Phospholipase A₂ activities in skin physiology and pathology

Skin inflammatory diseases are most commonly treated with corticosteroids, especially topical preparations, benefitting from high potency and unparalleled formulation flexibility. However, these benefits are limited due to side effects, especially under long-term use. Non-steroidal anti-inflammatory drugs (NSAIDs) which block the COX pathways have been used as safer alternatives to corticosteroids, and much effort and resources have been invested in developing COX inhibitors. However, synthetic NSAIDs are less potent than steroids, have limited formulation flexibility and have their own safety issues, thereby yielding unsatisfactory results, with some high-profile drugs (e.g., the COX-2 inhibitors Vioxx, Celebrex) being withdrawn from the market due to safety concerns. The potency and safety challenges of NSAIDs are related to inter-eicosanoid dynamics, pertaining to their pro-versus anti-inflammatory action, homeostatic functions and tissue-specific activities. Instead, the upstream control of phospholipase A2 (PLA2) enzymatic activity, which hydrolyzes cell membrane phospholipids to initiate the eicosanoid production, has been considered for inhibiting eicosanoid activation while maintaining the intricate balance needed for their homeostatic functions. Yet, PLA(2) inhibitors have hardly been tested for treating skin inflammatory/allergic conditions. In this article we review the involvement of PLA(2)s in skin physiology and pathology, and discuss the prospect of PLA(2) inhibition for the treatment of dermatological diseases.