Lipid body function in eicosanoid synthesis: an update.

Eicosanoids (prostaglandins, leukotrienes and lipoxins) are signaling lipids derived from arachidonic acid metabolism that have important roles in physiological and pathological processes. Lately, intracellular compartmentalization of eicosanoid-synthetic machinery has emerged as a key component in the regulation of eicosanoid synthesis and functions. Over the past years substantial progresses have been made demonstrating that precursors and enzymes involved in eicosanoid synthesis localize at lipid bodies (also known as lipid droplets) and lipid bodies are distinct sites for eicosanoid generation. Here we will review the current knowledge on the functions of lipid bodies as specialized intracellular sites of compartmentalization of signaling with major roles in eicosanoid formation within cells engaged in inflammatory, infectious and neoplastic process.

A new strategy for the identification of novel molecules with targeted proresolution of inflammation properties.

As our understanding of inflammatory resolution increases, drugs that trigger proresolution pathways may become significant in treating chronic inflammatory diseases. However, anti-inflammatory drugs are traditionally tested during the first hours of onset (i.e., to dampen leukocyte and edema formation), and their ability to trigger proresolution processes has never been investigated. Moreover, there is no model available to screen for putative proresolving agents. In this study, we present a new strategy to identify therapeutics for their ability to switch inflammation off and restore homeostasis. Injecting 1.0 mg of zymosan i.p. causes transient inflammation characterized by polymorphonuclear neutrophil clearance and dominated by recently described resolution-phase macrophages along with an innate-type lymphocyte repopulation, the latter being a marker of tissue homeostasis. In contrast, 10 mg of zymosan elicits an aggressive response characterized by classically activated macrophages leading to systemic inflammation and impaired lymphocyte repopulation. Although this latter model eventually resolves, it nonetheless represents inflammation in the clinically relevant setting of polymorphonuclear neutrophil/classically activated macrophage dominance driving a cytokine storm. Treating such a reaction therapeutically with proresolution drugs provides quantifiable indices of resolution--polymorphonuclear neutrophil/macrophage clearance, macrophage phenotype switching (classically activated to resolution phase), and repopulation with resolution-phase lymphocytes--cardinal signs of inflammatory resolution and homeostasis in the peritoneum. As an illustration, mice bearing peritonitis induced by 10 mg of zymosan were given ibuprofen, resolvin E1, a prostaglandin D(2) receptor 1 agonist, dexamethasone, rolipram, or azithromycin, and their ability to trigger resolution and homeostasis in this new inflammatory setting was investigated. We present the first model for testing drugs with targeted proresolution properties using quantifiable parameters of inflammatory resolution and homeostasis.