Abnormal expression of phospholipases A_2 and human diseases

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We have examined the expression and function of phospholipase A_2 (PLA_2) isoforms that are implicated in arachidonate metabolism and their possible prticipation in human diseases.1. Analysis of PLA_2 isoforms(1) Cytosolic PLA_2 (cPLA_2) was expressed in various mamalian cells ubiquitously and consititutively. It was essential for the immediate phase of arachidonate methabolism that occurs within a few minutes after cell activation. In most cases, arachidonic acid released by cPLA_2 in the immediate phase was converted to prostanoids by constitutive cyclooxygenase COX-1.(2) Secretory type II PLA_2 was induced in various types of cell in response to proinflammatory stimuli. This enzyme was functionally coupled with inducible COX-2 to provide delayd phase of prostanoid generation that lasts for several hours.(3) Two novel secretory PLA_2 members, type IIC and V,were cloned from testis and heart, respectively. Recombinant expression of these enzymes was carried out. the expression and function of these PLA_2s in mammalian cells are currently under investigation.2. Implication of PLA_2 isozymes in human diseases(1) Multiple organ dysfunction : Gut ishchemia/reperfusion in the rat, used as a model system, caused lung injury via a mechanism which involved type II PLA_2.(2) Rheumatoid arthritis : There was significant correlation between IL-6 and type II PLA_2 in the synovial fluid of patients with rheumatoid arthritis.(3) Diabetes : Platelets from patients with diabetes contained higher level of cPLA_2 than normal littermates.(4) Cancer : Several lung carcinomas were found to contain some unknown cPLA_2-inhibitory substances.