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. Author manuscript; available in PMC: 2020 Dec 14.

Published in final edited form as: J Allergy Clin Immunol. 2019 Oct;144(4):875–881. doi: 10.1016/j.jaci.2019.08.022

Figure 1. — A. Under physiological conditions, PGE₂ derives from either constitutively expressed COX-1 or inducibly expressed COX-2. COX-derived PGH2 can be converted to PGE₂ by three different terminal PGE₂ synthase (PGES) enzymes; cytosolic (c)PGES, and microsomal (m)PGES-1 and -2. During inflammation, the concomitantly induced expressions of COX-2 and mPGES-1 markedly increase the production of PGE₂. Because COX-2 is much less sensitive to aspirin than is COX-1, this increase is relatively resistant to low dose aspirin. PGE₂ elicits signaling through EP receptors 1-4. EP₂ and EP₄ activate the cAMP/PKA pathway that stabilizes MCs and blocks leukotriene formation by phosphorylating 5-LO. B. In AERD, the impaired expression and function of the COX-2/mPGES-1 system renders PGE₂ production disproportionately dependent on COX-1 and susceptible to inhibition by low dose aspirin. The effects of PGE₂ depletion is potentiated by diminished EP₂ receptor expression, leading to unbraking of MCs and 5-LO.

Figure 1. — A. Under physiological conditions, PGE₂ derives from either constitutively expressed COX-1 or inducibly expressed COX-2. COX-derived PGH2 can be converted to PGE₂ by three different terminal PGE₂ synthase (PGES) enzymes; cytosolic (c)PGES, and microsomal (m)PGES-1 and -2. During inflammation, the concomitantly induced expressions of COX-2 and mPGES-1 markedly increase the production of PGE₂. Because COX-2 is much less sensitive to aspirin than is COX-1, this increase is relatively resistant to low dose aspirin. PGE₂ elicits signaling through EP receptors 1-4. EP₂ and EP₄ activate the cAMP/PKA pathway that stabilizes MCs and blocks leukotriene formation by phosphorylating 5-LO. B. In AERD, the impaired expression and function of the COX-2/mPGES-1 system renders PGE₂ production disproportionately dependent on COX-1 and susceptible to inhibition by low dose aspirin. The effects of PGE₂ depletion is potentiated by diminished EP₂ receptor expression, leading to unbraking of MCs and 5-LO.