Specific physiological roles of cytosolic phospholipase A(2) as defined bygene knockouts

The cytosolic 85 kDa phospholipase A(2) (cPLA(2)) is a unique member of the phospholipase A(2) (PLA(2)) superfamily. Because PLA(2) activity and eicos anoid production are important in normal and pathophysiological states we a nd the laboratory of Shimizu created a mouse deficient in cPLA(2) (cPLA(2)( -/-) mouse), cPLA(2)(-/-) mice develop normally but the females have severe reproductive defects. cPLA(2)(-/-) mice suffer smaller infarcts and fewer neurological deficits after transient occlusion of the middle cerebral arte ry and have less injury after administration of a dopaminergic selective ne urotoxin. cPLA(2)(-/-) mice have a more rapid recovery from allergen-induce d bronchoconstriction and have no airway hyperresponsiveness. Peritoneal ma crophages from CPLA(2)(-/-) mice fail to produce prostaglandins, leukotrien e B-4 and cysteinyl leukotrienes after stimulation. Bone marrow-derived mas t cells from cPLA(2)(-/-) mice fail to produce eicosanoids in either immedi ate or delayed phase responses. Thus the cPLA(2) knockout mouse has reveale d important roles of cPLA(2) in normal fertility, generation of eicosanoids from inflammatory cells, brain injuries and allergic responses. Furthermor e the cPLA(2)(-/-) mouse reveals that the many other forms of PLA(2) cannot replace many functions of cPLA(2). The importance of cPLA(2) in inflammati on and tissue injury suggests that pharmacological targeting of this enzyme may have important therapeutic benefits. (C) 2000 Elsevier Science B.V. Al l rights reserved.