Two groups of lipid molecules synthesized by stimulated cells act as powerful mediators and regulators of inflammatory responses: the arachidonic acid (AA) metabolites, or eicosanoids, and the acetylated triglycerides, usually called platelet-activating factors. Both groups of molecules may be rapidly generated from the same lysophospholipid precursors by the enzymatic action of cellular phospholipases such as phospholipase A2 (Fig 1-4).
All eicosanoids are derived from AA. It is liberated from membrane phospholipids by phospholipase A2, which is activated by various agonists; AA is oxidized by 2 major pathways to generate the various mediators:
the cyclooxygenase (COX) pathway, which produces prostaglandins, thromboxanes, and prostacyclins
the 5-lipoxygenase pathway, which produces 5-hydroperoxyeicosatetraenoic acid, lipoxins, and leukotrienes
The COX-derived products are evanescent compounds induced in virtually all cells by a variety of stimuli. In general, they act in the immediate environment of their release to directly mediate many inflammatory activities. These include effects on vascular permeability, cell recruitment, platelet function, and smooth-muscle contraction.
Depending on conditions, COX-derived products can either upregulate or downregulate the production of cytokines, enzyme systems, and oxygen metabolites. The 2 forms of COX are COX-1 and COX-2. COX-1 is thought to be constitutively expressed by many cells, especially cells that use prostaglandin for basal metabolic functions, such as cells of the gastric mucosa and renal tubular epithelium. COX-2 is inducible by many inflammatory stimuli, including other inflammatory mediators (eg, PAF and some cytokines) and innate stimuli (eg, LPS).
Prostaglandins may be the cause of uveitic macular edema in association with anterior segment surgery or inflammation. Posterior diffusion of one or more of the eicosanoids through the vitreous is assumed to alter the permeability of the perifoveal capillary network, leading to macular edema. Clinical trials in humans suggest that topical treatment with COX inhibitors (eg, NSAIDs) reduces the incidence of macular edema after cataract surgery.
Figure 1-4 Overview of the essential intermediates of the eicosanoid and platelet-activating factor (PAF) pathways. 5-HPETE = 5-hydroperoxyeicosatetraenoic acid; NSAIDs = nonsteroidal anti-inflammatory drugs.
(Modified with permission from Pepose JS, Holland GN, Wilhelmus KR, eds. Ocular Infection and Immunity. St Louis, MO: Mosby; 1996.)
Derivatives of 5-lipoxygenase, an enzyme found mainly in granulocytes and some mast cells, have been detected in the brain and retina. Leukotrienes probably contribute significantly to inflammatory infiltration; some leukotrienes have 1000 times the effect of histamine on vascular permeability. Another lipoxygenase product, lipoxin, is a potent stimulator of superoxide anion. Because many of the COX-derived prostaglandins down-regulate the lipoxygenase pathway, NSAIDs can tilt AA metabolism toward increased production of inflammatory metabolites, leukotrienes, and lipoxins.
Platelet-activating factors are a family of phospholipid-derived mediators that appear to be important stimuli in the early stage of inflammation. These factors also serve physiologic functions unrelated to inflammation, especially in reproductive biology, the physiology of secretory epithelium, and neurobiology. In these physiologic roles, a de novo biosynthetic pathway has been identified. However, the remodeling pathway is the one implicated in PAF inflammatory actions.
Phospholipase A2 metabolizes phosphocholine precursors in cell membranes, releasing AA and PAF precursors, which are acetylated into multiple species of PAF. PAF release is stimulated by various innate immune triggers, such as bacterial toxins, trauma, and cytokines. Platelet-activating factors activate not only platelets but also most leukocytes, which in turn produce and release additional PAFs. They function by binding to one or more guanosine triphosphate protein–associated receptors on target cells.
In vitro, PAFs induce an impressive repertoire of responses, including phagocytosis, exocytosis, superoxide production, chemotaxis, aggregation, proliferation, adhesion, eicosanoid generation, degranulation, and calcium mobilization, as well as diverse morphologic changes. PAFs are a major regulator of cell adhesion and vascular permeability in many forms of acute inflammation, trauma, shock, and ischemia.
The precise role of PAFs in intraocular inflammation remains unknown, but synergistic interactions probably exist among PAFs, nitric oxide, eicosanoids, and cytokines. However, intravitreal injection of PAFs in animals induces an acute retinitis and photoreceptor toxicity.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.