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1.
Front Immunol ; 13: 850494, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35418991

RESUMO

Chronic rhinosinusitis with nasal polyps is affecting up to 3% of Western populations. About 10% of patients with nasal polyps also suffer from asthma and intolerance to aspirin, a syndrome called aspirin-exacerbated respiratory disease. Although eosinophilic inflammation is predominant in polyps of both diseases, phenotypic differences in the tissue-derived microenvironment, elucidating disease-specific characteristics, have not yet been identified. We sought to obtain detailed information about phenotypic and transcriptional differences in epithelial and immune cells in polyps of aspirin-tolerant and intolerant patients. Cytokine profiles in nasal secretions and serum of patients suffering from aspirin-exacerbated respiratory disease (n = 10) or chronic rhinosinusitis with nasal polyps (n = 9) were assessed using a multiplex mesoscale discovery assay. After enrichment for immune cell subsets by flow cytometry, we performed transcriptomic profiling by employing single-cell RNA sequencing. Aspirin-intolerant patients displayed significantly elevated IL-5 and CCL17 levels in nasal secretions corresponding to a more pronounced eosinophilic type 2 inflammation. Transcriptomic profiling revealed that epithelial and mast cells not only complement one another in terms of gene expression associated with the 15-lipoxygenase pathway but also show a clear type 2-associated inflammatory phenotype as identified by the upregulation of POSTN, CCL26, and IL13 in patients with aspirin-exacerbated respiratory disease. Interestingly, we also observed cellular stress responses indicated by an increase of MTRNR2L12, MTRNR2L8, and NEAT1 across all immune cell subsets in this disease entity. In conclusion, our findings support the hypothesis that epithelial and mast cells act in concert as potential drivers of the pathogenesis of the aspirin-exacerbated respiratory disease.


Assuntos
Asma Induzida por Aspirina , Eosinofilia , Pólipos Nasais , Sinusite , Aspirina/efeitos adversos , Asma Induzida por Aspirina/genética , Asma Induzida por Aspirina/patologia , Doença Crônica , Eosinofilia/patologia , Células Epiteliais/metabolismo , Humanos , Inflamação/patologia , Mastócitos/metabolismo , Pólipos Nasais/metabolismo , Transcriptoma
2.
Curr Opin Allergy Clin Immunol ; 22(1): 42-48, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34739410

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to provide a comprehensive summary of the current understanding of the pathogenesis of aspirin-exacerbated respiratory disease (AERD), and an update on its management. RECENT FINDINGS: Elevated levels of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a newly described metabolite of arachidonic acid, have been identified in nasal polyps of AERD patients. In nasal polyps, activated basophils, and interleukin-5 -receptor-α-positive IL-5Rα+ plasma cells are associated with more severe nasal polyposis in AERD. Alveolar monocyte-derived macrophages and their persistent proinflammatory activation were suggested as putative factors contributing to AERD. Although not AERD-specific, three biological agents are now available for the management of both nasal polyposis and asthma. SUMMARY: A newly downstream product of 15-lipoxygenase, 15-Oxo-ETE, was recently found to be significantly elevated in nasal polyps from AERD patients. This eicosanoid metabolite likely originates from an interplay between epithelial cells and mast cells. Nasal polyp basophils, IL-5Rα+ plasma cells, and alveolar macrophages were identified as important contributors to inflammation in AERD. Besides traditional aspirin desensitization and treatment for AERD management, several biologics for treatment of asthma are available, including three that have been approved for nasal polyposis. These biologic agents show variable rates of success in controlling AERD symptoms.


