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1.
J Allergy Clin Immunol ; 154(2): 458-467.e3, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38704098

RESUMEN

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a severe disease involving dysregulated type 2 inflammation. However, the role other inflammatory pathways play in AERD is poorly understood. OBJECTIVE: We sought to broadly define the inflammatory milieu of the upper respiratory tract in AERD and to determine the effects of IL-4Rα inhibition on mediators of nasal inflammation. METHODS: Twenty-two AERD patients treated with dupilumab for 3 months were followed over 3 visits and compared to 10 healthy controls. Nasal fluid was assessed for 45 cytokines and chemokines using Olink Target 48. Blood neutrophils and cultured human mast cells, monocytes/macrophages, and nasal fibroblasts were assessed for response to IL-4/13 stimulation in vitro. RESULTS: Of the nasal fluid cytokines measured, nearly one third were higher in AERD patients compared to healthy controls, including IL-6 and the IL-6 family-related cytokine oncostatin M (OSM), both of which correlated with nasal albumin levels, a marker of epithelial barrier dysregulation. Dupilumab significantly decreased many nasal mediators, including OSM and IL-6. IL-4 stimulation induced OSM production from mast cells and macrophages but not from neutrophils, and OSM and IL-13 stimulation induced IL-6 production from nasal fibroblasts. CONCLUSION: In addition to type 2 inflammation, innate and IL-6-related cytokines are also elevated in the respiratory tract in AERD. Both OSM and IL-6 are locally produced in nasal polyps and likely promote pathology by negatively affecting epithelial barrier function. IL-4Rα blockade, although seemingly directed at type 2 inflammation, also decreases mediators of innate inflammation and epithelial dysregulation, which may contribute to dupilumab's therapeutic efficacy in AERD.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Asma Inducida por Aspirina , Subunidad alfa del Receptor de Interleucina-4 , Interleucina-6 , Oncostatina M , Transducción de Señal , Humanos , Oncostatina M/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Interleucina-6/metabolismo , Interleucina-6/inmunología , Adulto , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Subunidad alfa del Receptor de Interleucina-4/inmunología , Asma Inducida por Aspirina/inmunología , Mastocitos/inmunología , Mastocitos/metabolismo , Células Cultivadas , Anciano , Fibroblastos/metabolismo , Fibroblastos/inmunología , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo
2.
J Allergy Clin Immunol ; 152(3): 700-710.e3, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37068712

RESUMEN

BACKGROUND: Aspirin-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. OBJECTIVE: Our aim was to determine whether ifetroban, a TP receptor antagonist, attenuates aspirin-induced respiratory symptoms in patients with AERD. METHODS: A 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. RESULTS: Ifetroban 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. CONCLUSION: Contrary 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.


Asunto(s)
Asma Inducida por Aspirina , Sinusitis , Animales , Ratones , Humanos , Prostaglandinas , Tromboxanos/uso terapéutico , Leucotrieno E4 , Receptores de Tromboxanos/uso terapéutico , Asma Inducida por Aspirina/tratamiento farmacológico , Asma Inducida por Aspirina/diagnóstico , Aspirina/efectos adversos , Eicosanoides , Dinoprostona , Homeostasis , Sinusitis/inducido químicamente
3.
Am J Rhinol Allergy ; 37(2): 132-139, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36848270

RESUMEN

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogenous group of inflammatory conditions impacting the nose and paranasal sinuses. Our understanding of the underlying pathobiology of CRSwNP has substantially improved due to ongoing translational research efforts. Advances in treatment options, including targeted respiratory biologic therapy for CRSwNP, allow for more personalized approaches for CRSwNP patient care. Patients with CRSwNP are typically classified to one or more endotype based on the presence of type 1, type 2, and type 3 inflammation. This review will discuss recent advances in our understanding of CRSwNP and how this may impact current and future treatment approaches for patients with CRSwNP.


Asunto(s)
Pólipos Nasales , Sinusitis , Humanos , Pólipos Nasales/diagnóstico , Sinusitis/diagnóstico , Inflamación , Nariz , Fenotipo , Enfermedad Crónica
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