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yielding unsatisfactory results, with some high-profile drugs (e.g., the COX-2 inhibitors Vioxx, Celebrex) being withdrawn from the market due to safety concerns.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.

We have previously shown that cell surface proteoglycans protect the cell membrane from the action of extracellular phospholipase A2 (PLA2) enzymes [Dan, P., Nitzan, D. W., Dagan, A., Ginsburg, I., and Yedgar, S. (1996) FEBS Lett. 383, 75-78]. Cell-impermeable PLA2 inhibitors (ExPLIs) were prepared by linking phosphatidylethanolamine (PE) to polymeric carriers, specifically, carboxymethylcellulose, heparin, or hyaluronic acid. The structure of these inhibitors enables the incorporation of their PE moiety into the membrane while the polymer remains at the membrane surface. In the present study, we show that the ExPLIs are effective inhibitors of the hydrolysis of different phospholipids in biological (Escherichia coli) and model (phospholipid vesicle) membranes, by diverse types of PLA2 enzymes, specifically human recombinant synovial fluid and C. atrox (type II), as well as Naja mocambique and porcine pancreatic (type I) PLA2. It is proposed that the external polymers of the ExPLIs, which are anchored to the membrane by the PE, mimic the naturally occurring cell surface proteoglycans and similarly protect membranes from the action of exogenous PLA2.

Phospholipase A2 (PLA2) plays a key role in the production of proinflammatory mediators, namely the arachidonic acid‐derived eicosanoids, lysophospholipids, and platelet‐activating factor, and indirectly influences the generation of cytokines, nitric oxide (NO), and free radicals. Accordingly, regulation of its activity is important in the treatment of inflammation. Since the main site of PLA2 action in inflammatory processes is the cell membrane, we synthesized extracellular PLA2 inhibitors (ExPLIs) composed of N‐derivatized phosphatidyl‐ethanolamine linked to polymeric carriers. These membrane‐anchored lipid conjugates do not penetrate the cell and interfere with vital phospholipid metabolism or cell viability. The ExPLIs markedly inhibited central nervous system inflammation. This was reflected by the suppressed production and secretion of lipopolysaccharide‐induced sPLA2, prostaglandin E2, and NO by glial cells and by the amelioration of experimental autoimmune encephalomyelitis in rats and mice. © 2003 Wiley‐Liss, Inc.

Background. This in vitro study aimed to elucidate the extent and kind of involvement of hyaluronic acid (HA) in the currently accepted view of synovial joint lubrication, in which surface-active phospholipids (SAPL) constitute the main boundary lubricant. The integrity of SAPL is apparently threatened by the lysing activity of phospholipase A(2) (PLA(2)).Methods. The effects of increasing concentrations of HA degraded by free radicals and non-degraded HA on the lysing activity of PLA2 were examined in vitro. Liposomes (lipid model membrane) containing phosphatidylcholine (PC) were used as the substrate, on the assumption that they are appropriate representatives of SAPL.Results. HA adhered to the phospholipid membrane (liposomes), inhibiting their lysis by PLA(2). However, in its degraded form, IIA not only failed to inhibit PLA(2)-lysing activity, but accelerated it.Conclusions. It is reasonable to assume that IIA plays an important indirect role in the steady state of the boundary lubrication process of joints by protecting SAPL from being lysed by PLA(2). However, as excessive loading generates free radicals within the joint (among other effects), the HA that is degraded in this way is incapable of protecting SAPL front lysis by PLA(2). When the rate of degradation exceeds that of synthesis, there will be insufficient replacement of HA and/or SAPL, resulting in denudation of the articular surfaces. These are then exposed to increasing friction, and hence increased danger of degenerative joint changes.

Phospholipase A2 (PLA2) and H2O2, secreted from activated inflammatory cells, play a central role in the tissue damage occurring in inflammatory processes. However, while exogenous PLA2 alone does not cause cell lysis, it readily does so when acting with H2O2. We have found that H2O2 degrades cell surface proteoglycans, thus rendering the membrane PL accessible to hydrolysis by exogenous PLA2. This novel mechanism introduces a role for cell surface proteoglycans in protection of cells from damage by pro-inflammatory agents, and may assign a central role for the combined action of H2O2 and PLA2 in inflammatory and bacteriocidal processes.

Phospholipase A2 (PLA2) in the cell surface membrane is considered a regulator of cellular secretion. The distinction between the role of the cell surface and the intracellular PLA2 is not clear, since it has not been possible to differentiate unequivocally the activity of the enzymes in the various organelles. The use of an extracellular inhibitor of PLA2 can greatly contribute to the understanding of cell surface PLA2 function. In this paper, the preparation of a cell-impermeable inhibitor of PLA2 is presented. This substance incorporates into lipid membranes and is capable of blocking the hydrolysis of membrane phospholipids by snake venom as well as by cell membrane PLA2.

Aggregation of two positively charged dyes, Methylene Blue, MB+(1), and pinacyanol chloride, PC+, (2) is induced in aqueous SiO2, colloids. In colloidal SiO2, MB+ aggregates into the dimeric form, and PC+ is aggregated into H-assemblies. The aggregation processes are a result of high local dye concentrations in the vicinity of the colloid owing to binding of the positively charged dyes to the negatively charged colloidal interface. De-aggregation of thionin, (3), is accomplished in water by the addition of cyclohexa-amylose, α-CD, and cyclohepta-amylose, β-CD. Monomeric thionin binds to α-CD and β-CD (Kass= 6.67 × 102M–1 and 1.78 × 103M–1, respectively). Conversion of thionin dimer into the monomeric form, upon addition of α-CD or β-CD, is attributed to association of the monomeric form to the hydrophobic cavity of CD. This conversion is accompanied by changes in the absorption and fluorescence spectra of the dye.

Abstract Association of p-nitrothiphenol to a nicotinoyl functionalized α-cyclodextrin, is 5-fold enhanced as compared with its binding to nonfunctionalized α-cyclodextrin. This enhancement is attributed to an acid-base interaction operative in the association process.