Blockade of Human Group X Secreted Phospholipase A2 (GX-sPLA2)-induced Airway Inflammation and Hyperresponsiveness in a Mouse Asthma Model by a Selective GX-sPLA2 Inhibitor

摘要

Group X (GX) phospholipase A2, a member of a large group of secreted phospholipases A2 (sPLA2s), has recently been demonstrated to play an important in vivo role in the release of arachidonic acid and subsequent formation of eicosanoids. In a Th2 cytokine-driven mouse asthma model, deficiency of mouse GX (mGX)-sPLA2 significantly impairs development of the asthma phenotype. In this study, we generated mGX-sPLA2^−/− mice with knock-in of human GX (hGX)-sPLA2 (i.e. hGX-sPLA2^+/+ knock-in mice) to understand more fully the role of GX-sPLA2 in these allergic pulmonary responses and to assess the effect of pharmacological blockade of the GX-sPLA2-mediated responses. Knock-in of hGX-sPLA2 in mGX-sPLA2^−/− mice restored the allergen-induced airway infiltration by inflammatory cells, including eosinophils, goblet cell metaplasia, and hyperresponsiveness to methacholine in the mGX-sPLA2-deficient mice. This knock-in mouse model enabled the use of a highly potent indole-based inhibitor of hGX-sPLA2, RO061606 (which is ineffective against mGX-sPLA2), to assess the potential utility of GX-sPLA2 blockade as a therapeutic intervention in asthma. Delivery of RO061606 via mini-osmotic pumps enabled the maintenance in vivo in the mouse asthma model of plasma inhibitor concentrations near 10 μm, markedly higher than the IC50 for inhibition of hGX-sPLA₂ in vitro. RO061606 significantly decreased allergen-induced airway inflammation, mucus hypersecretion, and hyperresponsiveness in the hGX-sPLA₂^+/+ knock-in mouse. Thus, development of specific hGX-sPLA₂ inhibitors may provide a new pharmacological opportunity for the treatment of patients with asthma.