Inflammatory effects of snake venom myotoxic phospholipases A2

Snake venom phospholipases A(2) (PLA(2)) show a remarkable functional diversity. Among their toxic activities, some display the ability to cause rapid necrosis of skeletal muscle fibers, thus being myotoxic PLA(2)s. Besides myotoxicity, these enzymes evoke conspicuous inflammatory and nociceptive events in experimental models. Local inflammation and pain are important characteristics of snakebite envenomations inflicted by viperid and crotalid species, whose venoms are rich sources of myotoxic PLA(2)s. Since the discovery that mammalian PLA(2) is a key enzyme in the release of arachidonic acid, the substrate for the synthesis of several lipid inflammatory mediators, much interest has been focused on this enzyme in the context of inflammation. The mechanisms involved in the proinflammatory action of secretory PLA(2)s are being actively investigated, and part of the knowledge on secretory PLA(2) effects has been gained by using snake venom PLA(2)s as tools, due to their high structural homology with human secretory PLA(2)s. The inflammatory events evoked by PLA(2)s are primarily associated with enzymatic activity and to the release of arachidonic acid metabolites. However, catalytically inactive Lys49 PLA(2)s trigger inflammatory and nociceptive responses comparable to those of their catalytically active counterparts, thereby evidencing that these proteins promote inflammation and pain by mechanisms not related to phospholipid hydrolysis nor to mobilization of arachidonic acid. These studies have provided a boost to the research in this field and various approaches have been used to identify the amino acid residues and the specific sites of interaction of myotoxic PLA(2)s with cell membranes potentially involved in the PLA(2)-induced inflammatory and nociceptive effects. This work reviews the proinflammatory and nociceptive effects evoked by myotoxic PLA(2)s and their mechanisms of action. (C) 2004 Published by Elsevier Ltd.