Increased expression of serine palmitoyl transferase and ORMDL3 polymorphism are associated with eosinophilic inflammation and airflow limitation in aspirin-exacerbated respiratory disease

Ban, Ga Young; Youn, Dong-Ye; Ye, Young-Min; park, hae-sim

doi:10.1371/journal.pone.0240334

Cited by 8 publications

(8 citation statements)

References 36 publications

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“…30 Increased levels of serine palmitoyl transferase, long-chain base subunit 2, 28 and SMPD1 31 have been suggested to induce ceramide increase, and augment eosinophilic inflammation in AERD. 28,31 In this context, we found the SMPD3 gene was hypo-methylated and up-regulated in patients with AERD compared to those with ATA. This finding indicates that sphingolipids may play a role in the pathogenesis of AERD, which is strengthened by previous study results.…”

Section: Discussionmentioning

confidence: 74%

“…Dysregulation of sphingolipids in AERD and severe asthma has been reported in several studies. 6,[26][27][28] Increased levels of ceramides enhanced the release of asthma-related cytokines and chemokines in an asthma mouse model. 29 Ceramides can be generated via the de novo pathway by serine palmitoyl transferase and sphingomyelinase pathways regulated by sphingomyelinases, or the recycling pathway.…”

Section: Discussionmentioning

confidence: 99%

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Nasal transcriptome and epigenome analysis identifies the pathogenic features of aspirin-exacerbated respiratory disease

Ban

Kwon

Kang

et al. 2022

Preprint

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Background: Dysregulation of the arachidonic acid metabolic pathway is the most widely known pathomechanism of AERD. We performed integrative analysis of transcriptomic and epigenomic profiling with network analysis to determine the novel pathogenic features of AERD. Methods: Ten patients with asthma including 5 patients with AERD and another 5 patients with aspirin tolerant asthma (ATA) were enrolled. Nasal epithelial scraping was performed and nasal mucosa was used in omics profiling. Peripheral eosinophil counts, sputum eosinophil counts, FeNO levels, and pulmonary function test results were evaluated. Differentially expressed genes (DEGs), differentially methylated probes (DMPs) and differentially correlated genes (DCGs) between patients with AERD and those with ATA were analyzed. Network analysis using Ingenuity Pathway Analysis (IPA) was performed to determine the gene connection network and signaling pathways. Results: In total, 1,736 DEGs and 1,401 DMPs were identified. Finally, 19 pairs for DCGs were selected. Among DCGs, genes related to vesicle transport (e.g. STX2 and RAB3B) and sphingolipid dysregulation (e.g. SMPD3) were found to be hypo-methylated and up-regulated in patients with AERD. A total number of 78 asthma-related DEGs were identified by the IPA knowledge base. Using the canonical pathway analysis of IPA, signaling pathways of T helper cell differentiation/activation and Fcε receptor I were generated. Up-regulation of RORγt and down-regulation of MHCII, TNFR, and TGF-β as well as up-regulation of FCER1A and JAK and down-regulation of VAV and cPLA2 were noted in patients with AERD. Conclusions: Distinct pathogenic features were identified by using integrative multi-omics data analysis in patients with AERD.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Nasal transcriptome and epigenome analysis identifies the pathogenic features of aspirin-exacerbated respiratory disease

Ban

Kwon

Kang

et al. 2022

Preprint

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“…Especially, NERD was defined as a typical clinical history (recurrent exacerbations of upper or lower respiratory reactions after ingestion of aspirin/NSAIDs) and/or a positive response to the lysine‐aspirin bronchial provocation test (Lys‐ASA BPT). The Lys‐ASA BPT was conducted with increasing doses of Lys‐ASA solution up to 300 mg/ml as previously reported 15,16 …”

Section: Methodsmentioning

confidence: 99%

“…The Lys-ASA BPT was conducted with increasing doses of Lys-ASA solution up to 300 mg/ml as previously reported. 15,16 The asthmatics were in a stable condition, and the levels of FEV 1 (%) were higher than 70% of the predicted value in the Lys-ASA BPT. All antiasthmatic drugs, including leukotriene modifiers, were stopped for at least 3 days before the Lys-ASA BPT.…”

Section: Patient Recruitment and Clinical Characteristicsmentioning

confidence: 97%

Contribution of dipeptidyl peptidase 10 to airway dysfunction in patients with NSAID‐exacerbated respiratory disease

