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转化生长因子-β相关激酶1参与病程较长的哮喘患者的固定性气道阻塞,且与气道嗜酸性粒细胞增多无关。

Involvement of Transforming Growth Factor-β-Associated Kinase 1 in Fixed Airway Obstruction in Asthmatic Patients with Longer Disease Duration Independent on Airway Eosinophilia.

作者信息

Maneechotesuwan Kittipong, Wongsurakiat Phunsup, Assawabhumi Jirawat, Kasetsinsombat Kanda, Wongkajornsilp Adisak

机构信息

Division of Respiratory Disease and Tuberculosis, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

出版信息

J Asthma Allergy. 2023 Apr 4;16:343-354. doi: 10.2147/JAA.S403645. eCollection 2023.

Abstract

OBJECTIVE

Transforming growth factor-β-associated kinase 1 (TAK1) mediates non-canonical TGF-β signalling by promoting adhesive, migratory, proliferative and contractile responses of fibroblasts to TGF-β. However, TAK1 expression status in asthmatic patients with or without fixed airway obstruction (FAO) is unknown.

PATIENTS AND METHODS

A total of 60 adult asthmatics with FAO were recruited and compared to 43 those without FAO (nFAO). TGF-β concentrations, and total TAK1 and phosphorylated TAK1 (p-TAK1) levels were determined in sputum supernatants, cytospin, and whole cell lysate by ELISA, immunocytochemistry, and Western blot analysis, respectively, in asthmatics with and without FAO.

RESULTS

Asthmatic patients with FAO had much greater sputum TGF-β concentrations than those without FAO. This was independent of airway eosinophilia as there was no significant difference in TGF-β levels between high and low eosinophil counts within FAO and nFAO groups. In contrast, patients with FAO in the presence of sputum eosinophilia had greater expression of TAK1 and p-TAK1 than those without sputum eosinophilia (=0.0032 and =0.0061, respectively). The Western Blot data of total TAK1 and p-TAK1 were consistent with the immunocytochemistry, showing upregulation in all sputum cell types (neutrophils, eosinophils, macrophages, lymphocytes and airway epithelial cells). In addition, total TAK1 expression negatively correlated with pre- and post-bronchodilator FEV/FVC ratio.

CONCLUSION

TAK1 may play a key role in asthmatic patients with fixed airway obstruction, which was independent of eosinophilic airway inflammation. The interruption of TAK1 might have favourable clinical impact.

摘要

目的

转化生长因子-β相关激酶1(TAK1)通过促进成纤维细胞对转化生长因子-β的黏附、迁移、增殖和收缩反应来介导非经典转化生长因子-β信号传导。然而,伴有或不伴有固定性气道阻塞(FAO)的哮喘患者中TAK1的表达状态尚不清楚。

患者与方法

共招募了60例患有FAO的成年哮喘患者,并与43例无FAO的患者(nFAO)进行比较。分别通过酶联免疫吸附测定(ELISA)、免疫细胞化学和蛋白质免疫印迹分析,测定伴有和不伴有FAO的哮喘患者痰液上清液、细胞涂片和全细胞裂解物中的转化生长因子-β浓度以及总TAK1和磷酸化TAK1(p-TAK1)水平。

结果

患有FAO的哮喘患者痰液中的转化生长因子-β浓度比无FAO的患者高得多。这与气道嗜酸性粒细胞增多无关,因为在FAO组和nFAO组中,嗜酸性粒细胞计数高和低的患者之间转化生长因子-β水平没有显著差异。相比之下,伴有痰液嗜酸性粒细胞增多的FAO患者比无痰液嗜酸性粒细胞增多的患者TAK1和p-TAK1的表达更高(分别为P = 0.0032和P = 0.0061)。总TAK1和p-TAK1的蛋白质免疫印迹数据与免疫细胞化学结果一致,显示在所有痰液细胞类型(中性粒细胞、嗜酸性粒细胞、巨噬细胞、淋巴细胞和气道上皮细胞)中均上调。此外,总TAK1表达与支气管扩张剂使用前后的第1秒用力呼气容积/用力肺活量(FEV₁/FVC)比值呈负相关。

结论

TAK1可能在伴有固定性气道阻塞的哮喘患者中起关键作用,这与嗜酸性气道炎症无关。阻断TAK1可能会产生有利的临床影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ce49/10082578/6140497ec2d1/JAA-16-343-g0001.jpg

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