Specific physiological roles of cytosolic phospholipase A_2 as defined by gene knockouts

摘要

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 eicosanoid production are important in normal and pathophysiological states we and 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 artery and have less injury after administration of a dopaminergic selective neurotoxin. cPLA_2~(-/-) mice have a more rapid recovery from allergen-induced bronchoconstriction and have no airway hyperresponsiveness. Peritoneal macrophages from cPLA_2~(-/-) mice fail to produce prostaglandins, leukotriene B_4 and cysteinyl leukotrienes after stimulation. Bone marrow-derived mast cells from cPLA_2~(-/-) mice fail to produce eicosanoids in either immediate or delayed phase responses. Thus the cPLA_2 knockout mouse has revealed important roles of cPLA_2 in normal fertility, generation of eicosanoids from inflammatory cells, brain injuries and allergic responses. Furthermore 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 inflammation and tissue injury suggests that pharmacological targeting of this enzyme may have important therapeutic benefits.