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Deletion of Secretory Group V Phospholipase A₂ Attenuates Cell Migration and Airway Hyperresponsiveness in Immunosensitized Mice¹

Nilda M. Muñoz^*, Angelo Y. Meliton^*, Jonathan P. Arm, Joseph V. Bonventre, Wonhwa Cho and Alan R. Leff^2,*,

^* 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^–/–, gVPLA₂^null mice; WT, wild type; pla2g5^+/+, gVPLA₂ WT mice; pla2g4^–/–, cytosolic gIVaPLA₂^null mice; pla2g4^+/+, cytosolic gIVaPLA₂ WT mice; Rrs, airway lung resistance; MCh, methacholine; BALF, bronchoalveolar lavage fluid.

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The JI 2007 179: 4297-4298. [Full Text]  

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