Abstract
Cysteinyl leukotriene (cysLT) overproduction and eosinophil activation are hallmarks of aspirin-exacerbated respiratory disease (AERD). However, pathogenic mechanisms of AERD remain to be clarified. Here, we aimed to find the significance of transforming growth factor beta 1 (TGF-β1) in association with cysteinyl leukotriene E4 (LTE4) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-β1, first cohort enrolled AERD (n = 336), ATA (n = 442) patients and healthy control subjects (HCs, n = 253). In addition, second cohort recruited AERD (n = 34) and ATA (n = 25) patients to investigate a relation between levels of serum TGF-β1 and urinary LTE4. The function of TGF-β1 in LTE4 production was further demonstrated by ex vivo (human peripheral eosinophils) or in vivo (BALB/c mice) experiment. As a result, the levels of serum TGF-β1 were significantly higher in AERD patients than in ATA patients or HCs (P = .001; respectively). Moreover, levels of serum TGF-β1 and urinary LTE4 had a positive correlation (r = 0.273, P = .037). In the presence of TGF-β1, leukotriene C4 synthase (LTC4S) expression was enhanced in peripheral eosinophils to produce LTE4, which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-β1, significantly induced eosinophilia with increased LTE4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-β1 in AERD patients may contribute to LTE4 production via enhancing LTC4S expression which induces eosinophil degranulation, accelerating airway inflammation.
Highlights
Aspirin-exacerbated respiratory disease (AERD) typically presents moderate-to-severe phenotypes of asthma, chronic rhinosinusitis (CRS) and/or nasal polyps with persistent eosinophilia in the upper and lower airway mucosa
Considering that persistent eosinophilic inflammation is a key feature of AERD and that studies evaluating the function of TGF-β1 in eosinophilic airway inflammation are still lacking, the present study focuses on the effect of TGF-β1 on eosinophil activation in AERD pathogenesis
When asthmatic patients were divided into the TGF-β1-low and -high subgroups, the TGF-β1-high subgroup showed lower baseline FEV1 (%) than the TGF-β1-low subgroup within the AERD group (P = .034), while no differences were found within the ATA group (Table 2)
Summary
Aspirin-exacerbated respiratory disease (AERD) typically presents moderate-to-severe phenotypes of asthma, chronic rhinosinusitis (CRS) and/or nasal polyps with persistent eosinophilia in the upper and lower airway mucosa. Function of TGF-β1 in aspirin-exacerbated respiratory disease and analysis, decision to publish, or preparation of the manuscript
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