title: 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.
abstract: Group X (GX) phospholipase A(2), a member of a large group of secreted phospholipases A(2) (sPLA(2)s), 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)-sPLA(2) significantly impairs development of the asthma phenotype. In this study, we generated mGX-sPLA(2)(-/-) mice with knock-in of human GX (hGX)-sPLA(2) (i.e. hGX-sPLA(2)(+/+) knock-in mice) to understand more fully the role of GX-sPLA(2) in these allergic pulmonary responses and to assess the effect of pharmacological blockade of the GX-sPLA(2)-mediated responses. Knock-in of hGX-sPLA(2) in mGX-sPLA(2)(-/-) mice restored the allergen-induced airway infiltration by inflammatory cells, including eosinophils, goblet cell metaplasia, and hyperresponsiveness to methacholine in the mGX-sPLA(2)-deficient mice. This knock-in mouse model enabled the use of a highly potent indole-based inhibitor of hGX-sPLA(2), RO061606 (which is ineffective against mGX-sPLA(2)), to assess the potential utility of GX-sPLA(2) 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 IC(50) for inhibition of hGX-sPLA(2) in vitro. RO061606 significantly decreased allergen-induced airway inflammation, mucus hypersecretion, and hyperresponsiveness in the hGX-sPLA(2)(+/+) knock-in mouse. Thus, development of specific hGX-sPLA(2) inhibitors may provide a new pharmacological opportunity for the treatment of patients with asthma.
authors.affiliation: Center for Allergy and Inflammation, Department of Medicine, University of Washington, Seattle, Washington 98195-1700, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Henderson
authors.forename: Rob C
authors.initials: RC
authors.lastname: Oslund
authors.forename: James G
authors.initials: JG
authors.lastname: Bollinger
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
authors.forename: Ying-Tzang
authors.initials: YT
authors.lastname: Tien
authors.forename: Jun
authors.initials: J
authors.lastname: Xue
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
mesh_terms: D000485:Allergens / Q000633:toxicity; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D055879:Gene Knock-In Techniques; D054509:Group X Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism
chemical_list: D000485:Allergens; D004791:Enzyme Inhibitors; D054509:Group X Phospholipases A2; C516365:PLA2G10 protein, human; C516366:Pla2g10 protein, mouse