收稿日期: 2022-12-12
录用日期: 2023-03-17
网络出版日期: 2023-07-11
基金资助
国家自然科学基金(81370124)
Research progress in the roles of airway epithelial cells in the pathogenesis of asthma
Received date: 2022-12-12
Accepted date: 2023-03-17
Online published: 2023-07-11
Supported by
National Natural Science Foundation of China(81370124)
哮喘是一种常见的慢性呼吸道疾病。作为一种异质性疾病,其发病机制由免疫、遗传、环境等多种因素共同驱动,由多种细胞共同参与。近些年越来越多的证据表明,气道上皮细胞在哮喘发病中发挥核心作用。气道上皮细胞作为机体呼吸系统抵御外界环境的第一道防线,主要通过细胞间各种连接阻止有害刺激进入,并通过黏液纤毛系统和抗菌肽清除变应原、病毒等外来有害因素。气道黏膜受到外来有害刺激时,气道上皮细胞屏障可能被破坏,上皮细胞释放各种上皮源性细胞因子,有效激活树突状细胞(dendritic cell,DC)和Ⅱ型固有免疫淋巴细胞(type Ⅱ innate lymphoid cell,ILC),从而引发后续辅助性T细胞2免疫级联反应,导致哮喘发生。鉴于气道上皮细胞在哮喘中的上述作用,针对气道上皮细胞来源的细胞因子,如胸腺基质淋巴细胞生成素(thymic stromal lymphopoietin,TSLP)等的靶向治疗药物也逐渐投入临床应用。该文针对气道上皮细胞在哮喘发病机制中的作用,及以气道上皮细胞为潜在靶点的治疗在未来的临床应用进行综述。
徐瀛濂 , 田静 , 张翔 , 赵顺英 . 气道上皮细胞在哮喘发病机制中的作用研究进展[J]. 上海交通大学学报(医学版), 2023 , 43(5) : 619 -623 . DOI: 10.3969/j.issn.1674-8115.2023.05.013
Asthma is a common chronic respiratory disease, and as a heterogeneous disease, it is driven by a combination of immune, genetic, and environmental factors and involves multiple cells. In recent years, there has been increasing evidence that airway epithelial cells play a core role in the pathogenesis of asthma. As the first line of defense of the respiratory system against the external environment, airway epithelial cells mainly prevent harmful stimuli from entering through various intercellular connections and remove harmful foreign factors such as allergens and viruses through the mucus and cilia system and the antimicrobial peptides. The airway epithelial barrier can be disrupted when the airway mucosa is exposed to foreign harmful stimuli, and epithelial cells can release various epithelial-derived cytokines that effectively activate dendritic cells and type Ⅱ innate lymphoid cells, thereby triggering a subsequent helper T cell 2 immune cascade response that leads to the development of asthma. In view of these roles of airway epithelial cells in asthma, targeted therapeutic agents targeting the cytokines from airway epithelial cells such as thymic stromal lymphopoietin, are gradually coming into clinical use. This article reviews the role of airway epithelial cells in the pathogenesis of asthma and the future clinical applications of therapies targeting airway epithelial cells as potential targets.
Key words: asthma; airway epithelium; cytokine; targeted therapy
1 | REDDEL H K, BACHARIER L B, BATEMAN E D, et al. Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes[J]. Eur Respir J, 2022, 59(1): 2102730. |
2 | MILLER R L, GRAYSON M H, STROTHMAN K. Advances in asthma: new understandings of asthma′s natural history, risk factors, underlying mechanisms, and clinical management[J]. J Allergy Clin Immunol, 2021, 148(6): 1430-1441. |
3 | GOHY S, HUPIN C, LADJEMI M Z, et al. Key role of the epithelium in chronic upper airways diseases[J]. Clin Exp Allergy, 2020, 50(2): 135-146. |
4 | CALVéN J, AX E, R?DINGER M. The airway epithelium: a central player in asthma pathogenesis[J]. Int J Mol Sci, 2020, 21(23): E8907. |
5 | NOUREDDINE N, CHALUBINSKI M, WAWRZYNIAK P. The role of defective epithelial barriers in allergic lung disease and asthma development[J]. J Asthma Allergy, 2022, 15: 487-504. |
6 | HELLINGS P W, STEELANT B. Epithelial barriers in allergy and asthma[J]. J Allergy Clin Immunol, 2020, 145(6): 1499-1509. |
7 | LEGENDRE M, ZARAGOSI L E, MITCHISON H M. Motile cilia and airway disease[J]. Semin Cell Dev Biol, 2021, 110: 19-33. |
8 | GHEZZI M, POZZI E, ABBATTISTA L, et al. Barrier impairment and type 2 inflammation in allergic diseases: the pediatric perspective[J]. Children (Basel), 2021, 8(12): 1165. |