Assuntos
Asma Induzida por Aspirina , Pólipos Nasais , Sinusite , Aspirina/efeitos adversos , Asma Induzida por Aspirina/patologia , Asma Induzida por Aspirina/terapia , Basófilos , Humanos , Pólipos Nasais/patologia , Pólipos Nasais/terapia , Sinusite/patologia
3.
J Allergy Clin Immunol ; 148(2): 283-291, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34364538

RESUMO

Aspirin-exacerbated respiratory disease (AERD) is a condition composed of chronic rhinosinusitis with nasal polyposis and asthma that is defined by respiratory hypersensitivity reactions to the cyclooxygenase 1-inhibitory effects of nonsteroidal anti-inflammatory drugs. It is diagnosed in 5% to 15% of patients with asthma and is even more common in those with comorbid nasal polyposis. Diagnosis is confirmed after an aspirin challenge procedure, yet many patients present with all components and can reliably be diagnosed by history. Patients with AERD commonly experience severe uncontrolled nasal polyposis and require multispecialty evaluation to properly stage and treat this condition. The presence of nasal polyposis plays a large component in the diminished quality of life in patients with AERD. In the last decade, multiple new therapeutic areas have been approved for type 2 airway diseases, offering patients with AERD many more options for control. This makes an early and accurate diagnosis of AERD important in the care of the larger population of type 2 airway diseases.


Assuntos
Asma Induzida por Aspirina , Pólipos Nasais , Sinusite , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Asma Induzida por Aspirina/diagnóstico , Asma Induzida por Aspirina/patologia , Asma Induzida por Aspirina/terapia , Humanos , Pólipos Nasais/induzido quimicamente , Pólipos Nasais/diagnóstico , Pólipos Nasais/patologia , Pólipos Nasais/terapia , Sinusite/induzido quimicamente , Sinusite/diagnóstico , Sinusite/patologia , Sinusite/terapia
4.
J Allergy Clin Immunol ; 148(2): 309-318, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34364539

RESUMO

Aspirin-exacerbated respiratory disease (AERD) is a complex inflammatory disorder that is not generally viewed as a disease involving the adaptive immune system but instead one largely driven by the innate immune system. This article focuses on the cellular dysregulation involving 4 central cell types: eosinophils, basophils, mast cells, and innate lymphoid type 2 cells. AERD can be envisioned as involving a self-perpetuating vicious circle in which mediators produced by a differentiated activated epithelial layer, such as IL-25, IL-33, and thymic stromal lymphopoietin, engage and activate each of these innate immune cells. The activation of these innate immune cells with their production of additional cytokine/chemokine and lipid mediators leads to further recruitment and activation of these innate immune cells. More importantly, numerous mediators produced by these innate immune cells provoke the epithelium to induce further inflammation. This self-perpetuating cycle of inflammation partially explains both current interventions suggested to ameliorate AERD (eg, aspirin desensitization, leukotriene modifiers, anti-IL-5/IL-5 receptor, anti-IL-4 receptor, and anti-IgE) and invites exploration of novel targets as specific therapies for this condition (prostaglandin D2 antagonists or cytokine antagonists [IL-25, IL-33, thymic stromal lymphopoietin]). Several of these interventions currently show promise in small retrospective analyses but now require definite clinical trials.


Assuntos
Aspirina/efeitos adversos , Asma Induzida por Aspirina/imunologia , Citocinas/imunologia , Imunidade Inata/efeitos dos fármacos , Leucócitos/imunologia , Animais , Aspirina/uso terapêutico , Asma Induzida por Aspirina/patologia , Asma Induzida por Aspirina/terapia , Humanos , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Inflamação/terapia , Leucócitos/patologia
5.
PLoS One ; 16(8): e0256237, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34437574

