Seibold, M A

Abstract Background Prostaglandin E2 (PGE2) exerts paradoxical effects in asthma, acting as both a protective mediator and a contributor to pathology depending on context. Its role is shaped by type 2 (T2)-status, eosinophilia, and exacerbation frequency. In epithelial cell cultures from asthmatic and healthy individuals, interleukin (IL)-13 suppresses PGE2 synthesis genes (PTGS2 and PGES) while upregulating HPGD, which encodes for the PGE2 catabolic enzyme 15-prostaglandin dehydrogenase (15-PGDH) (PMID:16751012), suggesting diminished PGE2 availability during T2 inflammation. Similarly, in aspirin-exacerbated respiratory disease (AERD), impaired cyclooxygenase disrupts PGE2 biosynthesis, fueling unchecked leukotriene production and eosinophilic inflammation (PMID: 30516547), underscoring PGE2’s protective role in limiting disease progression. Conversely, in nasal polyps, tuft cells are activated by IL-13 to produce PGE2 (PMID: 35608904), highlighting PGE2’s potential pathogenicity. Objective To assess associations between PGE2-pathway gene expression in bronchial brushings and asthma severity, and to determine how nasal polyp history modifies these relationships. Methods We analyzed bronchial epithelial brushings from 109 adults with asthma (mean age 42.4±12.1, 64% female, 52% severe asthma, 18% nasal polyps) using normalized and batch-corrected RNA-seq data from the baseline visit in the Severe Asthma Research Program (SARP)3 (PMID: 36796454). Age-adjusted and nasal polyp-adjusted relationships were calculated between ratios of PGE2 synthesis and metabolism genes and clinical outcomes (ASSESS score, FEV1 %predicted). The composite PGE2 score (PMID: 35608904), derived from nasal polyp analysis, was calculated from the average scaled log-normalized expression of six PGE2-responsive genes. All data were analyzed using a linear regression mixed model with a random effect for site. Results Ratios of PGE2 synthesis genes (PTGS1/2, PTGES2) to HPGD were significantly associated with greater disease severity (change in ASSESS Score) (Fig.1A, solid lines) and lower lung function (change in FEV1 %predicted) (Fig.1B, solid lines). These relationships persisted after adjusting for nasal polyps (Fig.1, dashed lines). The composite PGE2 score was also related to disease severity (Fig.1A, black solid line) but attenuated when nasal polyps were accounted for (Fig.1A, black dashed lines). Interestingly, lower lung function remained associated with the PGE2 score even after nasal polyp adjustment (Fig.1B, dashed black lines). Conclusions Our analysis demonstrates that the balance between PGE2 synthesis and degradation in the bronchial epithelium is closely linked to asthma severity and lung function, independent of nasal polyp status. Future work will integrate transcriptomic and clinical data longitudinally to establish whether PGE2 could serve as a biomarker for asthma trajectory. This abstract is funded by: HL115118 (LCD), U10HL109152 (S.E.W.), U10HL109172 (to E.I. and B.D.L), U10HL109168 (N.N.J.), U10HL109250 (S.C.E), U10HL109164 (W.C.M), U10HL109257 (M.C), and U10HL109146 (to P.G.W. and S.A.C.)

Abstract Rationale The activity of fucosyltransferase 2 (FUT2) determines if mucin glycan structures in epithelial mucus include histo-blood group antigens (HBGAs). People with active FUT2 express HBGAs in epithelial mucus secretions and are terms “secretors”, while non-secretors lack HBGAs in their secretions because they have a FUT2 genotype that inactivates the glycosyl transferase. Prior research suggests that secretors who are blood type O (type O secretors) are susceptible to asthma exacerbations1 and that FUT2 knockout mice (functional non-secretors) are protected from mucus plugging in allergen challenge models2,3. We set out here to determine if secretor status influences mucus plug prevalence in asthma and to confirm if type O secretors are susceptible to asthma exacerbations. Methods We determined secretor status in asthma participants from the Severe Asthma Research Program-3 (SARP-3) cohort (N = 507) in two ways, a specific fucose lectin binding assay in sputum and FUT2 genotyping. Blood group type was determined using ABO genotyping. We analyzed mucus plug segment scores, asthma exacerbations rates and other clinical and biological features in patients stratified by secretor status and blood type (non-secretors, type O secretors, and non-type O secretors). Results Secretor status determined by lectin binding in sputum was strongly concordant with genotypic analysis. Within the SARP-3 cohort, 26.2% were non-secretors, 32.3% type were O secretors, and 41.4% were non-type O secretors. Mucus plug segment scores, annualized asthma exacerbation rates, and other measures of asthma severity were similar in non-secretors, type O secretors, and non-type O secretors (Table). Although type O secretors had increased values for fractional exhaled nitric oxide (FeNO) and higher expression of type 2 gene network genes in their sputum cells, measures of sputum eosinophil inflammation were not higher in this subgroup (Table). Conclusion Secretor status does not influence the prevalence of mucus plugging in asthma patients, and we did not confirm a prior report that type O secretors have an increased risk of asthma exacerbation. Although type O secretors have modestly increased FeNO levels and increased expression of type 2 immune genes in their sputum, it is not clear if this is a biologically important signal. 1. Innes et al. AJRCCM; 2011. 2. Saku et al. JACI; 2019. 3. Hara et al. AJRCMB; 2025 This abstract is funded by: The study was supported by the National Institutes of Health grants R01 HL080414 (JVF), P01 HL107202 (JVF), R01 HL164787 (JVF), U10 HL109172 (EI), U10 HL109152 (SEW), U10 HL109257 (MC), U10 HL109250 (SCE), U10 HL109146 (JVF), U10 HL109164 (ERB), U01 HL146002 (BDL), U10 HL109086 (DTM) and Sandler Asthma Basic Research Center at UCSF (JVF). The following companies provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up: AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi–Genzyme Regeneron, and Teva. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative.