Study note
PathologyInflammation and Repair

Major inflammatory mediators and pharmacologic inhibition of eicosanoids

THE CONTEXT
Inflammatory mediators have overlapping vascular and leukocyte effects. Drugs targeting eicosanoid synthesis can reduce inflammatory symptoms.

Cell-derived mediators

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Prostaglandins from mast cells and leukocytes produce vasodilation, pain, and fever.
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Leukotrienes from mast cells and leukocytes increase vascular permeability and promote chemotaxis, leukocyte adhesion, and activation.
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Cytokines such as tumor necrosis factor and interleukins 1 and 6 arise from macrophages, endothelial cells, and mast cells. Locally, they activate endothelium and induce adhesion molecule expression; systemic effects include fever, metabolic abnormalities, and hypotension or shock.
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Chemokines from leukocytes and activated macrophages promote chemotaxis and leukocyte activation.
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Platelet-activating factor from leukocytes and mast cells causes vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, and oxidative burst.

Plasma-derived mediators

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Complement is produced in the liver and present in plasma. Its actions include leukocyte chemotaxis and activation, direct target killing through the membrane attack complex, and vasodilation through mast cell stimulation.
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Kinins are plasma mediators produced in the liver that increase vascular permeability and cause smooth muscle contraction, vasodilation, and pain.

Cyclooxygenase inhibition

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Aspirin and other nonsteroidal antiinflammatory drugs, such as ibuprofen, inhibit COX-1 and COX-2, reducing prostaglandin synthesis and treating pain and fever.
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Aspirin irreversibly inactivates cyclooxygenases.
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Selective COX-2 inhibitors were developed to target prostaglandins involved in inflammatory reactions.
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COX-2 inhibitors may increase cardiovascular and cerebrovascular risk by impairing endothelial production of antithrombotic prostacyclin while preserving platelet COX-1-mediated production of thromboxane A2, which promotes platelet aggregation.
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The passage describes COX-2 inhibitors as used mainly for arthritis and perioperative pain in patients without cardiovascular risk factors.

Lipoxygenase inhibition

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Nonsteroidal antiinflammatory drugs do not affect 5-lipoxygenase.
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Zileuton inhibits leukotriene production and is useful in the treatment of asthma.
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