Author: Chen, Chongjia C ; Buchheit, Kathleen M ; Laidlaw, Tanya M ; Feng, Chunli ; Hacker, Jonathan ; Boyce, Joshua A ; Israel, Elliot ; Cho, Laura ; Cahill, Katherine N ; Le, Meghan ; Cui, Jing

BACKGROUNDAspirin-exacerbated respiratory disease (AERD) is the triad of asthma, nasal polyposis, and respiratory reactions to COX-1 inhibitors. Overproduction of cysteinyl leukotrienes and underproduction of prostaglandin E₂ (PGE₂) are hallmarks of AERD. A mouse model predicted a key role for the thromboxane-prostanoid (TP) receptor in AERD.OBJECTIVEOur aim was to determine whether ifetroban, a TP receptor antagonist, attenuates aspirin-induced respiratory symptoms in patients with AERD.METHODSA total of 35 patients with AERD completed a 4-week double-blinded, placebo-controlled trial of ifetroban and underwent an oral aspirin challenge. The primary outcome was change in the provocative dose of aspirin that caused a 2-point increase in Total Nasal Symptom Score. Changes in lung function, eicosanoid levels, and platelet and mast cell activation were assessed. Cultured human nasal fibroblasts were stimulated with or without the TP agonist U46619 and assayed for prostanoid production.RESULTSIfetroban was well tolerated in AERD and did not change the mean 2-point increase in Total Nasal Symptom Score (P = .763). Participants taking ifetroban had greater aspirin-induced nasal symptoms and a greater decline in FEV₁ value than did participants receiving placebo (-18.8% ± 3.6% with ifetroban vs -8.4% ± 2.1% with placebo [P = .017]). Four weeks of ifetroban significantly increased urinary leukotriene E₄ levels and decreased nasal PGE₂ levels compared with placebo. Peak aspirin-induced urinary thromboxane levels correlated with peak urinary leukotriene E₄ and prostaglandin D₂ metabolite levels in participants taking ifetroban. U46119 significantly potentiated the production of PGE₂ by cultured nasal fibroblasts from subjects with AERD but not by cultured nasal fibroblasts from controls without polypoid sinusitis.CONCLUSIONContrary to our hypothesis, TP receptor blockade worsened aspirin-induced reactions in AERD, possibly by exacerbating dysregulation of the eicosanoid system. TP signaling on stromal cells may be critical to maintaining PGE₂ production when COX-2 function is low.

07 Aug 2012·Journal of Allergy

Genetic Mechanisms in Aspirin-Exacerbated Respiratory Disease

Article

Author: Kim, Seung-Hyun ; Hwang, Eui-Kyung ; Jin, Hyun Jung ; Nam, Young Hee ; Shrestha Palikhe, Nami ; Park, Hae-Sim

Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in asthmatics following the exposure to aspirin or other nonsteroidal anti-inflammatory drugs. The key pathogenic mechanisms associated with AERD are the overproduction of cysteinyl leukotrienes (CysLTs) and increased CysLTR1 expression in the airway mucosa and decreased lipoxin and PGE2 synthesis. Genetic studies have suggested a role for variability of genes in disease susceptibility and the response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10, ACE, IL13, KIF3A, SLC22A2, CEP68, PTGER, and CRTH2 and a four-locus SNP set composed of B2ADR, CCR3, CysLTR1, and FCER1B. Future areas of investigation need to focus on comprehensive approaches to identifying biomarkers for early diagnosis.

01 Jan 2009·Yonsei Medical JournalQ4 · MEDICINE

Update on Recent Advances in the Management of Aspirin Exacerbated Respiratory Disease

Q4 · MEDICINE

ReviewOA

Author: Kim, Joo-Hee ; Park, Hae-Sim ; Palikhe, Nami Shrestha

Aspirin intolerant asthma (AIA) is frequently characterized as an aspirin (ASA)-exacerbated respiratory disease (AERD). It is a clinical syndrome associated with chronic severe inflammation in the upper and lower airways resulting in chronic rhinitis, sinusitis, recurrent polyposis, and asthma. AERD generally develops secondary to abnormalities in inflammatory mediators and arachidonic acid biosynthesis expression. Upper and lower airway eosinophil infiltration is a key feature of AERD; however, the exact mechanisms of such chronic eosinophilic inflammation are not fully understood. Cysteinyl leukotriene over-production may be a key factor in the induction of eosinophilic activation. Genetic studies have suggested a role for variability of genes in disease susceptibility and response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1*301, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10 -1082A > G, ACE -262A > T, and CRTH2 -466T > C; the four-locus SNP set was composed of B2ADR 46A > G, CCR3 -520T > G, CysLTR1 -634C > T, and FCER1B -109T > C. Management of AERD is an important issue. Aspirin ingestion may result in significant morbidity and mortality, and patients must be advised regarding aspirin risk. Leukotriene receptor antagonists (LTRA) that inhibit leukotriene pathways have an established role in long-term AERD management and rhinosinusitis. Aspirin desensitization may be required for the relief of upper and lower airway symptoms in AERD patients. Future research should focus on identification of biomarkers for a comprehensive diagnostic approach.

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