Effect of TGF-[beta]1 on eosinophils to induce cysteinyl leukotriene E.sub.4 production in aspirin-exacerbated respiratory disease

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-[beta]1) in association with cysteinyl leukotriene E.sub.4 (LTE.sub.4) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-[beta]1, 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-[beta]1 and urinary LTE.sub.4 . The function of TGF-[beta]1 in LTE.sub.4 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-[beta]1 were significantly higher in AERD patients than in ATA patients or HCs (P = .001; respectively). Moreover, levels of serum TGF-[beta]1 and urinary LTE.sub.4 had a positive correlation (r = 0.273, P = .037). In the presence of TGF-[beta]1, leukotriene C.sub.4 synthase (LTC.sub.4 S) expression was enhanced in peripheral eosinophils to produce LTE.sub.4, which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-[beta]1, significantly induced eosinophilia with increased LTE.sub.4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-[beta]1 in AERD patients may contribute to LTE.sub.4 production via enhancing LTC.sub.4 S expression which induces eosinophil degranulation, accelerating airway inflammation.