Induction of microvascular leakage and histamine release by promutoxin, an Arg49 phospholipase A2

It has been recognized that phospholipase A2 (PLA2) is a crucial factor of snake venom induced inflammation. Recently, promutoxin, a novel member of minor subgroup of snake venom PLA2 (R49 PLA2) has been characterized in our laboratory, but its roles in induction of inflammation remain uninvestigated. Using highly purified promutoxin, we found this enzymatically inactive PLA2 provoked a dose-dependent increase in microvascular leakage in the skin of rats. Pretreatment of rats with compound 48/80 diminished promutoxin-induced skin reaction and reduced mast cell numbers in rats. Cyproheptadine, terfenadine, Ginkgolide B and heparin inhibited promutoxin elicited microvascular leakage when they were co-injected with the stimulus to rat skin. Moreover, promutoxin was found to induce histamine release from human colon, lung and tonsil mast cells, and both metabolic inhibitors and pertussis toxin were capable of inhibiting promutoxin elicited histamine release. Provocation of microvascular leakage and mast cell activation by promutoxin suggests further that snake venom induced inflammation is related to mast cell activation and certain anti-inflammatory drugs could be therapeutic effective in treating snake wound.