{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T03:55:20Z","timestamp":1775102120769,"version":"3.50.1"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Reactions to aspirin and nonsteroidal anti-inflammatory drugs in patients with aspirin-exacerbated respiratory disease (AERD) are triggered when constraints upon activated eosinophils, normally supplied by PGE2, are removed secondary to cyclooxygenase-1 inhibition. However, the mechanism driving the concomitant cellular activation is unknown. We investigated the capacity of aspirin itself to provide this activation signal. Eosinophils were enriched from peripheral blood samples and activated with lysine ASA (LysASA). Parallel samples were stimulated with related nonsteroidal anti-inflammatory drugs. Activation was evaluated as Ca2+ flux, secretion of cysteinyl leukotrienes (CysLT), and eosinophil-derived neurotoxin (EDN) release. CD34+ progenitor-derived mast cells were also used to test the influence of aspirin on human mast cells with measurements of Ca2+ flux and PGD2 release. LysASA induced Ca2+ fluxes and EDN release, but not CysLT secretion from circulating eosinophils. There was no difference in the sensitivity or extent of activation between AERD and control subjects, and sodium salicylate was without effect. Like eosinophils, aspirin was able to activate human mast cells directly through Ca2+ flux and PGD2 release. AERD is associated with eosinophils maturing locally in a high IFN-\u03b3 milieu. As such, in additional studies, eosinophil progenitors were differentiated in the presence of IFN-\u03b3 prior to activation with aspirin. Eosinophils matured in the presence of IFN-\u03b3 displayed robust secretion of both EDN and CysLTs. These studies identify aspirin as the trigger of eosinophil and mast cell activation in AERD, acting in synergy with its ability to release cells from the anti-inflammatory constraints of PGE2.<\/jats:p>","DOI":"10.4049\/jimmunol.1301753","type":"journal-article","created":{"date-parts":[[2014,6,3]],"date-time":"2014-06-03T00:27:19Z","timestamp":1401755239000},"page":"41-47","source":"Crossref","is-referenced-by-count":55,"title":["Aspirin Activation of Eosinophils and Mast Cells: Implications in the Pathogenesis of Aspirin-Exacerbated Respiratory Disease"],"prefix":"10.1093","volume":"193","author":[{"given":"John W","family":"Steinke","sequence":"first","affiliation":[{"name":"Asthma and Allergic Disease Center, Department of Medicine, University of Virginia Health System , Charlottesville, VA 22908"},{"name":"Carter Immunology Center, University of Virginia Health System , Charlottesville, VA 22908"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Negri","sequence":"additional","affiliation":[{"name":"Asthma and Allergic Disease Center, Department of Medicine, University of Virginia Health System , Charlottesville, VA 22908"},{"name":"Carter Immunology Center, University of Virginia Health System , Charlottesville, VA 22908"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lixia","family":"Liu","sequence":"additional","affiliation":[{"name":"Asthma and Allergic Disease Center, Department of Medicine, University of Virginia Health System , Charlottesville, VA 22908"},{"name":"Carter Immunology Center, University of Virginia Health System , Charlottesville, VA 22908"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Spencer C","family":"Payne","sequence":"additional","affiliation":[{"name":"Asthma and Allergic Disease Center, Department of Medicine, University of Virginia Health System , Charlottesville, VA 22908"},{"name":"Carter Immunology Center, University of Virginia Health System , Charlottesville, VA 22908"},{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, University of Virginia Health System , Charlottesville, VA 22908"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larry","family":"Borish","sequence":"additional","affiliation":[{"name":"Asthma and Allergic Disease Center, Department of Medicine, University of Virginia Health System , Charlottesville, VA 22908"},{"name":"Carter Immunology Center, University of Virginia Health System , Charlottesville, VA 22908"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,7,1]]},"reference":[{"key":"2025030707190902100_r1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/182090","article-title":"Interleukin-4 in the generation of the AERD phenotype: implications for molecular mechanisms driving therapeutic benefit of aspirin desensitization","author":"Steinke","year":"2012","journal-title":"J. Allergy."},{"key":"2025030707190902100_r2","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/S1081-1206(10)61323-3","article-title":"Chronic hyperplastic eosinophilic sinusitis as a predictor of aspirin-exacerbated respiratory disease","volume":"94","author":"Mascia","year":"2005","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"2025030707190902100_r3","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S0091-6749(99)70106-5","article-title":"Aspirin-induced asthma: advances in pathogenesis and management","volume":"104","author":"Szczeklik","year":"1999","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030707190902100_r4","doi-asserted-by":"crossref","first-page":"S42","DOI":"10.1136\/thorax.55.suppl_2.S42","article-title":"Clinical features and diagnosis of aspirin induced asthma","volume":"55","author":"Szczeklik","year":"2000","journal-title":"Thorax"},{"key":"2025030707190902100_r5","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/S1081-1206(10)62084-4","article-title":"The natural history and clinical characteristics of aspirin-exacerbated respiratory disease","volume":"89","author":"Berges-Gimeno","year":"2002","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"2025030707190902100_r6","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1164\/ajrccm.153.2.8564100","article-title":"Inhaled PGE2 prevents aspirin-induced bronchoconstriction and urinary LTE4 excretion in aspirin-sensitive asthma","volume":"153","author":"Sestini","year":"1996","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030707190902100_r7","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1183\/09031936.93.06030391","article-title":"Cysteinyl leukotrienes overproduction and mast cell activation in aspirin-provoked bronchospasm in asthma","volume":"6","author":"Sladek","year":"1993","journal-title":"Eur. Respir. J."