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3.
Mucosal Immunol ; 12(3): 679-690, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30664709

RESUMO

Cysteinyl leukotrienes (cysLTs) facilitate eosinophilic mucosal type 2 immunopathology, especially in aspirin-exacerbated respiratory disease (AERD), by incompletely understood mechanisms. We now demonstrate that platelets, activated through the type 2 cysLT receptor (CysLT2R), cause IL-33-dependent immunopathology through a rapidly inducible mechanism requiring the actions of high mobility box 1 (HMGB1) and the receptor for advanced glycation end products (RAGE). Leukotriene C4 (LTC4) induces surface HMGB1 expression by mouse platelets in a CysLT2R-dependent manner. Blockade of RAGE and neutralization of HMGB1 prevent LTC4-induced platelet activation. Challenges of AERD-like Ptges-/- mice with inhaled lysine aspirin (Lys-ASA) elicit LTC4 synthesis and cause rapid intrapulmonary recruitment of platelets with adherent granulocytes, along with platelet- and CysLT2R-mediated increases in lung IL-33, IL-5, IL-13, and bronchoalveolar lavage fluid HMGB1. The intrapulmonary administration of exogenous LTC4 mimics these effects. Platelet depletion, HMGB1 neutralization, and pharmacologic blockade of RAGE eliminate all manifestations of Lys-ASA challenges, including increase in IL-33, mast cell activation, and changes in airway resistance. Thus, CysLT2R signaling on platelets prominently utilizes RAGE/HMGB1 as a link to downstream type 2 respiratory immunopathology and IL-33-dependent mast cell activation typical of AERD. Antagonists of HMGB1 or RAGE may be useful to treat AERD and other disorders associated with type 2 immunopathology.


Assuntos
Asma Induzida por Aspirina/imunologia , Plaquetas/imunologia , Proteína HMGB1/metabolismo , Pulmão/imunologia , Mastócitos/imunologia , Receptores de Leucotrienos/metabolismo , Animais , Células Cultivadas , Humanos , Interleucina-33/metabolismo , Leucotrieno C4/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prostaglandina-E Sintases/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptores de Leucotrienos/genética , Transdução de Sinais
4.
Curr Opin Pulm Med ; 25(1): 64-70, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30489335

RESUMO

PURPOSE OF REVIEW: NSAID-Exacerbated Disease (N-ERD) is a chronic eosinophilic inflammatory disorder of the respiratory tract occurring in patients with asthma and/or rhinosinusitis with nasal polyps, whose symptoms are exacerbated by NSAIDs. The purpose of this review is to provide an update on clinical characteristics, pathophysiology, and management of N-ERD, and to emphasize heterogeneity of this syndrome. RECENT FINDINGS: Growing evidence indicates that N-ERD, which has been considered a separate asthma phenotype, is heterogenous, and can be divided in several subphenotypes varying in clinical characteristics. Pathophysiology of N-ERD is complex and extends beyond abnormalities in the arachidonic acid metabolism. Heterogeneity of pathophysiological mechanisms underlying development of airway inflammation seems to be associated with variability in response to both anti-inflammatory and disease-specific treatments (e.g., with aspirin after desensitization). SUMMARY: Progress in understanding of the pathophysiology of N-ERD leads to discovery and validation of new biomarkers facilitating diagnosis and predicting the response to treatment of the chronic inflammation underlying upper (CRSwNP) and lower airway (asthma) symptoms. Better characterization of the immunophysiopathological heterogeneity of N-ERD (identification of endotypes) may allow more personalized, endotype-driven approach to treatment in the future.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Asma Induzida por Aspirina/diagnóstico , Asma Induzida por Aspirina/etiologia , Rinite/induzido quimicamente , Sinusite/induzido quimicamente , Asma Induzida por Aspirina/imunologia , Asma Induzida por Aspirina/prevenção & controle , Biomarcadores , Doença Crônica , Humanos , Pólipos Nasais/complicações , Fenótipo
5.
Curr Opin Allergy Clin Immunol ; 19(1): 38-45, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30516547

