Roles for cytosolic phospholipase A2alpha as revealed by gene-targeted mice.

Cytosolic phospholipase A2alpha (cPLA2alpha) has unique characteristics among phospholipase A2 (PLA2) family members. Under regulation by intracellular signaling system, cytosolic phospholipase A2alpha liberates arachidonic acid that can be metabolized by downstream enzymes to generate prostaglandins (PGs) and leukotrienes (LTs). Mice deficient in this enzyme have been generated by gene-targeting techniques. Cytosolic phospholipase A2alpha-deficient mice have a normal appearance and grow normally. Close examinations have revealed a renal concentration defect and intestinal ulcerative lesions. There may also be other disadvantages that are not manifested in well-regulated housing conditions. Although female mice are fertile, they become pregnant less frequently and have small litter sizes; moreover, impaired parturition results in few surviving pups. Primary cultured cells prepared from cytosolic phospholipase A2alpha-deficient mice produce significantly smaller amounts of prostaglandins and leukotrienes. Various disease models such as anaphylaxis, acute lung injury, brain injury induced by ischemia/reperfusion and neurotoxin, and polyposis have been investigated. In all these settings, cytosolic phospholipase A2alpha-deficient mice show significantly milder phenotypes. The mechanisms by which deficiencies of this enzyme exert protective effects may differ, but, a cytosolic phospholipase A2alpha inhibitor could have a wide spectrum of clinical targets. Specific functions of cytosolic phospholipase A2alpha have been clearly demonstrated using the gene-targeted mice. Also, comparisons with mice in which related enzymes and receptors have been manipulated using genetic technologies provide further insights into roles of lipid mediators in physiology and pathology.