},{"key":"2025030707190902100_r8","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1172\/JCI620","article-title":"Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma","volume":"101","author":"Cowburn","year":"1998","journal-title":"J. Clin. Invest."},{"key":"2025030707190902100_r9","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/S0091-6749(99)70324-6","article-title":"Association of urinary leukotriene E4 excretion during aspirin challenges with severity of respiratory responses","volume":"104","author":"Daffern","year":"1999","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030707190902100_r10","doi-asserted-by":"crossref","first-page":"3790","DOI":"10.1182\/blood-2011-10-384826","article-title":"Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes","volume":"119","author":"Laidlaw","year":"2012","journal-title":"Blood"},{"key":"2025030707190902100_r11","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1164\/ajrccm.157.4.9707089","article-title":"Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics","volume":"157","author":"Dahl\u00e9n","year":"1998","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030707190902100_r12","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/S0194-5998(98)70273-6","article-title":"Comparison of inflammatory cell profile and Th2 cytokine expression in the ethmoid sinuses, maxillary sinuses, and turbinates of atopic subjects with chronic sinusitis","volume":"118","author":"Kamil","year":"1998","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"2025030707190902100_r13","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1002\/lary.21969","article-title":"Evidence for distinct histologic profile of nasal polyps with and without eosinophilia","volume":"121","author":"Payne","year":"2011","journal-title":"Laryngoscope"},{"key":"2025030707190902100_r14","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/S0091-6749(97)80019-X","article-title":"IL-5 synthesis is upregulated in human nasal polyp tissue","volume":"99","author":"Bachert","year":"1997","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030707190902100_r15","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/j.jaci.2005.02.029","article-title":"Prostaglandin, leukotriene, and lipoxin balance in chronic rhinosinusitis with and without nasal polyposis","volume":"115","author":"P\u00e9rez-Novo","year":"2005","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030707190902100_r16","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/0091-6749(94)90123-6","article-title":"Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma","volume":"94","author":"Fischer","year":"1994","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030707190902100_r17","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.jaci.2013.05.008","article-title":"Prominent role of interferon-\u03b3 in aspirin-exacerbated respiratory disease","volume":"132","author":"Steinke","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030707190902100_r18","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1165\/ajrcmb.20.3.3060","article-title":"Immunolocalization of CD34 in nasal polyposis. Effect of topical corticosteroids","volume":"20","author":"Kim","year":"1999","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025030707190902100_r19","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1136\/thorax.55.suppl_2.S24","article-title":"Haemopoietic mechanisms in nasal polyposis and asthma","volume":"55","author":"Denburg","year":"2000","journal-title":"Thorax"},{"key":"2025030707190902100_r20","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1096\/fj.01-0390rev","article-title":"Cyclooxygenase-independent actions of cyclooxygenase inhibitors","volume":"15","author":"Tegeder","year":"2001","journal-title":"FASEB J."},{"key":"2025030707190902100_r21","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1254\/jphs.08R32FM","article-title":"Analysis of the mechanism for the development of allergic skin inflammation and the application for its treatment: aspirin modulation of IgE-dependent mast cell activation: role of aspirin-induced exacerbation of immediate allergy","volume":"110","author":"Suzuki","year":"2009","journal-title":"J. Pharmacol. Sci."},{"key":"2025030707190902100_r22","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1007\/s10875-011-9589-4","article-title":"Developmental, malignancy-related, and cross-species analysis of eosinophil, mast cell, and basophil siglec-8 expression","volume":"31","author":"Hudson","year":"2011","journal-title":"J. Clin. Immunol."