RESUMO

Cysteinyl leukotriene (cysLT) overproduction and eosinophil activation are hallmarks of aspirin-exacerbated respiratory disease (AERD). However, pathogenic mechanisms of AERD remain to be clarified. Here, we aimed to find the significance of transforming growth factor beta 1 (TGF-ß1) in association with cysteinyl leukotriene E4 (LTE4) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-ß1, first cohort enrolled AERD (n = 336), ATA (n = 442) patients and healthy control subjects (HCs, n = 253). In addition, second cohort recruited AERD (n = 34) and ATA (n = 25) patients to investigate a relation between levels of serum TGF-ß1 and urinary LTE4. The function of TGF-ß1 in LTE4 production was further demonstrated by ex vivo (human peripheral eosinophils) or in vivo (BALB/c mice) experiment. As a result, the levels of serum TGF-ß1 were significantly higher in AERD patients than in ATA patients or HCs (P = .001; respectively). Moreover, levels of serum TGF-ß1 and urinary LTE4 had a positive correlation (r = 0.273, P = .037). In the presence of TGF-ß1, leukotriene C4 synthase (LTC4S) expression was enhanced in peripheral eosinophils to produce LTE4, which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-ß1, significantly induced eosinophilia with increased LTE4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-ß1 in AERD patients may contribute to LTE4 production via enhancing LTC4S expression which induces eosinophil degranulation, accelerating airway inflammation.


Assuntos
Asma Induzida por Aspirina/sangue , Glutationa Transferase/urina , Anormalidades do Sistema Respiratório/sangue , Fator de Crescimento Transformador beta1/sangue , Adulto , Animais , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Asma Induzida por Aspirina/genética , Asma Induzida por Aspirina/patologia , Eosinófilos/metabolismo , Eosinófilos/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Leucotrieno E4/biossíntese , Leucotrieno E4/sangue , Leucotrieno E4/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Receptores de Leucotrienos/metabolismo , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/metabolismo , Sistema Respiratório/patologia , Anormalidades do Sistema Respiratório/induzido quimicamente , Anormalidades do Sistema Respiratório/genética , Anormalidades do Sistema Respiratório/patologia , Fator de Crescimento Transformador beta1/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
6.
Curr Opin Allergy Clin Immunol ; 21(1): 65-70, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33306487

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to summarize the complex cellular interactions of aspirin-exacerbated respiratory disease (AERD) and how these interactions promote pathogenic mechanisms of AERD. RECENT FINDINGS: In addition to characteristic changes in eicosanoid levels, recent studies have identified increases in alarmin cytokines (IL-33, thymic stromal lymphopoietin) as well as activated innate lymphoid and plasma cell populations in samples from AERD patients. SUMMARY: Patients with AERD typically demonstrate high levels of proinflammatory eicosanoids including cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2) and hyporesponsiveness to prostaglandin E2 (PGE2). CysLTs are released by mast cells, eosinophils, and adherent platelets and promote epithelial release of IL-33, which activates mast cells and group 2 innate lymphoid cells (ILC2s) in concert with CysLTs. TSLP induces PGD2 release from mast cells which activates and recruits eosinophils, basophils, Th2 cells, and ILC2s via CRTH2. In turn, ILC2s and other cell types produce Th2 cytokines IL-4, IL-5, and IL-13 that, along with CysLTs and PGD2, promote bronchoconstriction, eosinophilic tissue inflammation, and mucus production.


Assuntos
Aspirina/efeitos adversos , Asma Induzida por Aspirina/imunologia , Comunicação Celular/efeitos dos fármacos , Eosinofilia/imunologia , Asma Induzida por Aspirina/sangue , Asma Induzida por Aspirina/patologia , Basófilos/imunologia , Basófilos/metabolismo , Broncoconstrição/efeitos dos fármacos , Broncoconstrição/imunologia , Citocinas/sangue , Citocinas/metabolismo , Eicosanoides/sangue , Eicosanoides/metabolismo , Eosinofilia/sangue , Eosinofilia/induzido quimicamente , Humanos , Imunidade Inata/efeitos dos fármacos , Interleucina-33/sangue , Interleucina-33/metabolismo , Mastócitos/imunologia , Mastócitos/metabolismo , Plasmócitos/imunologia , Plasmócitos/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Células Th2/imunologia , Células Th2/metabolismo
7.
PLoS One ; 15(10): e0240334, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031402

