Eicosanoids and Their Functions

Intercellular Signaling

  • Eicosanoid Synthesis

What is an Eicosanoid?

  • Family of lipid-based signaling molecules.

  • Characterized by:

    • 20-carbon fatty acids with cis unsaturation points.

  • Major classes include:

    • Prostaglandins

    • Leukotrienes

    • Thromboxanes

    • Lipoxins

  • Functions:

    • Mediate inflammation.

    • Involved in immune responses.

    • Exhibit autocrine, paracrine, and endocrine functions.

    • Play a role in regulating:

    • Blood pressure

    • Blood clotting

Inflammation and Tissue Damage

  • Tissue damage leads to the release of:

    • Bradykinin (nonapeptide):

    • Causes vasodilation.

    • Activates pain receptors.

    • Promotes growth factor release for tissue repair.

  • Steps of eicosanoid production by bradykinin:

    1. Bradykinin binds to G protein, stimulating the enzyme: Phospholipase A2.

    2. Phospholipase A2 releases Arachidonic acid from the lipid bilayer.

    3. Arachidonic acid is the precursor to inflammatory eicosanoids.

Eicosanoid Classes

  • Prostaglandins:

    • Associated with inflammation, pain, and fever.

  • Leukotrienes:

    • Involved in allergic reactions, asthma, and inflammation.

  • Thromboxanes:

    • Play a role in blood clotting and platelet aggregation.

  • Dysregulation linked to:

    • Cardiovascular disease

    • Diabetes

    • Cancers

Pathways of Eicosanoid Formation

  • Eicosanoids are formed by two pathways:

    1. Cyclooxygenase pathway (COX):

    • Produces prostaglandins, prostacyclins (involved in pain and fever), and thromboxanes (blood clotting).

    1. Lipoxygenase pathway (LOX):

    • Produces leukotrienes and lipoxins (allergic reactions and asthma).

Arachidonic Acid Cascade: Cox Pathway

  • Responsible for prostanoid synthesis (e.g., prostaglandins, thromboxanes).

  • Reaction occurs from arachidonate with two O2 molecules.

  • Enzyme: Prostaglandin H synthase (PGHS or COX), which includes cyclooxygenase and peroxidase functions.

Cox Pathway Enzymes (inflammatory)

  • Prostaglandin H is a precursor to:

    • Prostaglandins D2, E2, F2

    • D2: involved in inflammation, sleep regulation, vasodilation, chemotaxis.

    • E2: involved in inflammation, GI function (stimulates acid secretion), cardiovascular function, bone metabolism, labor, tissue regeneration.

    • F2: involved in inflammation, uterine contractions, vasodilation, bone metabolism.

  • Thromboxane A2:

    • Vasoconstrictor produced by platelets.

  • Prostacyclin (PGI2):

    • Vasodilator produced by endothelial cells lining blood vessels.

Location of Cox Enzymes

  • Cox 1:

    • Constitutive (always present).

    • Location: gastric mucosa, kidney, endothelial cells, platelets.

  • Cox 2:

    • Inducible (present during inflammation).

    • Location: macrophages and monocytes.

Biological Activity of Prostaglandin E2

  • Produced by most tissues:

    • Endothelial cells and macrophages.

  • Acts as an intercellular signaling molecule through cAMP.

  • Results in:

    • Pain

    • Swelling

    • Smooth muscle contraction

Biological Activity of Prostaglandin I2 (Prostacyclins)

  • Produced by blood vessel walls.

  • Results in:

    • Inhibition of platelet aggregation.

    • causes bleeding

Biological Activity of Thromboxane A2

  • Produced by:

    • Platelets

    • Gastric mucosa

  • Results in:

    • Vasoconstriction

    • Platelet aggregation

    • clots

Lipoxygenase (LOX) Pathway (anti inflammatory)

  • Occurs in white blood cells and platelets.

  • Produces leukotrienes and lipoxins:

    • Arachidonic acid (AA) is converted in leukotriene synthesis.

Biological Activity of Leukotriene A4

  • Produced by leukocytes, platelets, and macrophages.

  • Results in:

    • Slow reacting substance of anaphylaxis (more potent than histamine).

    • Attracts and activates leukocytes in hypersensitivity reactions.

Biological Activity of Lipoxin A4

  • Produced by neutrophils, platelets, and epithelial cells.

  • Results in:

    • Decreasing neutrophil migration.

    • Increasing monocyte and macrophage activation.

    • Decreasing angiogenesis and fibrosis.

Drug Impact on COX/LOX Pathways

  • Steroids:

    1. Inhibit Phospholipase A2 (PLA2).

    2. Decrease transcription of PGHS2.

  • Aspirin:

    • Non-competitive inhibition of COX-1 enzyme.

  • Ibuprofen (NSAIDs), Naproxen:

    • Competitive inhibition of COX-1 enzyme.

  • Vioxx (Celebrex):

    • Inhibition of COX-2 enzyme.

  • Advair (Steroid inhalers):

    1. Inhibit PLA2.

    2. Decrease transcription of LOX enzyme.

Natural Remedies

  • Fish oil (omega-3 oils):

    • Inhibit Phospholipase A2 (PLA2).

  • Boswellia:

    • Modulates COX and LOX pathways.

  • Dietary changes:

    • Reduce or eliminate arachidonic acid in diet.

    • Eliminate dairy/beef fat, peanut oil, corn oil, and chicken skin.