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to describe the recent advances that have been made in understanding the protective role of prostaglandin E2 (PGE2) in aspirin-exacerbated respiratory disease (AERD), known in Europe as NSAID-exacerbated respiratory disease (N-ERD). RECENT FINDINGS: Decreased PGE2 signaling through the EP2 receptor in patients with AERD leads to an increase in leukotriene synthesis and signaling. Leukotriene signaling not only directly activates group 2 innate lymphoid cells and mast cells, but it also increases production of IL-33 and thymic stromal lymphopoietin. These cytokines drive Th2 inflammation in a suspected feed-forward mechanism in patients with AERD. SUMMARY: Recent discoveries concerning the role of PGE2 in leukotriene synthesis and signaling in AERD, as well as downstream effects on group 2 innate lymphoid cells and mast cells, allow for a more comprehensive understanding of the pathogenesis of this disease. These discoveries also identify new paths of potential investigation and possible therapeutic targets for AERD.


Assuntos
Asma Induzida por Aspirina/imunologia , Dinoprostona/metabolismo , Linfócitos/imunologia , Mastócitos/imunologia , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Animais , Citocinas/metabolismo , Humanos , Imunidade Inata , Interleucina-33/metabolismo , Leucotrienos/metabolismo , Células Th2/imunologia
6.
J Allergy Clin Immunol ; 143(1): 316-324.e7, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29890239

RESUMO

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, recurrent nasal polyposis, and respiratory reactions on ingestion of COX-1 inhibitors. Increased numbers of platelet-leukocyte aggregates are present in the sinus tissue and blood of patients with AERD compared with that of aspirin-tolerant patients, and platelet activation can contribute to aspirin-induced reactions. OBJECTIVE: We sought to determine whether treatment with prasugrel, which inhibits platelet activation by blocking the type 12 purinergic (P2Y12) receptor, would attenuate the severity of sinonasal and respiratory symptoms induced during aspirin challenge in patients with AERD. METHODS: Forty patients with AERD completed a 10-week, double-blind, placebo-controlled crossover trial of prasugrel. All patients underwent oral aspirin challenges after 4 weeks of prasugrel and after 4 weeks of placebo. The primary outcome was a change in the provocative dose of aspirin that would elicit an increase in Total Nasal Symptom Score (TNSS) of 2 points. Changes in lung function, urinary eicosanoids, plasma tryptase, platelet-leukocyte aggregates, and platelet activation were also recorded. RESULTS: Prasugrel did not significantly change the mean increase in TNSS of 2 points (79 ± 15 for patients receiving placebo and 139 ± 32 for patients receiving prasugrel, P = .10), platelet-leukocyte aggregates, or increases in urinary leukotriene E4 and prostaglandin D2 metabolite levels during aspirin-induced reactions in the study population as a whole. Five subjects (responders) reacted to aspirin while receiving placebo but did not have any reaction to aspirin challenge after the prasugrel arm. In contrast to prasugrel nonresponders (35 subjects), the prasugrel responders had smaller reaction-induced increases in TNSS; did not have significant aspirin-induced increases in urinary leukotriene E4, prostaglandin D2 metabolite, or thromboxane B2 levels; and did not display increases in serum tryptase levels during aspirin reactions on the placebo arm, all of which were observed in the nonresponders. CONCLUSION: In the overall study population, prasugrel did not attenuate aspirin-induced symptoms, possibly because it failed to decrease the frequencies of platelet-adherent leukocytes or to diminish aspirin-induced mast cell activation. In a small subset of patients with AERD who had greater baseline platelet activation and milder upper respiratory symptoms during aspirin-induced reactions, P2Y12 receptor antagonism with prasugrel completely inhibited all aspirin-induced reaction symptoms, suggesting a contribution from P2Y12 receptor signaling in this subset.