RESUMO

BACKGROUND: Patients with aspirin-exacerbated respiratory disease (AERD) are known to have poor clinical outcomes. The pathogenic mechanisms have not yet been completely understood. OBJECTIVE: We aimed to assess the involvement of the de-novo synthetic pathway of sphingolipid metabolism in patients with AERD compared to those with aspirin tolerant asthma (ATA). METHODS: A total of 63 patients with AERD and 79 patients with ATA were enrolled in this study. Analysis of mRNA expression of serine palmitoyl transferase, long-chain base subunit 2 (SPTLC2) and genotyping of ORMDL3 SNP (rs7216389) was performed. RESULTS: Significantly higher levels of SPTLC2 mRNA expression were noted in patients with AERD, which showed significant positive correlations with peripheral/sputum eosinophil counts and urine LTE4 (all P<0.05). The levels of SPTLC2 mRNA expression showed significant negative correlations with the level of FEV1 and FEV1/FVC (P = 0.033, r = -0.274; P = 0.019, r = -0.299, respectively). Genotype frequencies of ORMDL3 SNP (rs7216389) showed no significant differences between the AERD and ATA groups. Patients with AERD carrying the TT genotype of ORMDL3 had significantly lower levels of FVC (%) and PC20 methacholine than those carrying the CT or CC genotype (P = 0.026 and P = 0.030). CONCLUSION & CLINICAL RELEVANCE: This is the first study that shows the dysregulated de novo synthetic pathway of sphingolipids may be involved in the eosinophilic inflammation and airflow limitation in AERD.


Assuntos
Asma Induzida por Aspirina/patologia , Eosinofilia/etiologia , Proteínas de Membrana/genética , Serina C-Palmitoiltransferase/metabolismo , Adolescente , Adulto , Idoso , Alelos , Asma/genética , Asma/patologia , Asma Induzida por Aspirina/genética , Eosinofilia/genética , Feminino , Volume Expiratório Forçado , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Testes de Função Respiratória , Serina C-Palmitoiltransferase/genética , Regulação para Cima , Adulto Jovem
8.
Curr Opin Immunol ; 66: 9-13, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32299015

RESUMO

Aspirin-exacerbated respiratory disease (AERD) classically presents with severe asthma, nasal polyposis, and respiratory exacerbations in response to cyclooxygenase (COX)-1 inhibition. Recent advances in our understanding of AERD have revealed multiple facets of immune dysregulation, including diminished prostaglandin E2 (PGE2) function and elevated levels of both cysteinyl leukotrienes (CysLTs) and innate cytokines such as interleukin 33 (IL-33). Inflammatory mediators in AERD heighten the recruitment and activation of innate lymphoid cells type 2 (ILC2), mast cells, eosinophils, and platelet-adherent leukocytes. This contributes to a cyclical pattern of type 2 inflammation. Here, we highlight current understanding of the immunopathogenesis of AERD.


Assuntos
Asma Induzida por Aspirina/imunologia , Asma Induzida por Aspirina/patologia , Humanos
9.
Allergol Int ; 68(3): 289-295, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31235242

RESUMO

The characteristics in AERD are severe adult-onset asthma, eosinophilic rhinosinusitis with nasal polyposis, and CysLT overproduction. The cause of AERD have remained unclear, however the decrease in the production of PGE2 caused by the reduction in COX-2 activity is considered to main pathological mechanism of AERD. The mast cell activation and the interaction between platelets and granulocytes are lead to the CysLT overproduction and severe eosinophilic inflammation. The ongoing activation of mast cells is important key pathogenesis in not only stable AERD but exacerbated AERD by aspirin and NSAIDs. In recent years, type 2 inflammation caused by ILC2 activation in patients with AERD have been attracting attention. Omalizumab is effective option for AERD via suppression of mast cell activation and CysLT overproduction. Dupilumab improves sinus symptoms especially in patients with AERD. In near future, anti-platelet drug, CRTH2 antagonist, and anti-TSLP antibody may be useful candidates of therapeutic options in patients with AERD.


