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.

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.

Lipoxins

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 of the lipoxins triggers the natural pathways leading to termination and resolution of inflammatory responses.

Lipoxin A₄ (LXA₄) and lipoxin B₄ (LXB₄) were the first-recognized eicosanoid-related mediators that display both potent anti-inflammatory and pro-resolving actions in animal models of disease. The LX act as agonist ligands for specific GPCR resulting in the activation of cellular responses important to inflammation and inflammatory resolution. The LX and their analogs exert important activities related to airway inflammation, asthma, arthritis, cardiovascular disorders, gastrointestinal disease, periodontal disease, kidney diseases and graft-versus-host disease (GVHD), and many other diseases/disorders where uncontrolled inflammation is a key mediator of disease pathogenesis (Figure 24-1).

The synthesis of the lipoxins occurs via 3 distinct pathways, one of which is triggered via the actions of aspirin. The 2 “classical” pathways for the synthesis of the lipoxins are the result of the concerted actions of 15-LOX acting on arachidonic acid in epithelial cells (eg, airway epithelia) and 5-LOX in leukocytes or through the actions of 5-LOX in leukocytes followed by 12-LOX action in platelets (Figure 24-2). This latter activity requires that platelets interact directly with adherent neutrophils as occurs only following platelet activation. Activated leukocytes that adhere to epithelial cells as a consequence inflammation (such as gastrointestinal, airway, or kidney epithelia) induce the production of lipoxins. An additional stimulus that leads to production of lipoxins is epithelial cell conversion of LTA₄ that is released from airway epithelia.

Activities of the Lipoxins

The lipoxins are potent anti-inflammatory eicosanoids and counteract the actions of the pro-inflammatory eicosanoids (primarily LTB₄ but also PGE₂ and TXA₂). The lipoxins LXA₄ and 15 epi-LXA₄ (an aspirin-triggered lipoxin) elicit their effects by binding to a specific GPCR identified as ALXR. ALXR is a multirecognition receptor involved in immune responses, which was originally identified as the formyl peptide receptor-like 1 (FPRL1) protein; a member of the formyl peptide receptor (FPR) family of receptors that bind N-formulated peptides derived by the degradation of bacteria or host cells. The FPR family of receptors is involved in mediating immune responses to infection.

Both LXA₄ and LXB₄ have been shown to promote the relaxation of the vasculature (both aortic and pulmonary relaxation). Lipoxins and the epi-lipoxins inhibit polymorphonuclear leukocyte (PMN) chemotaxis, PMN-mediated increases in vasopermeability, and PMN adhesion and migration through the endothelium. The lipoxins also stimulate phagocytosis of apoptotic PMN by monocyte-derived macrophages. PMN phagocytosis represents the resolution phase of inflammatory events.

Additional anti-inflammatory actions of the lipoxins include blocking expression of the IL-8, a pro-inflammatory chemokine produced by macrophages and endothelial cells that stimulates neutrophil migration. Actions of the lipoxins also include inhibition of the release and actions of tumor necrosis factor-α (TNF-α), and stimulation of the activity of transforming growth factor-β (TGF-β). By regulating the actions of histamine, the lipoxins also lead to a reduction in swelling due to edema. The actions of LXA₄ in some tissues lead to the production of prostacyclin (PGI₂) and nitric oxide (NO), both of which are vasodilators and may play roles in the anti-inflammatory properties of the aspirin-triggered lipoxins.

Actions of Aspirin via Lipid Modulators of Inflammation

Aspirin is the acetylated form of salicylic acid. Salicylate is a common constituent of numerous medicinal plants, which have been used for thousands of years to treat pain and rheumatic fever. Salicylate has an extremely bitter taste and causes gastric irritation. This led to the development of acetylated salicylate giving rise to the advent of aspirin (acetylsalicylic acid).

In the 1970s it was determined that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) all exerted their effects through the inhibition of prostaglandin synthesis via the inhibition of cyclooxygenase. However, this did not explain all of the actions that were being described for aspirin, in particular the ability of aspirin to limit leukocyte migration into sites of inflammation, thereby dampening host inflammatory responses. At high doses, aspirin functions to block the prostaglandin and thromboxane-synthesizing activity of COX-1, which results in inhibition of the primary pro-inflammatory, pyretic, and pain-inducing action of these eicosanoids. In addition, aspirin is an important inhibitor of platelet activation by reducing the production of thromboxane A₂ (TXA₂). Aspirin also reduces endothelial cell production of prostacyclin (PGI₂), an inhibitor of platelet aggregation and a vasodilator. Localized to the site of coagulation is a balance between the levels of platelet-derived TXA₂ and endothelial cell-derived PGI₂. This allows for platelet aggregation and clot formation but prevents excessive accumulation of the clot, thus maintaining some level of blood flow around the site of injury. Endothelial cells regenerate active COX faster than platelets because mature platelets cannot synthesize the enzyme, requiring new platelets to enter the circulation (platelet half-life is approximately 4 days). Therefore, PGI₂ synthesis is greater than that of TXA₂. The net effect of aspirin is more in favor of endothelial cell-mediated inhibition of the coagulation cascade.

Aspirin is also the only NSAID that results in the production of nitric oxide (NO). The induction of NO by aspirin is correlated with a reduction in leukocyte accumulation at sites of inflammation. The induced production of NO by aspirin plays a significant role in the protective effects of aspirin on the cardiovascular system.

Part of the cardiovascular benefit of aspirin is related to its dose-dependent differential effects on inflammatory events. It was known for many years that aspirin inhibited the action of COX-1 and COX-2 by causing the acetylation of the enzyme (Figure 24-3). However, in endothelial and epithelial cells the aspirin-induced acetylation of COX-2 alters the enzyme activity such that it now converts arachidonic acid to 15R hydroxyeicosatetraenoic acid (15R-HETE). Only at low doses (eg, 81 mg) will aspirin elicit its most important anti-inflammatory benefits. The low-dose anti-inflammatory effects of aspirin are due to its ability to trigger the synthesis of stereoisomers (epimers) of LXA₄ and LXB₄ identified as 15 epi-LXA₄ and 15 epi-LXB₄. These compounds are referred to as aspirin-triggered lipoxins (ATL) and they exhibit biological activities similar to the lipoxins synthesized by the “classical” pathways. When produced in leukocytes, 15R-HETE is a substrate for 5-LOX, the product of which is then ultimately converted to the ATL (see Figure 24-3). This aspirin-triggered lipoxin synthesis pathway is initiated when activated circulating leukocytes (primarily neutrophils) adhere to the vascular endothelium.

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