Eosinophil production of prostaglandin D2 in patients with aspirin-exacerbated respiratory disease Xin Feng, MD, Madison K. Ramsden, BS, Julie Negri,

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Presentation transcript:

Eosinophil production of prostaglandin D2 in patients with aspirin-exacerbated respiratory disease Xin Feng, MD, Madison K. Ramsden, BS, Julie Negri, BS, MBA, Mary Grace Baker, MD, Spencer C. Payne, MD, Larry Borish, MD, John W. Steinke, PhD Journal of Allergy and Clinical Immunology Volume 138, Issue 4, Pages 1089-1097.e3 (October 2016) DOI: 10.1016/j.jaci.2016.04.042 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 hPGDS gene expression in sinus tissue determined by using qPCR. Tissue samples were homogenized after surgical removal, and RNA was isolated. Transcript levels of hPGDS were quantified by using PCR with SYBR Green detection. Data (mean ± SEM) reflect relative expression of each gene in comparison with the housekeeping gene EF1α (ΔCT). Control samples (n = 9) are depicted as black triangles, CHES samples (n = 17) as blue squares, and AERD samples (n = 9) as red circles. *P < .02 compared with CHES and control samples. Journal of Allergy and Clinical Immunology 2016 138, 1089-1097.e3DOI: (10.1016/j.jaci.2016.04.042) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Immunofluorescence for hPGDS in polyps from patients with AERD and patients with CHES. hPGDS staining of paraffin-embedded sinus tissue using a primary antibody directed against hPGDS and an allophycocyanin-labeled secondary antibody (red) with 4′,6-diamidino-2-phenylindole nuclear stain (blue). A, Control tissue. B, Tissue from a patient with CHES. C, Tissue from a patient with AERD. D, Insert (i) of tissue from a patient with AERD showing a close-up view. White arrows indicate eosinophils, and yellow arrows indicate mononuclear cells. Journal of Allergy and Clinical Immunology 2016 138, 1089-1097.e3DOI: (10.1016/j.jaci.2016.04.042) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 hPGDS expression in eosinophils. After separation of blood by using Ficoll-Hypaque density centrifugation, eosinophils were enriched with magnetic affinity column purification. A, Transcript levels of hPGDS were quantified by using PCR with SYBR Green detection. Data (mean ± SEM) reflect relative expression of each gene in comparison with the housekeeping gene EF1α (ΔCT). Control samples (n = 13) are depicted as black triangles, asthma samples (n = 12) as blue squares, and AERD samples (n = 14) as red circles. B, Measurement of hPGDS protein by means of Western hybridization. Eosinophils from 3 control subjects, asthmatic patients, and patients with AERD were collected and electrophoresed on a denaturing polyacrylamide gel and probed with rabbit antibody directed against hPGDS and β-actin as a loading control. C, Semiquantitative analysis of hPGDS protein levels (AERD, n = 9; asthma, n = 7; and control, n = 10). *P < .02 compared with control values. Journal of Allergy and Clinical Immunology 2016 138, 1089-1097.e3DOI: (10.1016/j.jaci.2016.04.042) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 PGD2 release from aspirin-activated eosinophils. Eosinophils isolated from peripheral blood of control subjects (black, n = 7), asthmatic patients (blue, n = 6), and patients with AERD (red, n = 9) were activated with various doses of LysASA for 30 minutes. Supernatants were collected, and PGD2 levels were quantified (in picograms per 105 cells). Data are presented as means ± SEMs. *P < .02 or **P < .005 in comparison with unstimulated cells. Journal of Allergy and Clinical Immunology 2016 138, 1089-1097.e3DOI: (10.1016/j.jaci.2016.04.042) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 PGD2 secretion by in vitro–differentiated eosinophils in the presence of IFN-γ. CD34+ enriched hematopoietic stem cells were differentiated into eosinophils with or without the additional presence of IFN-γ. Newly generated eosinophils were activated for 30 minutes, supernatants were collected, and PGD2 levels were quantified (in picograms per 105 cells). Data are presented as means ± SEMs (n = 10). *P < .004 compared with 0−IFN-γ, **P < .004 compared with 0+IFN-γ, and ***P < .006 compared to 0−IFN-γ. Journal of Allergy and Clinical Immunology 2016 138, 1089-1097.e3DOI: (10.1016/j.jaci.2016.04.042) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 COX-1 inhibition does not prevent aspirin-induced PGD2 release. Eosinophils isolated from peripheral blood were incubated with or without the COX-1 inhibitors, ibuprofen, or SC-560 for 30 minutes. Cells were washed and incubated for 30 minutes with increasing concentrations of LysASA, and supernatants were collected for measurement of PGD2. Data are presented as means ± SEMs (n = 3). *Not significant in comparison with no pretreatment cells. Journal of Allergy and Clinical Immunology 2016 138, 1089-1097.e3DOI: (10.1016/j.jaci.2016.04.042) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Isotype control of immunofluorescence for hPGDS. We performed immunofluorescence staining of polyp tissue, as described in the Methods section. A, Tissue from patients with AERD was incubated with polyclonal rabbit sera and allophycocyanin-labeled secondary antibody. B, Tissue from patients with AERD was incubated with rabbit anti-hPGDS primary and allophycocyanin-labeled secondary antibodies. Journal of Allergy and Clinical Immunology 2016 138, 1089-1097.e3DOI: (10.1016/j.jaci.2016.04.042) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Quantification of hPGDS+ cells detected by means of immunofluorescence. Images were generated as described and analyzed by counting hPGDS+ and total cells (with the exclusion of epithelial and glandular cells). A dot plot showing positive hPGDS+ cells/hpf for tissue samples from patients with AERD (n = 7), patients with CHES (n = 8), and control subjects (n = 6). Journal of Allergy and Clinical Immunology 2016 138, 1089-1097.e3DOI: (10.1016/j.jaci.2016.04.042) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions