Pathogenic Mechanisms and In Vitro Diagnosis of AERD
Figure 2
COX and 5-LO pathway in the metabolism of PGE2 and pLT for in vitro diagnosis of NSAID-triggered hypersensitivity. Simplified pictogram of eicosanoid pathways in the metabolism PGE2 and leukotrienes implicated for in vitro diagnosis of NSAID-triggered hypersensitivity. AA is enzymatically cleaved by calcium-dependent PLA2 from phospholipids (predominantly) or from DAG (minor amounts). AA is metabolised by the COX-pathway or 5-LO pathway (but also by several other pathways not figured out here). COXs generate PGH2, which is further processed by PGE-synthase forming PGE2 (other PGH2 metabolising pathways not mentioned here). PGE2 binds to EP subtypes of which EP2 and EP4 generate cAMP for signalling cascade. cAMP in turn causes negative feedback on the 5-LO pathway. AA is also metabolised by the 5-LO pathway (in part assisted by FLAP) generating LTA4. LTA4 is further processed by calcium-dependent LTA4-synthase forming amino acids bearing LTC4, which is exported and extracellularly metabolised by enzymes forming LTD4 and LTE4, collectively named pLTs All three LTs bind to cysLTs or GPR17 with differential selectivity. 5-LO: 5-lipoxygenase, AA: arachidonic acid, ASA: acetylsalicylic acid, cAMP: cyclic-adenosine monophosphate; cysLT: receptor of pLT, DAG: diacylglycerole, COX: cyclooxygenase, EP: PGE-receptor,GPR17: orphan receptor, binding pLT and nucleotides, HPETE: hydroxyperoxy-eicosatetraenoic acid, HETE: hydroxy-eicosatetraenoic acid, NSAID: nonsteroidal anti-inflammatory drugs, PLA2: phospholipase A2, PG: prostaglandin, pLT: peptidoleukotrienes.
