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* Section of Pulmonary and Critical Care Medicine, Department of Medicine, and
Department of Neurobiology Pharmacology and Physiology and Committees on Molecular Medicine, Clinical Pharmacology and Cell Physiology, University of Chicago, Chicago, IL 60637;
Department of Medicine, Harvard Medical School and the Brigham and Women’s Hospital, Boston, MA 02115; and
Department of Chemistry, University of Illinois, Chicago, IL 60607
We investigated the role of group V phospholipase A2 (gVPLA2) in OVA-induced inflammatory cell migration and airway hyperresponsiveness (AHR) in C57BL/6 mice. Repeated allergen challenge induced biosynthesis of gVPLA2 in airways. By aerosol, gVPLA2 caused dose-related increase in airway resistance in saline-treated mice; in allergic mice, gVPLA2 caused persistent airway narrowing. Neither group IIa phospholipase A2, a close homolog of gVPLA2, nor W31A, an inactive gVPLA2 mutant with reduced activity, caused airway narrowing in immune-sensitized mice. Pretreatment with MCL-3G1, a blocking Ab against gVPLA2, before OVA challenge blocked fully gVPLA2-induced cell migration and airway narrowing as marked by reduction of migrating leukocytes in bronchoalveolar lavage fluid and decreased airway resistance. We also assessed whether nonspecific AHR caused by methacholine challenge was elicited by gVPLA2 secreted from resident airway cells of immune-sensitized mice. MCL-3G1 also blocked methacholine-induced airway bronchoconstriction in allergic mice. Blockade of bronchoconstriction by MCL-3G1 was replicated in allergic pla2g5–/– mice, which lack the gene encoding gVPLA2. Bronchoconstriction caused by gVPLA2 in pla2g4–/– mice was comparable to that in pla2g4+/+ mice. Our data demonstrate that gVPLA2 is a critical messenger enzyme in the development of AHR and regulation of cell migration during immunosensitization by a pathway that is independent of group IVa phospholipase A2.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Heart, Lung, and Blood Institute Grants HL-46368 (to A.R.L.), HL-85779 (to A.R.L.), and HL-70946 (to J.P.A); and by the GlaxoSmithKline Center of Excellence (to A.R.L.).
2 Address correspondence and reprint requests to Dr. Alan R. Leff, Department of Medicine, M6076, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. E-mail address: aleff{at}medicine.bsd.uchicago.edu
3 Abbreviations used in this paper: PLA2, phospholipase A2; GVPLA2, group V phospholipase A2; gIVaPLA2, cytosolic group IVa PLA2; AHR, airway hyperresponsiveness; pla2g5–/–, gVPLA2null mice; WT, wild type; pla2g5+/+, gVPLA2 WT mice; pla2g4–/–, cytosolic gIVaPLA2null mice; pla2g4+/+, cytosolic gIVaPLA2 WT mice; Rrs, airway lung resistance; MCh, methacholine; BALF, bronchoalveolar lavage fluid.
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  B. P. Hurley and B. A. McCormick Multiple Roles of Phospholipase A2 during Lung Infection and Inflammation Infect. Immun., June 1, 2008; 76(6): 2259 - 2272. [Full Text] [PDF]
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