The Journal of Experimental Medicine
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Published online April 2, 2007
doi:10.1084/jem.20070029
The Journal of Experimental Medicine, Vol. 204, No. 4, 865-877
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Henderson et al.
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ARTICLE

 Importance of group X–secreted phospholipase A2 in allergen-induced airway inflammation and remodeling in a mouse asthma model

William R. Henderson, Jr.1, Emil Y. Chi2, James G. Bollinger3, Ying-tzang Tien2, Xin Ye1, Luca Castelli5, Yuri P. Rubtsov5, Alan G. Singer3, Gertrude K.S. Chiang1, Timo Nevalainen7, Alexander Y. Rudensky5,6, and Michael H. Gelb3,4

1 Center for Allergy and Inflammation, Department of Medicine, University of Washington, Seattle, WA 98109
2 Department of Pathology, 3 Department of Chemistry, 4 Department of Biochemistry, 5 Department of Immunology, and 6 Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195
7 Department of Pathology, University of Turku and Turku University Hospital, 20520 Turku, Finland

CORRESPONDENCE William R. Henderson Jr.: joangb{at}u.washington.edu OR Michael H. Gelb: gelb{at}chem.washington.edu

Arachidonic acid metabolites, the eicosanoids, are key mediators of allergen-induced airway inflammation and remodeling in asthma. The availability of free arachidonate in cells for subsequent eicosanoid biosynthesis is controlled by phospholipase A2s (PLA2s), most notably cytosolic PLA2-{alpha}. 10 secreted PLA2s (sPLA2s) have also been identified, but their function in eicosanoid generation is poorly understood. We investigated the role of group X sPLA2 (sPLA2-X), the sPLA2 with the highest in vitro cellular phospholipolysis activity, in acute and chronic mouse asthma models in vivo. The lungs of sPLA2-X–/– mice, compared with those of sPLA2-X+/+ littermates, had significant reduction in ovalbumin-induced infiltration by CD4+ and CD8+ T cells and eosinophils, goblet cell metaplasia, smooth muscle cell layer thickening, subepithelial fibrosis, and levels of T helper type 2 cell cytokines and eicosanoids. These data direct attention to sPLA2-X as a novel therapeutic target for asthma.

Abbreviations used: BAL, bronchoalveolar lavage; cysLT, cysteinyl leukotriene; cPLA2-{alpha}, cytosolic group IVA PLA2; EIA, enzyme immunoassay; i.n., intranasal; LTB4, LTC4, LTD4, and LTE4, leukotriene B4, C4, D4, and E4, respectively; MOX, methoxime; PAS, periodic acid Schiff; PGD2 and PGE2, prostaglandin D2 and E2, respectively; PLA2, phospholipase A2; RL, lung resistance; RT, real time; sPLA2, secreted PLA2; sPLA2-X, group X sPLA2.


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