The therapeutic potential for phospholipase A2 inhibitors

Abstract

Modulation of pro-inflammatory lipid mediator production by inhibition of phospholipase A2 (PLA2) activity remains a potential target for development of new drugs for the treatment of rheumatoid arthritis or other inflammatory diseases. Evidence now exists that more than one isoform of PLA2, including types IIa and V 14 and 85 kDa PLA2, is required for production of lipid mediators. Specific isoforms may be associated with production of either the prostaglandin or leukotriene class of lipid mediators in different cell types such as monocytes and neutrophils. Characterisation of isoform-selective inhibitors in models of inflammatory disease, such as rat adjuvant arthritis or phorbol myristate acetate (PMA)-induced mouse ear oedema, suggests that both 14 kDa and 85 kDa PLA2 may contribute to the development of the disease state and that both forms of PLA2 may be targets for modulation of inflammatory disease. Much work remains to clarify fully the relative roles of different PLA2 in the aetiology of inflammatory disease and to identify potent, selective and efficacious inhibitors of each PLA2.