Assuntos
Asma Induzida por Aspirina/tratamento farmacológico , Cloridrato de Prasugrel/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Receptores Purinérgicos P2Y12/imunologia , Adulto , Asma Induzida por Aspirina/imunologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
Respir Med ; 143: 39-41, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30261990

RESUMO

BACKGROUND: Aspirin desensitization (AD) has been the only available modifying treatment in aspirin-exacerbated respiratory disease (AERD). The mechanisms of AD are nonetheless poorly understood. Though very effective, AD is limited by its risks and side-effects. OBJECTIVE: Moving forward to the targeted biologicals era, the aim of this study was to characterize the airway inflammatory response to long-term AD, including TSLP dynamics, in order to assess potential new targets in AERD. PATIENTS AND METHODS: Adult patients with aspirin challenge-confirmed AERD underwent an oral AD followed by daily ingestion of aspirin for at least 6 months. Clinical data and inflammatory biomarkers were measured and compared, before and after AD. Induced sputum analyses were performed at baseline, one and six months after AD (differential cell count and levels of sputum supernatant leukotriene C4, prostaglandin D2 and E2, and TSLP). RESULTS: AD was followed by significant clinical improvement, as quantified by all monitored parameters. The good clinical outcomes of AD in our study are supported by overall changes observed in the arachidonic acid metabolites (decreased PGD2 over a constant LTC4/PGE2). TSLP increased (mean baseline 0.1 ±â€¯0.03; 1 month 3.68 ±â€¯7; 6 months 212.2 ±â€¯44 pg/ml; p < 0.01). CONCLUSIONS: Our findings suggest that new biologicals blocking TSLP might have a clinical benefit in AERD, by cutting down the TSLP-induced PGD2 generation.


Assuntos
Aspirina/efeitos adversos , Aspirina/imunologia , Asma Induzida por Aspirina/etiologia , Asma Induzida por Aspirina/terapia , Dessensibilização Imunológica/métodos , Adulto , Idoso , Aspirina/administração & dosagem , Asma Induzida por Aspirina/imunologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Prostaglandina D2/antagonistas & inibidores , Prostaglandina D2/metabolismo , Adulto Jovem
8.
Ann Allergy Asthma Immunol ; 121(1): 98-104, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29777744

RESUMO

BACKGROUND: Aspirin desensitization has been associated with benefit in management of aspirin-exacerbated respiratory disease (AERD). An intervention that would encourage aspirin desensitization to be performed more frequently has substantial potential for improving outcomes and quality of life in patients with AERD. OBJECTIVE: We investigated whether omalizumab administration would be associated with attenuation of aspirin-provoked bronchospasm in patients with AERD undergoing aspirin desensitization. METHODS: We carried out a randomized, double-blind, placebo-controlled study in which subjects with AERD who fulfilled label criteria for omalizumab received omalizumab or placebo for 16 weeks, and then underwent aspirin desensitization. RESULTS: Eleven subjects completed aspirin desensitization. Of the 7 who were randomized to omalizumab, 5 had no respiratory reaction during aspirin desensitization. Compared with placebo, omalizumab was associated with a significantly greater likelihood for subjects with AERD to have no respiratory reaction during desensitization (P = .04, Fisher exact test). There was an overall difference in urinary leukotriene E4 (LTE4) levels in subjects who received omalizumab and did not have a respiratory reaction during desensitization compared with subjects randomized to placebo (P = .035, mixed model with interaction). Urinary LTE4 levels were significantly higher with respiratory reaction in placebo subjects compared with levels obtained after the 100-mg dose in AERD subjects who had no respiratory reaction (P < .001, mixed model with interaction). CONCLUSION: In atopic AERD subjects, omalizumab administration for 16 weeks was associated with "clinically silent" desensitization. Further studies to investigate the therapeutic utility of omalizumab in patients with AERD who are candidates for aspirin desensitization are warranted based on these findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00555971.


