Lee, K E

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.)