Assuntos
Antiasmáticos/uso terapêutico , Asma Induzida por Aspirina/tratamento farmacológico , Asma Induzida por Aspirina/patologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/imunologia , Aspirina/efeitos adversos , Aspirina/imunologia , Asma Induzida por Aspirina/diagnóstico , Plaquetas/imunologia , Plaquetas/metabolismo , Humanos , Linfócitos/imunologia , Linfócitos/metabolismo , Mastócitos/imunologia , Mastócitos/metabolismo , Pólipos Nasais/patologia , Sinusite/patologia
10.
BMJ Case Rep ; 12(3)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30936362

RESUMO

Woakes' syndrome is a rare entity defined as recurrent sinonasal polyposis with a consequent nasal pyramid deformity. Only a few cases are reported in the literature. The goal of this study is to present the features of Woakes' syndrome through a clinical case. A 42-year-old man presented with a history of ASA triad. He started self-medication for 5 years. He returned to the otorhinolaryngology department for the aggravation and persistence of symptoms. CT scans showed the deformity and thinning of the nasal bones. A functional endoscopic sinus surgery and correction of nasal pyramid deformity were performed. At 6 months' follow-up, good functional and aesthetic outcomes were observed. Woakes' syndrome was described more than 130 years ago. Treatment includes endoscopic sinonasal surgery and local treatment. Adequate management and good adherence to the therapeutic protocol could be factors to prevent this syndrome.


Assuntos
Asma Induzida por Aspirina/tratamento farmacológico , Sinusite Etmoidal/tratamento farmacológico , Pólipos Nasais/tratamento farmacológico , Deformidades Adquiridas Nasais/diagnóstico por imagem , Procedimentos Cirúrgicos Otorrinolaringológicos/métodos , Adulto , Asma Induzida por Aspirina/patologia , Sinusite Etmoidal/patologia , Humanos , Masculino , Pólipos Nasais/patologia , Cirurgia Endoscópica por Orifício Natural , Deformidades Adquiridas Nasais/cirurgia , Rinoplastia , Síndrome , Tomografia Computadorizada por Raios X , Resultado do Tratamento
11.
Pharmacogenet Genomics ; 29(4): 69-75, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30694883

RESUMO

BACKGROUND: We previously found differences in the minor allele frequency (MAF) of single-nucleotide polymorphisms (SNPs) in transmembrane protein 196 (TMEM196) between 995 patients with aspirin-tolerant asthma (ATA) and 141 asthmatic patients with NSAID-exacerbated respiratory disease (NERD). In this study, we statistically analyzed the distributions of the genotypes and haplotypes of these SNPs to determine the exact association between TMEM196 genetic variants and the risk for NERD. MATERIALS AND METHODS: Lewontin's D' and r values were used to measure linkage disequilibrium between the biallelic loci having MAFs more than 0.05, and haplotypes were inferred using the PHASE algorithm (version 2.0). The genotype distribution was analyzed by logistic regression models using age of onset, smoking status (nonsmoker=0, ex-smoker=1, smoker=2), and BMI as covariates. Regression analysis of the association between SNPs and the risk of NERD was analyzed using SPSS version 12.0 and PLINK version 1.9. RESULTS: The MAF of rs9886152 C>T was significantly lower in NERD than in ATA [24.8 vs. 34.0%, odds ratio=0.64 (0.48-0.85), P=2.07×10, Pcorr=0.048]. The rate of the rs9886152 C>T minor allele was significantly lower in NERD than in ATA [44.0 vs. 56.4% in the codominant model, P=0.002, Pcorr=0.049, odds ratio=0.64 (0.48-0.85)]. An additional three SNPs (rs9639334 A>G, rs9638765 A>G, and rs2097811 G>A) showed similar associations with the risk of NERD. NERD patients had lower frequencies of the rs9639334 A>G minor allele (51.1 vs. 64.4%, P=0.002, Pcorr=0.043), rs9638765 A>G (49.7 vs. 64.2%, P=0.001, Pcorr=0.017), and rs2097811 G>A (51.1 vs. 64.5%, P=0.002, Pcorr=0.04) compared with ATA patients. Patients homozygous for the minor alleles of the four SNPs showed significantly less of an aspirin-induced decrease in forced expiratory volume in one second compared with those homozygous for the common alleles (P=0.003-0.012). CONCLUSION: The minor alleles of the four SNPs in TMEM196 may exert a protective effect against the development of NERD and may be useful genetic markers to predict the risk of NERD.