Assuntos
Antiasmáticos/uso terapêutico , Aspirina/efeitos adversos , Asma Induzida por Aspirina/tratamento farmacológico , Espasmo Brônquico/prevenção & controle , Dessensibilização Imunológica/métodos , Omalizumab/uso terapêutico , Adulto , Asma Induzida por Aspirina/etiologia , Asma Induzida por Aspirina/imunologia , Asma Induzida por Aspirina/urina , Biomarcadores/urina , Espasmo Brônquico/etiologia , Espasmo Brônquico/imunologia , Espasmo Brônquico/urina , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Leucotrieno E4/urina , Masculino , Pessoa de Meia-Idade
9.
Ann Allergy Asthma Immunol ; 121(1): 111-116.e1, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29653235

RESUMO

BACKGROUND: Aspirin desensitization is an appropriate procedure for many patients with aspirin-exacerbated respiratory disease (AERD). Patients can require aspirin re-dosing, which prolongs the desensitization process. The frequency of this is not widely reported, nor is it known which patients will require multiple re-dosing. OBJECTIVE: To determine the frequency of and factors associated with repeat aspirin re-dosing during desensitization. METHODS: Charts of aspirin desensitization procedures from 2011 to 2016 at the University of Michigan Allergy/Immunology Clinic were reviewed. Reactions with provoking doses and number of dose repetitions were characterized. Previous AERD history, medical history, medications, and baseline spirometry were also recorded. Bivariate correlation and multivariate logistic regression were used to analyze associations between patient characteristics and need for repeated dosing of aspirin. RESULTS: A total of 84 positive-reacting patients during desensitization were identified. Of these patients, 33% required 2 or more aspirin dose repetitions during desensitization. Requiring 2 or more repeat doses during desensitization was associated with male gender (odds ratio = 6.194, P = .008), forced expiratory volume in 1 second (FEV1) decrease during desensitization (odds ratio = 1.075 per percent point drop, P = .021), and initial aspirin provoking dose during desensitization of 81 mg or lower (odds ratio = 11.111, P = .003). No association was found with pre-desensitization medications, asthma severity, AERD duration, or number/character of reported previous aspirin reactions. CONCLUSION: During aspirin desensitization for AERD, approximately one third of our patients require multiple repeat doses. Risk factors for multiple repeated doses include male gender, drop in FEV1, and lower aspirin provoking doses during desensitization. This information can help inform which patients may require multiple re-dosing for desensitization.


Assuntos
Aspirina/administração & dosagem , Asma Induzida por Aspirina/tratamento farmacológico , Dessensibilização Imunológica/métodos , Administração Oral , Adulto , Idoso , Asma Induzida por Aspirina/etiologia , Asma Induzida por Aspirina/imunologia , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Estudos Retrospectivos , Fatores Sexuais
10.
Respir Med ; 135: 62-75, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29414455

RESUMO

Aspirin-exacerbated respiratory disease is a chronic and treatment-resistant disease, characterized by the presence of eosinophilic rhinosinusitis, nasal polyposis, bronchial asthma, and nonsteroidal anti-inflammatory drugs hypersensitivity. Alterations in arachidonic acid metabolism may induce an imbalance between pro-inflammatory and anti-inflammatory substances, expressed as an overproduction of cysteinyl leukotrienes and an underproduction of prostaglandin E2. Although eosinophils play a key role, recent studies have shown the importance of other cells and molecules in the development of the disease like mast cells, basophils, lymphocytes, platelets, neutrophils, macrophages, epithelial respiratory cells, IL-33 and thymic stromal lymphopoietin, making each of them promissory diagnostic and treatment targets. In this review, we summarize the most important clinical aspects of the disease, including the current topics about diagnosis and treatment, like provocation challenges and aspirin desensitization. We also discuss recent findings in the pathogenesis of the disease, as well as future trends in diagnosis and treatment, including monoclonal antibodies and a low salicylate diet as a treatment option.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Asma Induzida por Aspirina/imunologia , Asma/induzido quimicamente , Pólipos Nasais/induzido quimicamente , Doenças Respiratórias/induzido quimicamente , Rinite/induzido quimicamente , Sinusite/induzido quimicamente , Adulto , Anticorpos Monoclonais/uso terapêutico , Ácido Araquidônico/metabolismo , Asma/terapia , Asma Induzida por Aspirina/diagnóstico , Asma Induzida por Aspirina/epidemiologia , Asma Induzida por Aspirina/terapia , Cisteína/metabolismo , Citocinas/metabolismo , Dessensibilização Imunológica/métodos , Dinoprostona/metabolismo , Progressão da Doença , Síndrome de Hipersensibilidade a Medicamentos , Eosinófilos/metabolismo , Feminino , Humanos , Leucotrienos/metabolismo , Masculino , Mastócitos/metabolismo , Pólipos Nasais/terapia , Doenças Respiratórias/diagnóstico , Doenças Respiratórias/epidemiologia , Doenças Respiratórias/terapia , Rinite/terapia , Sinusite/terapia
11.
Am J Rhinol Allergy ; 32(1): 7-11, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29336282

