Longitudinal levels of eicosanoids after nasal allergen challenge in upper airways and urine of patients with asthma and rhinitis using a novel lc-ms/ms multiplexed method

SESSION TITLE: Asthma Treatment and Longitudinal Studies SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/09/2023 12:00 pm - 12:45 pm PURPOSE: Mast cells and their bioactive lipid mediators drive the pathogenesis of Type 2 inflammation in atopic diseases like asthma and rhinitis. The transience of mast cell activity makes it difficult to understand their contribution to disease, and their bioactive lipid mediators have been tough to measure due to the presence of isobaric species with distinct functions. To address this, we developed a highly sensitive and multiplexed targeted mass spectrometry method to longitudinally, and cross-compartmentally quantify mast cell lipids, prostaglandin (PGD2) and leukotriene (LTE4) levels in nasal and urine samples from patients with rhinitis and asthma who underwent a nasal allergen challenge (NAC). METHODS: Twenty subjects with mild atopic asthma and allergic rhinitis underwent a nasal allergen challenge (NCT03431961). Serial nasosorption and urine samples were collected pre-NAC and post-NAC beginning at 5 mins and 1 hr, respectively, up to 24 hrs. A high throughput, fully online liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to enable multiplexed quantitation of eicosanoids, including LTE4 and PGD2 in nasal samples and their metabolites in urine samples. RESULTS: At baseline, pre-NAC, levels of eicosanoids, LTE4, PGD2, and PGE2, were consistently detectable with values above the lower limit of quantification (LLOQ), in nasosorption. LTE4 and PGD2 levels in nasosorption significantly increased by 5 mins post-NAC and normalized back to pre-challenge levels within 1 hr and remained low through to 24 hrs. Also, there was a significant increase in LTE4 in the urine 1 hr post-NAC, which normalized back to baseline levels over a period of 4 hours. There were no significant changes in the PGD2 metabolite, tPGDM, in urine measured 1h post-NAC onwards, nor changes in the levels of PGE2, an isobaric lipid produced by many cell types, and its urinary metabolite tPGEM after NAC, in nasosorption and urine, respectively. CONCLUSIONS: Development of a novel targeted LC-MS/MS method enabled high sensitivity and robust quantification of eicosanoid levels in patient samples. Mast cell-produced eicosanoids were measurable and responsive to allergen challenge in samples collected non-invasively from the nose and urine. Nasal or urine sampling could be a viable surrogate to gain insights into mast cell activity in the airways, but this remains to be further explored. CLINICAL IMPLICATIONS: Taken together, these findings have promising utility in drug development to help us understand mast cell activation after acute allergen exposure and across compartments in the body. DISCLOSURES: Employee relationship with Genentech Please note: 2011-present Added 03/23/2023 by Veronica Anania, source=Web Response, value=Salary No relevant relationships by Prajna Banerjee Employee relationship with Genentech, a Roche company Please note: 07/16/2016 Added 03/27/2023 by Rebecca Bauer, source=Web Response, value=Salary No relevant relationships by Sue Beaudin No relevant relationships by Emilia Calderon Employee relationship with Genentech / Roche Please note: Since 2018 Added 03/27/2023 by Chen Chen, source=Web Response, value=Salary No relevant relationships by Gail Gauvreau No relevant relationships by Monika Kansal Speaker/Speaker's Bureau relationship with ALK Please note: 2021-2023 Added 03/28/2023 by PAUL KEITH, source=Web Response, value=Honoraria Scientific Medical Advisor relationship with Bausch Please note: 2022-2023 Added 03/28/2023 by PAUL KEITH, source=Web Response, value=Consulting fee Consultant relationship with CSL Behring Please note: 2021-2023 Added 03/28/2023 by PAUL KEITH, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with GSK Please note: 2021-2023 Added 03/28/2023 by PAUL KEITH, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Medexus Please note: 2021-2022 Added 03/28/2023 by PAUL KEITH, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Novartis Please note: 2021-2022 Added 03/28/2023 by PAUL KEITH, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Sanofi Please note: 2021-2023 Added 03/28/2023 by PAUL KEITH, source=Web Response, value=Honoraria Consultant relationship with Takeda Please note: 2021-2023 Added 03/28/2023 by PAUL KEITH, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Valeo Please note: 2021-2022 Added 03/28/2023 by PAUL KEITH, source=Web Response, value=Honoraria Advisory Committee Member relationship with Astra Zeneca Please note: 2021-2022 Added 03/28/2023 by PAUL KEITH, source=Web Response, value=Honoraria No relevant relationships by Olga Li Employee relationship with Genentech Please note: 4/2010 - present Added 03/22/2023 by Rod Mathews, source=Web Response, value=Salary No relevant relationships by Caroline Munoz Employee relationship with Genentech Inc. Please note: June 2021 to present Added 03/21/2023 by John-Paul Oliveria, source=Web Response, value=Salary No relevant relationships by Roma Sehmi No relevant relationships by Tracy Staton