Deletion of secretory group V phospholipase A2 attenuates cell migration and airway hyperresponsiveness in immunosensitized mice.
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.
Muñoz
Nilda M
NM
Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Meliton
Angelo Y
AY
Arm
Jonathan P
JP
Bonventre
Joseph V
JV
Cho
Wonhwa
W
Leff
Alan R
AR
D000818:Animals; D000906:Antibodies / Q000276:immunology; D000941:Antigens / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D015971:Gene Expression Regulation, Enzymologic; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology*; D010741:Phospholipases A / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D054467:Phospholipases A2; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D015854:Up-Regulation
D000906:Antibodies; D000941:Antigens; D016210:Methacholine Chloride; D010047:Ovalbumin; D010741:Phospholipases A; D054467:Phospholipases A2