RESUMO

Aspirin-exacerbated respiratory disease (AERD) is characterized by chronic eosinophilic nasal polyps, asthma, and airway reactions upon cyclooxygenase (COX) 1 inhibition. AERD is present in up to 7% of adult patients with asthma and the underlying pathogenesis remains largely elusive but prostaglandin D2, cysteinyl leukotrienes, mast cells, and type 2 cytokines are thought to contribute. A wealth of studies have recently implicated group 2 innate lymphoid cells (ILC2), a novel lineage-negative lymphocyte population that produces type 2 cytokines, in human allergic disease pathogenesis. Importantly, our recent work identified that ILC2s are recruited to the nasal mucosa of patients on AERD after COX-1 inhibitor administration. Here, we review the potential impact of ILC2s in the development and propagation of type 2 inflammation in AERD.


Assuntos
Asma Induzida por Aspirina/imunologia , Eosinófilos/imunologia , Inflamação/imunologia , Linfócitos/imunologia , Mastócitos/imunologia , Mucosa Nasal/imunologia , Pólipos Nasais/imunologia , Adulto , Ciclo-Oxigenase 1/metabolismo , Citocinas/metabolismo , Humanos , Imunidade Inata , Prostaglandina D2/metabolismo , Células Th2/imunologia
12.
J Immunol ; 200(3): 915-927, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29282304

RESUMO

Cysteinyl leukotrienes (cysLTs) facilitate mucosal type 2 immunopathology by incompletely understood mechanisms. Aspirin-exacerbated respiratory disease, a severe asthma subtype, is characterized by exaggerated eosinophilic respiratory inflammation and reactions to aspirin, each involving the marked overproduction of cysLTs. Here we demonstrate that the type 2 cysLT receptor (CysLT2R), which is not targeted by available drugs, is required in two different models to amplify eosinophilic airway inflammation via induced expression of IL-33 by lung epithelial cells. Endogenously generated cysLTs induced eosinophilia and expanded group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease-like Ptges-/- mice. These responses were mitigated by deletions of either Cysltr2 or leukotriene C4 synthase (Ltc4s). Administrations of either LTC4 (the parent cysLT) or the selective CysLT2R agonist N-methyl LTC4 to allergen sensitized wild-type mice markedly boosted ILC2 expansion and IL-5/IL-13 generation in a CysLT2R-dependent manner. Expansion of ILC2s and IL-5/IL-13 generation reflected CysLT2R-dependent production of IL-33 by alveolar type 2 cells, which engaged in a bilateral feed-forward loop with ILC2s. Deletion of Cysltr1 blunted LTC4-induced ILC2 expansion and eosinophilia but did not alter IL-33 induction. Pharmacological blockade of CysLT2R prior to inhalation challenge of Ptges-/- mice with aspirin blocked IL-33-dependent mast cell activation, mediator release, and changes in lung function. Thus, CysLT2R signaling, IL-33-dependent ILC2 expansion, and IL-33-driven mast cell activation are necessary for induction of type 2 immunopathology and aspirin sensitivity. CysLT2R-targeted drugs may interrupt these processes.