Assuntos
Aspirina/efeitos adversos , Asma Induzida por Aspirina/genética , Estudos de Associação Genética , Proteínas de Membrana/genética , Adulto , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/administração & dosagem , Asma Induzida por Aspirina/patologia , Feminino , Volume Expiratório Forçado , Frequência do Gene , Genótipo , Haplótipos/genética , Homozigoto , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
12.
Int Forum Allergy Rhinol ; 8(10): 1093-1097, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30007020

RESUMO

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by chronic eosinophilic rhinosinusitis, nasal polyps, asthma, and respiratory sensitivity to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). In addition to sensitivity to aspirin and NSAIDs, the majority of patients with AERD have been reported to have respiratory intolerance associated with the consumption of alcohol. METHODS: A multicenter prospective cohort study was performed. Patients with AERD confirmed by aspirin challenge were eligible to participate. Those who described themselves as able to tolerate alcohol consumption were excluded. Patients underwent aspirin desensitization following endoscopic sinus surgery. A questionnaire was distributed to patients before and after desensitization to determine pre-desensitization and post-desensitization symptoms associated with alcohol ingestion. RESULTS: Forty-five patients were enrolled and 37 patients completed the study. The most common pre-desensitization symptoms were nasal congestion (95.6%), rhinorrhea (46.7%), and wheezing (40%). Improvement in the ability to tolerate alcohol was noted in 86.5% of participants (95% confidence interval [CI], 75.5% to 97.5%) and 70.3% of participants (95% CI, 55.5% to 85.0%) described desensitization to be "very helpful" or "extremely helpful" for their ability to tolerate alcohol. CONCLUSION: The majority of patients with AERD who experience respiratory symptoms with alcohol consumption describe improvement in this domain following aspirin desensitization.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , Asma Induzida por Aspirina/prevenção & controle , Dessensibilização Imunológica , Hipersensibilidade Alimentar/prevenção & controle , Adulto , Idoso , Asma Induzida por Aspirina/etiologia , Asma Induzida por Aspirina/patologia , Dessensibilização Imunológica/normas , Feminino , Hipersensibilidade Alimentar/etiologia , Hipersensibilidade Alimentar/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
13.
Int Forum Allergy Rhinol ; 8(10): 1184-1189, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29897665

RESUMO

BACKGROUND: The endocannabinoid system represents a highly conserved, innate signaling network with direct and indirect control of eicosanoid-mediated inflammation. Activation of the type 2 cannabinoid receptor (CB2R) leads to decreased type 2 inflammation and reduced production of arachidonic acid (AA). Given that altered AA metabolism is associated with aspirin-exacerbated respiratory disease (AERD), we hypothesized that expression of the CB2R gene CNR2 is increased in AERD. METHODS: Nasal polyps from consecutive patients undergoing endoscopic sinus surgery for AERD or allergic fungal rhinosinusitis (AFRS) were prospectively evaluated. Control sphenoid mucosa was collected from patients undergoing endoscopic skull base procedures. Expression and localization of endocannabinoid receptors were evaluated by quantitative reverse transcript-polymerase chain reaction (qRT-PCR) and immunohistochemistry. A 2-group unpaired t test with unequal variances was used to evaluate group differences. RESULTS: Thirteen subjects were included in this pilot study, including 5 controls, 5 AFRS patients, and 3 AERD patients. Upregulated expression of CNR2 was detected in subjects with AERD vs both AFRS (p = 0.049) and controls (p = 0.047), with a mean increase of 5.2-fold. No significant differences in expression of the CB1R gene CNR1 were detected between control and AFRS groups. Immunohistochemistry predominantly localized CB1R and CB2R expression to the surface epithelium in all subjects. CONCLUSION: The endocannabinoid system is an emerging immunomodulatory network that may be involved in AERD. This is the first study of CB2R in sinonasal disease, showing significantly increased transcription in nasal polyps from subjects with AERD. Additional study is warranted to further evaluate the contribution and therapeutic potential of this novel finding in chronic rhinosinusitis.


