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Introduction

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High-Yield Terms

  • Lipoxin: anti-inflammatory and pro-resolution eicosanoids synthesized through lipoxygenase interactions

  • Aspirin-triggered lipoxin: epimeric lipoxins synthesized as a result of aspirin-mediated acetylation of COX-2

  • Eicosapentaenoic acid (EPA): an omega-3 polyunsaturated fatty acid that is a precursor for the synthesis of anti-inflammatory lipids

  • Docosahexaenoic acid (DHA): an omega-3 polyunsaturated fatty acid that can exert numerous activities by binding to a specific G-protein–coupled receptor (GPCR), also is a precursor for the synthesis of anti-inflammatory lipids

  • Polymorphonuclear leukocytes (PMN): commonly refers to neutrophils (can be any of the granulocyte family of leukocytes), characterized by the varying shapes of the nucleus which is usually lobed into 3 segments

  • Nonphlogistic: refers to the process of phagocytosis and clearance by macrophages within induction of inflammation

  • Apoptosis: the process of programmed cell death

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High-Yield Concept

Once initiated, an inflammatory response must be turned off following completion of the required processes triggered by the initiating challenge. This process is referred to as resolution of inflammation.

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As pointed out in Chapters 22 and 23, biological molecules derived from various polyunsaturated fatty acids (PUFAs) participate in the mediation of numerous physiologically relevant processes including, but not limited to, immune responses. Lipid mediators, such as the prostaglandins and leukotrienes, have been appreciated for many years for their activities that promote and enhance inflammatory responses. Through the activities of cyclooxygenase (COX-1 and COX-2) or lipoxygenase (5-LOX), leukocytes rapidly synthesize these lipid mediators from membrane-derived arachidonic acid within seconds to minutes of an acute challenge. The primary endogenous lipid mediators that are released by cells that infiltrate the site of immune challenge are prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). These molecules are important for host defense, but can also inadvertently lead to tissue damage if inappropriately and/or excessively produced.

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An active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. This resolution process is initiated following infiltration of granulocytes into the tissues. There are 3 types of granulocytes more commonly called neutrophils, eosinophils, and basophils. These leukocytes promote the switch of arachidonic acid–derived prostaglandin and leukotriene synthesis to that of lipoxin synthesis. The lipoxins then initiate the resolution and termination sequence. The recruitment of neutrophils to the inflammatory site ceases following the initiation of lipoxin synthesis and programmed death by apoptosis is engaged. Neutrophil apoptosis coincides with the biosynthesis of the resolvins (Rv) and protectins. These latter molecules are derived from the omega-3 PUFA, EPA and DHA.

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Lipoxins

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The lipoxins (LX), or the lipoxygenase interaction products, are generated from arachidonic acid via sequential actions of lipoxygenases (including 5-LOX, 12-LOX, and 15-LOX) and subsequent reactions to give rise to specific trihydroxytetraene-containing eicosanoids (Figure 24-1). These unique lipid compounds are formed during cell–cell interactions and appear to act at both temporally and spatially distinct sites from those of the pro-inflammatory eicosanoids. The synthesis ...

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