Assuntos
Aspirina/imunologia , Asma Induzida por Aspirina/patologia , Interleucina-33/imunologia , Mastócitos/imunologia , Receptores de Leucotrienos/imunologia , Animais , Asma Induzida por Aspirina/imunologia , Cisteína/biossíntese , Eosinofilia/imunologia , Eosinofilia/patologia , Células Epiteliais/metabolismo , Glutationa Transferase/genética , Interleucina-13/biossíntese , Interleucina-33/biossíntese , Interleucina-5/biossíntese , Leucotrieno E4/biossíntese , Leucotrienos/biossíntese , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prostaglandina-E Sintases/genética , Receptores de Leucotrienos/genética
14.
Mediators Inflamm ; 2017: 8160148, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28852271

RESUMO

Asthma is a common chronic disease with several variant phenotypes and endotypes. NSAID-exacerbated respiratory disease (NERD) is one such endotype characterized by asthma, chronic rhinosinusitis (CRS) with nasal polyps, and hypersensitivity to aspirin/cyclooxygenase-1 inhibitors. NERD is more associated with severe asthma than other asthma phenotypes. Regarding diagnosis, aspirin challenge tests via the oral or bronchial route are a standard diagnostic method; reliable in vitro diagnostic tests are not available. Recent studies have reported various biomarkers of phenotype, diagnosis, and prognosis. In this review, we summarized the known potential biomarkers of NERD that are distinct from those of aspirin-tolerant asthma. We also provided an overview of the different NERD subgroups.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores/sangue , Animais , Aspirina/uso terapêutico , Asma/sangue , Asma/tratamento farmacológico , Asma/imunologia , Asma Induzida por Aspirina/sangue , Asma Induzida por Aspirina/tratamento farmacológico , Asma Induzida por Aspirina/imunologia , Biomarcadores/metabolismo , Humanos , Transtornos Respiratórios/sangue , Transtornos Respiratórios/tratamento farmacológico , Transtornos Respiratórios/imunologia
15.
J Allergy Clin Immunol ; 140(1): 101-108.e3, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28279492

RESUMO

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by tissue eosinophilia and mast cell activation, including abundant production of prostaglandin D2 (PGD2). Group 2 innate lymphoid cells (ILC2s), which promote tissue eosinophilia and mast cell responses, undergo chemotaxis and cytokine production in response to PGD2, but it is unknown whether ILC2s are active in patients with AERD. OBJECTIVE: We sought to determine whether ILC2 numbers change in peripheral blood and the nasal mucosa during COX-1 inhibitor-induced reactions in patients with AERD. METHODS: Blood and nasal scrapings were collected at baseline, during reactions, and after completion of ketorolac/aspirin challenge/desensitization in 12 patients with AERD. ILC2s and eosinophils were quantitated by means of flow cytometry. Urine was also collected, and quantification of PGD2 metabolite and leukotriene E4 levels was done by using ELISA. Baseline and nonsteroidal anti-inflammatory drug reaction clinical data were correlated with cell changes. RESULTS: ILC2 numbers significantly increased in nasal mucosal samples and decreased in blood at the time of COX-1 inhibitor reactions in 12 patients with AERD. These changes were not observed in 2 patients without AERD. Furthermore, eosinophil numbers decreased in blood concurrently with significant increases in urinary PGD2 metabolite and leukotriene E4 levels. The magnitude of increases in nasal mucosal ILC2 numbers positively correlated with maximum symptom scores during challenges. Furthermore, blood ILC2 numbers during the reaction correlated with time for the reaction to resolve, possibly reflecting reaction severity. CONCLUSIONS: ILC2s are recruited to the nasal mucosa during COX-1 inhibitor-induced reactions in patients with AERD, correlating with enhanced production of prostaglandins and leukotrienes.


