COX Enzymes

Cyclooxygenase enzymes (COX-1 and COX-2) convert Arachidonic Acid into Prostaglandins and thromboxanes. They’re one of two major pathways for processing arachidonic acid (the other being 5-LOX → Leukotrienes).

COX-1 vs COX-2

COX-1 is constitutively expressed — it’s always active in most tissues. It produces prostaglandins involved in normal physiological functions: protecting the stomach lining, maintaining kidney blood flow, supporting platelet aggregation.

COX-2 is inducible — it’s upregulated during inflammation. It produces prostaglandins that drive pain, fever, and inflammatory responses.

Most NSAIDs (ibuprofen, naproxen) inhibit both COX-1 and COX-2. Selective COX-2 inhibitors (celecoxib) spare COX-1.

Why COX Inhibition Is Problematic in Mast Cell Conditions

When COX is blocked, arachidonic acid isn’t consumed. The free arachidonic acid is then available for the 5-LOX pathway → increased leukotriene production → potentially worse bronchoconstriction, vascular permeability, and inflammation than the prostaglandins would have caused.

This is the “NSAID shunt” and is the biochemical reason NSAIDs are generally avoided in MCAS. In aspirin-exacerbated respiratory disease (AERD), this shunt produces severe bronchospasm.

Additionally, NSAIDs are commonly cited as DAO inhibitors. This is a widespread claim in the mast cell community but is not supported by direct experimental evidence — see DAO for the full misconception breakdown. The primary mechanism by which NSAIDs worsen mast cell symptoms is the COX→5-LOX shunt described above, not DAO inhibition.