Phospholipase A2s are enzymes which share as their common characteristic the capacity to hydrolyze fatty acids from the sn-2 position of glycerophospholipids (for review see reference 1). Group I and group II phospholipase A2 are two sets of enzymes in a highly conserved family of secreted or extracellular phospholipase A2 (sPLA2) found in mammals. This family of sPLA2 has a number of features which distinguish it from the other major phospholipase A2 families such as group IV (cytolsolic) PLA2. These features include a relatively low molecular weight (14–16 kD), high disulfide bond content and a requirement for relatively high concentrations of Ca2+ for catalysis. sPLA2 have been studied extensively in mammals and snake venoms for the past six decades, yet little is currently known about the physiological and pathophysiological roles of these enzymes. Inspection of the many papers published in the last few years reveals that these sPLA2’s have the potential to mediate a wide range of biological activities including:(a) potent antibacterial effects;(b) a key component in the digestion of glycerophospholipids;(c) enzymatic producers of lyso-phospholipids that contribute to electrophysiologic alterations that lead to arrhythmogenesis in the heart or alter airway permeability and surfactant properties in the lung;(d) serum markers and potential regulators of severe illnesses such as sepsis, shock, organ injury, and pancreatitis, all of which are linked to the development of adult respiratory distress syndrome and multiple organ failure;(e) regulators of platelet aggregation and hemorrhagic diseases;(f) pro-inflammatory components in diseases such as rheumatoid arthritis and asthma; and (g) initiators of cell proliferation in several cancer cell lines and a potent modifying locus of intestinal tumorigenesis in mice. This daunting list of activities and diseases raises fundamental questions as to whether sPLA2 causes or is merely associated with many of the aforementioned effects. Perhaps the only place where sPLA2 unambiguously has been demonstrated to regulate an in vivo process is digestion of glycerophospholipids in the intestine. However, even in this case, it is unlikely that the gut is the only site of action for group I sPLA2 since large quantities of message and protein levels are found in other tissues including the lung and spleen. Group II sPLA2 is also found in many cells and tissues including platelets, mast cells, neutrophils, vascular smooth muscle cells, liver, spleen, placenta, cartilage, and intestinal mucosa. Therefore, the somewhat ubiquitous distribution of group I and group II among mammalian cells and tissues also provides few hints as to the major physiological and pathophysiological roles of these enzymes.

With the backdrop of so many potential biological activities and potential sources for both group I and group II sPLA2, new specific inhibitors or models are critically needed to better define the essential processes induced by sPLA2 activation. While some inhibitors have been developed which block PLA2