Prostaglandins

Prostaglandins are lipid mediators synthesized from Arachidonic Acid by the COX Enzymes (cyclooxygenase-1 and cyclooxygenase-2). Mast Cells are a major source, producing them during the delayed phase of Degranulation — minutes to hours after activation.

The Key Player: PGD2

Prostaglandin D2 is the dominant prostaglandin released by mast cells. Its effects include:

• Vasodilation — particularly in the skin (flushing) and systemically (contributing to hypotension)
• Bronchoconstriction — through the DP2/CRTH2 receptor on airway smooth muscle
• Eosinophil and Th2 cell recruitment — amplifying the allergic/inflammatory response
• Sleep promotion — PGD2 in the brain promotes NREM sleep (which may seem contradictory to Sleep and Histamine, but the mediator effects can compete with each other)
• Pain sensitization — lowers the threshold of nociceptors (pain-sensing nerves)

PGD2 is metabolized to 11β-PGF2α and then to 2,3-dinor-11β-PGF2α, which is measurable in urine. This urine metabolite is one of the more sensitive markers for mast cell activation in 24-Hour Urine Testing.

PGE2

Also produced by mast cells (and many other cell types). PGE2 is broadly pro-inflammatory: fever, pain sensitization, edema, and immune cell activation. It’s the primary target of NSAID therapy in the general population, but blocking it with NSAIDs in mast cell patients can shunt Arachidonic Acid toward Leukotrienes — see Salicylates.

Why Antihistamines Don’t Cover This

Prostaglandins act on their own receptor families (DP1, DP2, EP1-4), which are completely distinct from Histamine receptors. A person on full H1 + H2 antihistamine coverage can still have significant prostaglandin-driven symptoms — flushing, pain, bronchoconstriction, fatigue. This is why multi-mediator thinking (see Mast Cell Mediators) matters and why adding Montelukast or other interventions may be necessary.