TY - JOUR T1 - cPLA2α inhibitor ASB14780 suppresses airway MMP-9 production and improves respiratory function in cigarette-smoke induced model JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - P1790 AU - Maki Terakawa AU - Megumi Goto AU - Toshiyuki Tomoo AU - Toyoko Katayama AU - Yasuhiro Hayashi AU - Kazuhiro Nagahira Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/P1790.abstract N2 - Cytosolic phospholipase A2 α (cPLA2α) is a key enzyme for the stimuli-induced production of inflammatory lipid mediators and thought to contribute to the pathogenesis of various inflammatory diseases. In this study, the involvement of cPLA2α in the pathogenesis of lung inflammation was evaluated using lung inflammation models induced by elastase and cigarette smoke (CS).Eicosanoid levels as well as number of cPLA2α-expressed inflammatory cells were increased in bronchoalveolar lavage fluid (BALF) and the lung tissues by CS-exposure. Oral administration of specific cPLA2α inhibitor, ASB14780 (IC50 for human cPLA2α is 0.014µM), suppressed concentrations of PGE2 and LTB4 in these models, suggesting a pivotal role of cPLA2α in eicosanoid production. In addition, ASB14780 treatment decreased activity of MMP-9 in BALF. In vitro study demonstrated that PGE2 and LTB4 induced MMP-9 release from macrophages and neutrophils in an autocrine manner. In 4 weeks CS exposure model, ASB14780 treatment (once a day for 4 weeks) significantly inhibited the increases of specific airway resistance (sRAW), functional residual capacity (FRC) and residual volume (RV) at doses of 3 mg/kg and higher.These results support a potential therapeutic role of cPLA2α inhibitors for the treatment of COPD. ER -