Assuntos
Asma Induzida por Aspirina/imunologia , Inibidores de Ciclo-Oxigenase/efeitos adversos , Linfócitos/imunologia , Mucosa Nasal/imunologia , Adulto , Idoso , Asma Induzida por Aspirina/sangue , Asma Induzida por Aspirina/urina , Contagem de Células , Dessensibilização Imunológica , Dinoprosta/urina , Feminino , Humanos , Cetorolaco/administração & dosagem , Leucotrieno E4/urina , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/citologia
16.
Respir Med ; 123: 71-78, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28137499

RESUMO

BACKGROUND: Aspirin-exacerbated respiratory diseases (AERD) are caused by ingestion of non-steroidal anti-inflammatory drugs and are characterized by acute bronchospasms and marked infiltration of eosinophils, the latter being attributable to altered synthesis of cysteinyl leukotrienes (LT) and prostaglandins (PG). Recently, the innate Th2 response is revealed to induce eosinophil infiltration in allergic inflammation, however the role of the innate Th2 response has not been studies in AERD. Thus, we evaluated the relationship between the innate Th2 cytokines including IL-25, thymic stromal lymphopoietin (TSLP) and IL-33 and the development of AERD. METHODS AND MATERIALS: Plasma IL-25, IL-33, and TSLP levels were measured before and after aspirin challenge in subjects with AERD (n = 25) and aspirin-tolerant asthma (ATA, n = 25) by enzyme-linked immunosorbent assay (ELISA). Pre and post-aspirin challenge levels of LTC4 and PGD2 were measured using ELISA. RESULTS: Basal plasma IL-25 levels were significantly higher in AERD group than in normal controls and in ATA group (p = 0.025 and 0.031, respectively). IL-33 and TSLP levels were comparable in the AERD and ATA groups. After the aspirin challenge, the IL-25 levels were markedly decreased in the ATA group (p = 0.024), while not changed in the AERD group. The post-challenge IL-25 levels of all asthmatic subjects were significantly correlated with aspirin challenge - induced declines in FEV1 (r = 0.357, p = 0.011), but not with basal and post challenge LTC4 and PGD2 levels. CONCLUSIONS: IL-25 is associated with bronchospasm after aspirin challenge, possibly via mechanisms other than altered LTC4 and PGD2 production.


Assuntos
Asma Induzida por Aspirina/imunologia , Interleucina-17/sangue , Adulto , Idoso , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Asma Induzida por Aspirina/sangue , Asma Induzida por Aspirina/fisiopatologia , Citocinas/sangue , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Interleucina-33/sangue , Leucotrieno C4/sangue , Masculino , Pessoa de Meia-Idade , Prostaglandina D2/sangue
17.
Curr Allergy Asthma Rep ; 17(1): 2, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28097500

RESUMO

Aspirin-exacerbated respiratory disease (AERD) is an acquired disease characterized by chronic eosinophilic airway inflammation with underlying dysregulation of arachidonic acid metabolism. The purpose of this paper is to review the latest developments in our understanding of the underlying pathophysiology including the role of eosinophils, mast cells, innate lymphoid cells (ILC2), and platelets. Clinical features such as respiratory reactions induced by alcohol, aggressive nasal polyposis, and anosmia will allow for earlier recognition of these patients in clinical practice. The current state of the art management of AERD will be addressed including the ongoing central role for aspirin desensitization and high-dose aspirin therapy.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Asma Induzida por Aspirina/terapia , Animais , Asma Induzida por Aspirina/imunologia , Asma Induzida por Aspirina/patologia , Humanos
18.
Clin Exp Allergy ; 47(1): 37-47, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27533637

