. ER -