Prostaglandin E2 receptors in asthma and in chronic rhinosinusitis/nasal polyps with and without aspirin hypersensitivity

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma frequently coexist and are always present in patients with aspirin exacerbated respiratory disease (AERD). Although the pathogenic mechanisms of this condition are still unknown, AERD may be due, at least in part, to an imbalance in eicosanoid metabolism (increased production of cysteinyl leukotrienes (CysLTs) and reduced biosynthesis of prostaglandin (PG) E2), possibly increasing and perpetuating the process of inflammation. PGE2 results from the metabolism of arachidonic acid (AA) by cyclooxygenase (COX) enzymes, and seems to play a central role in homeostasis maintenance and inflammatory response modulation in airways. Therefore, the abnormal regulation of PGE2 could contribute to the exacerbated processes observed in AERD. PGE2 exerts its actions through four G-protein-coupled receptors designated E-prostanoid (EP) receptors EP1, EP2, EP3, and EP4. Altered PGE2 production as well as differential EP receptor expression has been reported in both upper and lower airways of patients with AERD. Since the heterogeneity of these receptors is the key for the multiple biological effects of PGE2 this review focuses on the studies available to elucidate the importance of these receptors in inflammatory airway diseases.

Figure 1

Cyclooxygenase and 5-lipoxygenase pathways with special reference to aspirin exacerbated respiratory disease. Simplified pictogram of biosynthetic pathways of prostaglandin (PG) E₂ and cysteinyl leukotrienes (CysLTs). Arachidonic acid (AA) is metabolized by the cyclooxygenase (COX) or 5-lipoxygenase (5-LO) pathways. COX enzymes generate PGH₂ which through PGE₂ synthase is converted into PGE₂. PGE₂ couples to four subtypes of G-protein-coupled membrane receptors denominated E-prostanoid (EP) receptors. The activation of EP2 and EP4 receptors generates cyclic adenosine monophosphate (cAMP). This mediator negatively regulates the 5-LO pathway by activating protein kinase A (PKA). AA is also metabolized by the 5-LO pathway to generate leukotriene (LT) A₄. LTA₄ is subsequently metabolized by LTC₄ synthase, which conjugates reduced glutathione into LTC₄. LTC₄ is metabolized into LTD₄, which is then metabolized into LTE₄. LTC₄, LTD₄ and LTE₄ are designated as CysLTs. CysLTs bind to CysLT₁, CysLT₂ and GPR17 receptors. In aspirin exacerbated respiratory disease (AERD) the inhibition of COX pathway accounts for a reduced production of cAMP since the production of PGE₂ is diminished. This is a simplified pictogram where some pathways and compounds generated are not mentioned.