Throughout evolution, numerous proteins have been convergently recruited into the venoms of various animals, including centipedes, cephalopods, cone snails, fish, insects (several independent venom systems), platypus, scorpions, shrews, spiders, toxicoferan reptiles (lizards and snakes), and sea anemones. The protein scaffolds utilized convergently have included AVIT/colipase/prokineticin, CAP, chitinase, cystatin, defensins, hyaluronidase, Kunitz, lectin, lipocalin, natriuretic peptide, peptidase S1, phospholipase A 2 , sphingomyelinase D, and SPRY. Many of these same venom protein types have also been convergently recruited for use in the hematophagous gland secretions of invertebrates (e.g., fleas, leeches, kissing bugs, mosquitoes, and ticks) and vertebrates (e.g., vampire bats). Here, we discuss a number of overarching structural, functional, and evolutionary generalities of the protein families from which these toxins have been frequently recruited and propose a revised and expanded working definition for venom. Given the large number of striking similarities between the protein compositions of conventional venoms and hematophagous secretions, we argue that the latter should also fall under the same definition. 483

Arachidonic acid metabolites, the eicosanoids, are key mediators of allergen-induced airway inflammation and remodeling in asthma. The availability of free arachidonate in cells for subsequent eicosanoid biosynthesis is controlled by phospholipase A2s (PLA2s), most notably cytosolic PLA2-α. 10 secreted PLA2s (sPLA2s) have also been identified, but their function in eicosanoid generation is poorly understood. We investigated the role of group X sPLA2 (sPLA2-X), the sPLA2 with the highest in vitro cellular phospholipolysis activity, in acute and chronic mouse asthma models in vivo. The lungs of sPLA2-X−/− mice, compared with those of sPLA2-X+/+ littermates, had significant reduction in ovalbumin-induced infiltration by CD4+ and CD8+ T cells and eosinophils, goblet cell metaplasia, smooth muscle cell layer thickening, subepithelial fibrosis, and levels of T helper type 2 cell cytokines and eicosanoids. These data direct attention to sPLA2-X as a novel therapeutic target for asthma.

Group IIA secreted phospholipase A 2 (sPLA2) is known to display potent Gram-positive bactericidal activity in vitro and in vivo. We have analyzed the bactericidal activity of the full set of recombinant murine and human groups I, II, V, X, and XII sPLA2s on Listeria monocytogenes, Staphylococcus aureus, and Escherichia coli. The rank order potency among human sPLA2s against Gram-positive bacteria is group IIA > X > V > XII > IIE > IB, IIF (for murine sPLA2s: IIA > IID > V > IIE > IIC, X > IB, IIF), and only human group XII displays detectable bactericidal activity against the Gramnegative bacterium E. coli. These studies show that highly basic sPLA2s display potent bactericidal activity with the exception of the ability of the acidic human group X sPLA2 to kill Gram-positive bacteria. By studying the Bacillus subtilis and S. aureus bactericidal potencies of a large panel of human group IIA mutants in which basic residues were mutated to acidic residues, it was found that: 1) the overall positive charge of the sPLA2 is the dominant factor in dictating bactericidal potency; 2) basic residues on the putative membrane binding surface of the sPLA2 are modestly more important for bactericidal activity than are other basic residues; 3) relative bactericidal potency tracks well with the ability of these mutants to degrade phospholipids in the bacterial membrane; and 4) exposure of the bacterial membrane of Gram-positive bacteria by disruption of the cell wall dramatically reduces the negative effect of charge reversal mutagenesis on bactericidal potency.The secreted phospholipases A 2 (sPLA2s) 1 comprise a large family of water-soluble enzymes that have the ability to bind to membrane surfaces as a prelude to the hydrolysis of the sn-2 ester of membrane phospholipids (1). Pancreatic sPLA2 (group IB sPLA2) was the first of these enzymes to be purified and extensively studied as a paradigm for interfacial enzymology.

Necrosectomy with postoperative continuous local lavage was performed in a prospective study involving 95 patients with necrotizing pancreatitis. In the same period 567 patients with oedematous-interstitial pancreatitis were treated non-operatively with a hospital mortality rate of 0.7 per cent. In patients with necrotizing pancreatitis the median Ranson criteria score was 4.5 points; operation was required at a median of 7 days after the onset of symptoms because of non-response to conservative treatment. In all, 59 per cent of the patients (56 out of 95) developed extended intrapancreatic parenchymal necrosis, 70 per cent had ascites, and 66 per cent had intra- and extrapancreatic necrosis; 42 per cent of the patients had bacterial infection of the necrotic tissue. For lavage a median of 8 l/24 h of fluid were instilled postoperatively for 25 days (median). The lavage fluid showed high levels of immunoreactive trypsin, phospholipase A2, and endotoxin in the early postoperative period. Hospital mortality rate was 8.4 per cent. Necrosectomy and continuous postoperative lavage can achieve high survival rates in patients with necrotizing pancreatitis. Postoperative local lavage allows the continuous non-operative evacuation of biologically active compounds and devitalized tissue, and avoids damage to remaining vital exocrine and endocrine pancreatic tissue.