title: Biochemical pathogenesis of aspirin exacerbated respiratory disease (AERD).
abstract: Aspirin exacerbated respiratory disease (AERD) is a distinct clinical entity characterized by eosinophilic rhinosinusitis, asthma and often nasal polyposis. Exposure to aspirin or other nonsteroid anti-inflammatory drugs (NSAIDs) exacerbates bronchospasms with asthma and rhinitis. Disease progression suggests a skewing towards TH2 type cellular response along with moderate to severe eosinophil and mast cell infiltration. Alterations in upper and lower airway cellular milieu with abnormalities in eicosanoid metabolism and altered eicosanoid receptor expression are the key features underlying AERD pathogenesis. Dysregulation of arachidonic acid (AA) metabolism, notably reduced prostaglandin E2 (PGE2) synthesis compared to their aspirin tolerant counterpart and relatively increased PGD2 production, a TH2/eosinophil chemoattractant are reported in AERD. Underproduced PGE2 is metabolized by overexpression of 15 prostaglandin dehydrogenase (15-PGDH) to inactive products further reducing PGE2 at real time. This relives the inhibitory effect of PGE2 on 5-lipoxygenase (5-LOX) resulting in overproduction of cysteinyl leukotrienes (CysLTs). Diminished formation of CysLT antagonists called lipoxins (LXs) also augments CysLTs responsiveness. Occasional intake of NSAIDs favors even more 5-LOX product formation, further narrowing the bronchoconstrictive bottle neck, resulting in acute asthmatic exacerbations along with increased mucus production. This review focuses on abnormalities in biochemical and molecular mechanisms in eicosanoid biosynthesis, eicosanoid receptor dysregulation and associated polymorphisms with special reference to arachidonic acid metabolism in AERD.
authors.affiliation: Department of Immunoallergy and Asthma, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Calzada de Tlalpan 4502, Col. Sección XVI, Delegación Tlalpan, C.P. 14080, Mexico. n.arun.lifescience@gmail.com
authors.forename: Arun
authors.initials: A
authors.lastname: Narayanankutty
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Reséndiz-Hernández
authors.forename: Ramcés
authors.initials: R
authors.lastname: Falfán-Valencia
authors.forename: Luis M
authors.initials: LM
authors.lastname: Teran
mesh_terms: D016718:Arachidonic Acid / Q000378:metabolism; D055963:Asthma, Aspirin-Induced / Q000503:physiopathology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D006801:Humans; D044045:Lipoxins / Q000378:metabolism; D058945:Lipoxygenases / Q000378:metabolism
chemical_list: D015777:Eicosanoids; D044045:Lipoxins; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D058945:Lipoxygenases