},{"key":"2025030707190902100_r23","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1182\/blood.V94.7.2333.419k30_2333_2342","article-title":"Demonstration that human mast cells arise from a progenitor cell population that is CD34(+), c-kit(+), and expresses aminopeptidase N (CD13)","volume":"94","author":"Kirshenbaum","year":"1999","journal-title":"Blood"},{"key":"2025030707190902100_r24","first-page":"815","article-title":"Characterization of a novel human mast cell line that responds to stem cell factor and expresses functional FcepsilonRI","volume-title":"J. Allergy Clin. Immunol.","author":"Laidlaw","year":"2011"},{"key":"2025030707190902100_r25","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/S1081-1206(10)60012-9","article-title":"Intranasal ketorolac challenge for the diagnosis of aspirin-exacerbated respiratory disease","volume":"97","author":"White","year":"2006","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"2025030707190902100_r26","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.anai.2010.05.020","article-title":"Use of intranasal ketorolac and modified oral aspirin challenge for desensitization of aspirin-exacerbated respiratory disease","volume":"105","author":"Lee","year":"2010","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"2025030707190902100_r27","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1164\/ajrccm\/143.5_Pt_1.1025","article-title":"Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects","volume":"143","author":"Christie","year":"1991","journal-title":"Am. Rev. Respir. Dis."},{"key":"2025030707190902100_r28","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1164\/ajrccm.154.6.8970343","article-title":"Bronchial aspirin challenge causes specific eicosanoid response in aspirin-sensitive asthmatics","volume":"154","author":"Szczeklik","year":"1996","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030707190902100_r29","doi-asserted-by":"crossref","first-page":"S137","DOI":"10.1164\/ajrccm.161.supplement_1.ltta-27","article-title":"Treatment of aspirin-intolerant asthma with antileukotrienes","volume":"161","author":"Dahl\u00e9n","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030707190902100_r30","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1067\/mai.2003.67","article-title":"Cysteinyl leukotriene expression in chronic hyperplastic sinusitis-nasal polyposis: importance to eosinophilia and asthma","volume":"111","author":"Steinke","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030707190902100_r31","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1189\/jlb.0812374","article-title":"Editorial: yin-yang of EP receptor expression","volume":"92","author":"Steinke","year":"2012","journal-title":"J. Leukoc. Biol."},{"key":"2025030707190902100_r32","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1164\/ajrccm.161.2.9902034","article-title":"Differential metabolism of arachidonic acid in nasal polyp epithelial cells cultured from aspirin-sensitive and aspirin-tolerant patients","volume":"161","author":"Kowalski","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030707190902100_r33","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jaci.2005.10.037","article-title":"Aspirin-sensitive rhinosinusitis is associated with reduced E-prostanoid 2 receptor expression on nasal mucosal inflammatory cells","volume":"117","author":"Ying","year":"2006","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030707190902100_r34","doi-asserted-by":"crossref","first-page":"16987","DOI":"10.1073\/pnas.1313185110","article-title":"Prostaglandin E2 deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes","volume":"110","author":"Liu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030707190902100_r35","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1164\/ajrccm\/144.4.957","article-title":"The potent and selective sulfidopeptide leukotriene antagonist, SK&F 104353, inhibits aspirin-induced asthma","volume":"144","author":"Christie","year":"1991","journal-title":"Am. Rev. Respir. Dis."},{"key":"2025030707190902100_r36","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/S0091-6749(05)80179-4","article-title":"Salsalate cross-sensitivity in aspirin-sensitive patients with asthma","volume":"86","author":"Stevenson","year":"1990","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030707190902100_r37","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/0091-6749(79)90036-8","article-title":"Hypersensitivity to nonsteroidal antiinflammatory drugs: indications and methods for oral challenges","volume":"64","author":"Mathison","year":"1979","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025030707190902100_r38","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1046\/j.1365-2745.2002.01507.x","article-title":"A comparative study of eicosanoid concentrations in sputum and urine in patients with aspirin-intolerant asthma","volume":"32","author":"Higashi","year":"2002","journal-title":"Clin. Exp. Allergy"},{"key":"2025030707190902100_r39","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1067\/mai.2003.1387","article-title":"A controlled study of 9alpha,11beta-PGF2 (a prostaglandin D2 metabolite) in plasma and urine of patients with bronchial asthma and healthy controls after aspirin challenge","volume":"111","author":"Bochenek","year":"2003","journal-title":"J. Allergy Clin. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/193\/1\/41\/62226928\/1301753.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/193\/1\/41\/62226928\/1301753.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T07:43:45Z","timestamp":1741333425000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/193\/1\/41\/7955008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,7,1]]},"references-count":39,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2014,7,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1301753","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,7]]},"published":{"date-parts":[[2014,7,1]]}}}