Background: 15(S)-HETE, a bioactive lipid mediator derived from arachidonic acid, is closely associated with eosinophilic inflammation and recurrence in chronic rhinosinusitis with nasal polyps (CRSwNP). Nevertheless, its impact on fibroblast-associated transcriptional regulation remains poorly characterized. Objective: To characterize the transcriptional and immunologic alterations in fibroblasts following 15(S)-HETE exposure. Methods: Human fibroblasts (MRC-5) were exposed to either 15(S)-HETE or a dimethyl sulfoxide vehicle control before RNA sequencing. Differential expression analysis was combined with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway annotation to characterize functional alterations. Pathway-level transcriptional changes were additionally explored using gene set enrichment analysis and weighted gene co-expression network analysis. Fibroblast viability was further assessed with a Cell Counting Kit-8 assay. Results: Transcriptomic profiling of the 15(S)-HETE-treated group revealed 96 differentially expressed genes, consisting of 54 upregulated and 42 downregulated genes. Upregulated genes were enriched in cytokine-related and inflammatory pathways, particularly interleukin-17 and tumor necrosis factor signaling. In contrast, downregulated genes were mainly involved in interferon-mediated antiviral responses. Gene set enrichment analysis further revealed significant suppression of interferon-α and interferon-γ response signatures. Weighted Gene Co-expression Network Analysis identified inflammation-related gene modules associated with 15(S)-HETE stimulation, in which CXCL1 was upregulated. In addition, 15(S)-HETE treatment significantly increased fibroblast viability. Conclusion: 15(S)-HETE was associated with changes in fibroblast transcriptional programs, including reduced interferon-related signatures and increased cytokine signaling. These findings suggest a potential role for 15(S)-HETE in fibroblast-associated immune regulation relevant to CRSwNP.
Background: Allergic rhinitis (AR) is an inflammation of the nasal mucosa primarily mediated by antigen-specific immunoglobulin E (IgE) and characterized predominantly by type 2 inflammation, in which the Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a critical role. Targeted inhibition of this pathway using small-molecule JAK inhibitor nasal sprays may represent a promising therapeutic strategy for AR. Objective: To evaluate the pharmacological profiles of pumecitinib (aka PG-011), a JAK inhibitor formulated as a nasal spray, for the treatment of AR in a mouse model. Methods: The inhibitory activity and selectivity of pumecitinib against JAK kinases were assessed in enzymatic assays. Its effects on cytokine-induced STAT phosphorylation (pSTAT) were evaluated in cellular assays. The pharmacological effects of pumecitinib nasal spray were investigated in an ovalbumin (OVA)-induced AR mouse model. Results: Pumecitinib was identified as a potent and selective inhibitor of JAK1 and JAK2 kinases relative to JAK3 and TYK2. It effectively suppressed pSTAT production induced by multiple cytokines, including interleukin (IL)-4, IL-31, and granulocyte-macrophage colony-stimulating factor. In the OVA-induced AR model, intranasal administration of 0.1% pumecitinib spray significantly reduced the frequency of sneezing episodes, as well as markedly attenuated nasal mucosal epithelial thickness, goblet cell hyperplasia, and eosinophil infiltration. The 0.05% concentration also produced significant reductions in epithelial thickness and eosinophil count. Both concentrations significantly lowered OVA-specific IgE levels in nasal lavage fluid. Conclusion: These findings demonstrate that pumecitinib nasal spray, through targeted inhibition of JAK1/2 kinases, exhibits pharmacological activity in a mouse model of AR, supporting its potential as a therapeutic candidate for further translational investigation in AR.
Peach allergy is a common plant food allergy; specifically, sensitization to gibberellin-regulated protein (GRP; Pru p 7) and lipid-transfer protein (LTP; Pru p 3) is considered a predictor of severe allergic reactions in patients with peach allergy. However, the allergenic mechanisms in patients who are negative for these components remain unclear. Herein, we report the case of a 26-year-old Japanese man with a history of atopic dermatitis and pollinosis. The patient developed systemic allergic symptoms, including oral pruritus, pharyngeal swelling, respiratory discomfort, palpitations, and pallor, after ingesting a whole raw peach. Specific immunoglobulin E (IgE) to peach extract and Pru p 1 was positive, whereas specific IgE to Pru p 3, Pru p 4, and Pru p 7 was negative. Skin prick testing was positive for raw peach but negative for purified peach GRP. A proteomic approach was used to identify causative allergens. Two-dimensional electrophoresis and immunoblotting revealed an IgE-binding protein spot at approximately 25 kDa. Mass spectrometry identified the protein as peptidyl-prolyl cis-trans isomerase FKBP20-1 (FKBP20-1). Recombinant FKBP20-1 showed strong IgE reactivity with the patient’s serum but not with sera from nonallergic controls. Therefore, FKBP20-1 may represent a potential IgE-binding allergen involved in systemic reactions to peaches in patients who are not sensitized to GRP or LTP. Further studies are needed to clarify the clinical relevance of these findings.