RESUMO

BACKGROUND: To date, there has been no reliable in vitro test to diagnose aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: To investigate potential diagnostic biomarkers for AERD using metabolomic analysis. METHODS: An untargeted profile of serum from asthmatics in the first cohort (group 1) comprising 45 AERD, 44 patients with aspirin-tolerant asthma (ATA), and 28 normal controls was developed using the ultra-high-performance liquid chromatography (UHPLC)/Q-ToF MS system. Metabolites that discriminate AERD from ATA were quantified in both serum and urine, which were collected before (baseline) and after the lysine-aspirin bronchoprovocation test (Lys-ASA BPT). The serum metabolites were validated in the second cohort (group 2) comprising 50 patients with AERD and 50 patients with ATA. RESULTS: A clear discrimination of metabolomes was found between patients with AERD and ATA. In group 1, serum levels of LTE4 and LTE4 /PGF2 α ratio before and after the Lys-ASA BPT were significantly higher in patients with AERD than in patients with ATA (P < 0.05 for each), and urine baseline levels of these two metabolites were significantly higher in patients with AERD. Significant differences of serum metabolite levels between patients with AERD and ATA were replicated in group 2 (P < 0.05 for each). Moreover, serum baseline levels of LTE4 and LTE4 /PGF2 α ratio discriminated AERD from ATA with 70.5%/71.6% sensitivity and 41.5%/62.8% specificity, respectively (AUC = 0.649 and 0.732, respectively P < 0.001 for each). Urine baseline LTE4 levels were significantly correlated with the fall in FEV1 % after the Lys-ASA BPT in patients with AERD (P = 0.008, r = 0.463). CONCLUSIONS AND CLINICAL RELEVANCE: Serum metabolite level of LTE4 and LTE4 /PGF2 α ratio was identified as potential in vitro diagnostic biomarkers for AERD using the UHPLC/Q-ToF MS system, which were closely associated with major pathogenetic mechanisms underlying AERD.


Assuntos
Asma Induzida por Aspirina/diagnóstico , Asma Induzida por Aspirina/metabolismo , Biomarcadores , Metaboloma , Metabolômica , Adolescente , Adulto , Idoso , Asma Induzida por Aspirina/sangue , Asma Induzida por Aspirina/imunologia , Progressão da Doença , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Neutrófilos , Adulto Jovem
20.
Curr Opin Pulm Med ; 23(1): 89-96, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27653792

RESUMO

PURPOSE OF REVIEW: The pathophysiology of aspirin-exacerbated respiratory disease (AERD) is not fully understood and diagnostic methods and so far, treatments for AERD have not been standardized. We summarize recent research into the pathological mechanisms of AERD, diagnostic methods, and treatments for AERD patients. RECENT FINDINGS: In AERD pathophysiology, not only the reduced expression of E prostanoid 2 but also the dysfunction of its pathway could be involved. Moreover, eosinophils of AERD patients could be directly activated by aspirin to produce prostaglandin D2. Platelet activations are well known to be involved in AERD; however, plasma markers do not change during aspirin challenge tests. Additionally, novel genetic polymorphisms, such as P2RY12 and dipeptidyl peptidase 10 gene, and epigenetic predispositions of AERD were found. In AERD diagnosis, bronchial and nasal aspirin challenges have been applied in addition to oral challenge. Serum periostin has been suggested as a potential biomarker for AERD. Apart from standard pharmacological treatment and aspirin desensitization, biologics, including omalizumab and mepolizumab, as well as CRTH2 antagonists have been suggested as promising therapies for AERD treatment. SUMMARY: AERD is usually associated with severe asthma phenotypes. AERD pathophysiology mainly involves the dysregulation of eicosanoid metabolisms, activations of effector cells, which could be influenced by genetic/epigenetic factors. Understanding the pathophysiology of AERD is key to improve the diagnostic methods and proper management of AERD patients.


Assuntos
Aspirina/efeitos adversos , Asma Induzida por Aspirina , Asma Induzida por Aspirina/genética , Asma Induzida por Aspirina/imunologia , Biomarcadores/metabolismo , Dessensibilização Imunológica , Humanos , Fenótipo , Polimorfismo Genético
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