Assuntos
Asma Induzida por Aspirina/genética , Receptor CB2 de Canabinoide/genética , Regulação para Cima , Adolescente , Adulto , Asma Induzida por Aspirina/metabolismo , Asma Induzida por Aspirina/patologia , Doença Crônica , Epitélio/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Pólipos Nasais/metabolismo , Pólipos Nasais/patologia , Projetos Piloto , Receptor CB2 de Canabinoide/metabolismo , Rinite Alérgica/genética , Rinite Alérgica/metabolismo , Rinite Alérgica/patologia , Sinusite/metabolismo , Sinusite/patologia , Adulto Jovem
14.
Am J Otolaryngol ; 39(3): 293-298, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29534838

RESUMO

PURPOSE: The term aspirin-exacerbated respiratory disease (AERD) refers to a combination of asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and acute respiratory tract reactions to nonsteroidal anti-inflammatory drugs. AERD has now been included among the CRSwNP endotypes, and is considered one of the most aggressive in terms of disease recurrence. Cortactin is a multi-domain protein with a part in several cellular mechanisms involving actin assembly and cytoskeleton arrangement. Cortactin seems to have a role in inflammatory responses and to be implicated in human airway secretion and contraction mechanisms. The novel aim of the present study was to examine cortactin expression in nasal polyps of a consecutive cohort of AERD patients and in nasal mucosa of a control group of patients. MATERIALS AND METHODS: Cortactin expression was assessed immunohistochemically in nasal polyps from 18 consecutive AERD patients who underwent endoscopic sinus surgery and in nasal mucosa of 19 patients without chronic rhinosinusitis. RESULTS: Concomitant allergy was found in 11 AERD patients, most of them male (8 cases; p = 0.02). Cortactin expression in nasal polyps was definitely high (+3) in 17 out of 18 cases, in both epithelial cells (cytoplasmic and membranous immunoreactivity) and activated fibroblasts. A higher cortactin expression was seen in female than in male AERD patients (p = 0.05). CONCLUSIONS: Given this preliminary evidence of cortactin upregulation in the polyps of AERD patients, prospective studies could further investigate the role of cortactin in the biology of AERD, and the potential role of cortactin-targeted approaches in integrated AERD treatments.


Assuntos
Asma Induzida por Aspirina/epidemiologia , Asma Induzida por Aspirina/patologia , Cortactina/genética , Regulação da Expressão Gênica , Pólipos Nasais/patologia , Adulto , Distribuição por Idade , Asma Induzida por Aspirina/genética , Biópsia por Agulha , Estudos de Casos e Controles , Doença Crônica , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Incidência , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/genética , Estudos Retrospectivos , Rinite/complicações , Distribuição por Sexo , Sinusite/complicações , Estatísticas não Paramétricas , Síndrome , Regulação para Cima
15.
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
16.
J Allergy Clin Immunol ; 140(3): 720-729, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28238741