Sim

Choi

Lee

et al. 2021

Clin Experimental Allergy

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Background: Genetic variants of dipeptidyl peptidase 10 (DPP10) have been suggested to contribute to the development of NSAID-exacerbated respiratory disease (NERD). However, the mechanisms of how DPP10 contributes to NERD phenotypes remain unclear. Objective: To demonstrate the exact role of DPP10 in the pathogenesis of NERD. Methods: Patients with NERD (n = 110), those with aspirin-tolerant asthma (ATA, n = 130) and healthy control subjects (HCs, n = 80) were enrolled. Clinical characteristics were analysed according to the serum DPP10 levels in both NERD and ATA groups. The function of DPP10 in airway inflammation and remodelling was investigated with in vitro, ex vivo and in vivo experiments.Results: NERD patients had higher levels of serum DPP10 and TGF-β1 with lower FEV 1 than ATA patients or HCs (p < .05 for each). NERD patients with higher DPP10 levels had higher TGF-β1, but lower FEV 1 (p < .05 for all), whilst no differences were noted in ATA patients. Moreover, the seum DPP10 levels had a positive correlation with TGF-β1 (r = 0.384, p < .001), but a negative correlation with FEV 1 (r = −0.230, p = .016) in NERD patients. In in vitro studies, expression of DPP10 in airway epithelial cells was enhanced by TGF-β1 treatments. Furthermore, DPP10 was found to be produced from immune cells and this molecule induced the ERK phosphorylation in airway epithelial cells, which was suppressed by anti-DPP10 treatment. In asthmatic mouse models, increased levels of DPP10 in the serum and TGF-β1 in the bronchoalveolar lavage fluid were noted, which were suppressed by anti-DPP10 treatment. Moreover, anti-DPP10 treatment inhibited the ERK phosphorylation and extracellular matrix deposition in the lungs. Conclusions and ClinicalRelevance: These findings suggest that increased production of DPP10 may contribute to TGF-β1-mediated airway dysfunction in NERD patients, where blockade of DPP10 may have potential benefits.

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“…For the quantitative determination of creatinine in urine samples, 10 μL of the urine sample were applied to the Creatinine Parameter Assay Kit (R&D Systems, Minneapolis, MN, USA). 19 Pulmonary function test, fractional exhaled nitric oxide (FeNO) measurement, questionnaires survey using the asthma control test (ACT), and asthma quality of life (AQLQ) and asthma control questionnaire (ACQ-6: ACQ mean of 6 individual item scores) were performed on the same day of enrollment.…”

Section: Collection Of Clinical Data and Samplesmentioning

confidence: 99%

Persistent Eosinophilic Inflammation in Adult Asthmatics with High Serum and Urine Levels of Leukotriene E4

Ban¹,

Kim²,

Park³

2021

JAA

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Background: Cysteinyl leukotrienes (CysLTs) are key mediators for bronchoconstriction, eosinophil recruitment and mucus production in the airways of asthmatic patients. To better understand the role of CysLTs in different asthma phenotypes, we compared the levels of arachidonic acid metabolites in relation to asthma control status and phenotypes in adult asthmatics on regular anti-asthma medications. Methods: A total of 137 adult asthmatics (47 with aspirin-exacerbated respiratory disease [AERD] and 90 asthmatics with aspirin-tolerant asthma [ATA]) and 20 healthy controls were enrolled. Arachidonic acid metabolites in serum and urine were analyzed using LC-MS/MS methods, and clinical data, including asthma control status, exhaled NO (FeNO) and lung function tests, were collected. Results: Urine LTE 4 levels were significantly higher in AERD patients on inhaled corticosteroid-long-acting β 2 -agonist plus leukotriene receptor antagonist (LTRA) treatment than in ATA patients (P=0.001). No differences were found in the serum or urine levels of 15-HETE, TXB 2, or PGF 2α. High serum LTE 4 levels were associated with lower FEV1% and uncontrolled status in AERD patients (P=0.006 and P=0.002, respectively), but not in ATA patients. Multivariate analysis demonstrated that blood eosinophil counts, FeNO levels and aspirin hypersensitivity were significant factors affecting urine LTE 4 levels. Conclusion: Despite LTRA treatment in AERD, the LTE 4 levels remained high and showed close associations with blood eosinophilia, high FeNO levels and impaired disease control. Our real-world evidence indicates that control of asthma is not fully achieved by blocking the CysLT pathway with LTRA. Thus, introduction of treatment modalities targeting eosinophilia could be a better option for patients with high CysLTs.

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Increased expression of serine palmitoyl transferase and ORMDL3 polymorphism are associated with eosinophilic inflammation and airflow limitation in aspirin-exacerbated respiratory disease

Cited by 8 publications

References 36 publications

Nasal transcriptome and epigenome analysis identifies the pathogenic features of aspirin-exacerbated respiratory disease

Nasal transcriptome and epigenome analysis identifies the pathogenic features of aspirin-exacerbated respiratory disease

Contribution of dipeptidyl peptidase 10 to airway dysfunction in patients with NSAID‐exacerbated respiratory disease

Persistent Eosinophilic Inflammation in Adult Asthmatics with High Serum and Urine Levels of Leukotriene E4

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