RESUMO

BACKGROUND: Microparticles (MPs) are submicron-sized shed membrane vesicles released from activated or injured cells and are detectable by flow cytometry. MP levels have been used as biomarkers to evaluate cell injury or activation in patients with pathological conditions. OBJECTIVE: We sought to compare MP types and levels in nasal lavage fluids (NLFs) from controls and patients with chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD). METHODS: We collected NLFs from patients with CRSsNP (n = 33), CRSwNP (n = 45), and AERD (n = 31) and control (n = 24) subjects. Standardized flow cytometry methods were used to characterize the following MP types: endothelial MPs, epithelial MPs (epithelial cell adhesion molecule [EpCAM](+)MPs, E-cadherin(+)MPs), platelet MPs (CD31(+)CD41(+)MPs), eosinophil MPs (EGF-like module-containing mucin-like hormone receptor-like 1[EMR1](+)MPs), mast cell MPs (high-affinity IgE receptor [FcεRI](+)c-kit(+)MPs), and basophil MPs (CD203c(+)c-kit(-)MPs). Basophil activation was evaluated by the mean fluorescence intensity of CD203c on basophil MPs. RESULTS: Activated mast cell MPs (CD137(+) FcεRI(+)c-kit(+)MPs) were significantly increased in NLFs of controls compared with NLFs of patients with CRSsNP (2.3-fold; P < .02), CRSwNP (2.3-fold; P < .03), and AERD (7.4-fold; P < .0001). Platelet MPs (3.5-fold; P < .01) and basophil MPs (2.5-fold; P < .05) were increased only in patients with AERD. Mean fluorescence intensity of CD203c on MPs was increased in patients with CRSwNP (P < .002) and AERD (P < .0001), but not in patients with CRSsNP. EpCAM(+)MPs in patients with CRSwNP were no different from control (P = .91) and lower than those in patients with CRSsNP (P < .02) and AERD (P < .002). CONCLUSIONS: Based on released MPs, mast cells, platelets, and basophils were more highly activated in patients with AERD than in patients with CRS. Epithelial injury was lower in patients with CRSwNP than in patients with CRSsNP and AERD. MP analysis may help identify phenotypes of CRS, and in distinguishing AERD from CRSwNP.


Assuntos
Asma Induzida por Aspirina/patologia , Micropartículas Derivadas de Células , Líquido da Lavagem Nasal/citologia , Pólipos Nasais/patologia , Rinite/patologia , Sinusite/patologia , Adulto , Biomarcadores , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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
20.
Curr Drug Targets ; 17(16): 1963-1970, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27719658

RESUMO

Aspirin is the oldest non-steroidal anti-inflammatory drug (NSAID), and it sometimes causes asthma-like symptoms known as aspirin-exacerbated respiratory disease (AERD), which can be serious. Unwanted effects of aspirin (aspirin intolerance) are also observed in patients with food-dependent exercise-induced anaphylaxis, a type I allergy disease, and aspirin-induced urticaria (AIU). However the target and the mechanism of the aspirin intolerance are still unknown. There is no animal or cellular model of AERD, because its pathophysiological mechanism is still unknown, but it is thought that inhibition of cyclooxygenase by causative agents leads to an increase of free arachidonic acid, which is metabolized into cysteinyl leukotrienes (cysLTs) that provoke airway smooth muscle constriction and asthma symptoms. As the bed-tobench approach, to confirm the clinical discussion in experimental cellular models, we have tried to develop a cellular model of AERD using activated RBL-2H3 cells, a rat mast cell like cell line. Indomethacin (another NSAID and also causes AERD), enhances in vitro cysLTs production by RBL-2H3 cells, while there is no induction of cysLTs production in the absence of inflammatory activation. Since this suggests that all inflammatory cells with activation of prostaglandin and cysLT metabolism should respond to NSAIDs, and then I have concluded that aspirin intolerance should be separated from subsequent bronchoconstriction. Evidence about the cellular mechanisms of NSAIDs may be employed for development of in vitro AERD models as the approach from bench-to-bed.


Assuntos
Asma Induzida por Aspirina/patologia , Mastócitos/patologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Asma Induzida por Aspirina/metabolismo , Linhagem Celular , Humanos , Mastócitos/metabolismo , Modelos Teóricos , Ratos
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