9 | MORETTA A, SCIEUZO C, PETRONE A M, et al. Antimicrobial peptides: a new hope in biomedical and pharmaceutical fields[J]. Front Cell Infect Microbiol, 2021, 11: 668632. |
10 | VON MUTIUS E, SMITS H H. Primary prevention of asthma: from risk and protective factors to targeted strategies for prevention[J]. Lancet, 2020, 396(10254): 854-866. |
11 | GON Y, HASHIMOTO S. Role of airway epithelial barrier dysfunction in pathogenesis of asthma[J]. Allergol Int, 2018, 67(1): 12-17. |
12 | LI B, ZOU Z, MENG F, et al. Dust mite-derived Der f 3 activates a pro-inflammatory program in airway epithelial cells via PAR-1 and PAR-2[J]. Mol Immunol, 2019, 109: 1-11. |
13 | REDES J L, BASU T, RAM-MOHAN S, et al. Aspergillus fumigatus-secreted alkaline protease 1 mediates airways hyperresponsiveness in severe asthma[J]. ImmunoHorizons, 2019, 3(8): 368-377. |
14 | GASPAR R, DE MATOS M R, CORTES L, et al. Pollen proteases play multiple roles in allergic disorders[J]. Int J Mol Sci, 2020, 21(10): 3578. |
15 | GODBOLD G D, KAPPELL A D, LESASSIER D S, et al. Categorizing sequences of concern by function to better assess mechanisms of microbial pathogenesis[J]. Infect Immun, 2022, 90(5): e0033421. |
16 | LOOI K, BUCKLEY A G, RIGBY P J, et al. Effects of human rhinovirus on epithelial barrier integrity and function in children with asthma[J]. Clin Exp Allergy, 2018, 48(5): 513-524. |
17 | MILLS J T, SCHWENZER A, MARSH E K, et al. Airway epithelial cells generate pro-inflammatory tenascin-C and small extracellular vesicles in response to TLR3 stimuli and Rhinovirus infection[J]. Front Immunol, 2019, 10: 1987. |
18 | BOULET L P. Airway remodeling in asthma: update on mechanisms and therapeutic approaches[J]. Curr Opin Pulm Med, 2018, 24(1): 56-62. |
19 | MIETHE S, GUARINO M, ALHAMDAN F, et al. Effects of obesity on asthma: immunometabolic links[J]. Pol Arch Intern Med, 2018, 128(7/8): 469-477. |
20 | MICHALIK M, WóJCIK-PSZCZO?A K, PAW M, et al. Fibroblast-to-myofibroblast transition in bronchial asthma[J]. Cell Mol Life Sci, 2018, 75(21): 3943-3961. |
21 | ROUT-PITT N, FARROW N, PARSONS D, et al. Epithelial mesenchymal transition (EMT): a universal process in lung diseases with implications for cystic fibrosis pathophysiology[J]. Respir Res, 2018, 19(1): 136. |
22 | ANDERSON E D, ALISHAHEDANI M E, MYLES I A. Epithelial-mesenchymal transition in atopy: a mini-review[J]. Front Allergy, 2020, 1: 628381. |
23 | YüKSEL H, TUNCA S. Destiny of airway disease: interplay between epithelial barrier and the innate immune system[J]. Tissue Barriers, 2022, 10(4): 2020706. |
24 | DAVIS J D, WYPYCH T P. Cellular and functional heterogeneity of the airway epithelium[J]. Mucosal Immunol, 2021, 14(5): 978-990. |
25 | WHETSTONE C E, RANJBAR M, OMER H, et al. The role of airway epithelial cell alarmins in asthma[J]. Cells, 2022, 11(7): 1105. |
26 | KLIMOV V, CHEREVKO N, KLIMOV A, et al. Neuronal-immune cell units in allergic inflammation in the nose[J]. Int J Mol Sci, 2022, 23(13): 6938. |
27 | BOROWCZYK J, SHUTOVA M, BREMBILLA N C, et al. IL-25 (IL-17E) in epithelial immunology and pathophysiology[J]. J Allergy Clin Immunol, 2021, 148(1): 40-52. |
28 | DENG C, PENG N, TANG Y, et al. Roles of IL-25 in type 2 inflammation and autoimmune pathogenesis[J]. Front Immunol, 2021, 12: 691559. |
29 | WANG W, LI Y, LV Z, et al. Bronchial allergen challenge of patients with atopic asthma triggers an alarmin (IL-33, TSLP, and IL-25) response in the airways epithelium and submucosa[J]. J Immunol, 2018, 201(8): 2221-2231. |
30 | HARTUNG F, ESSER-VON BIEREN J. Trained immunity in type 2 immune responses[J]. Mucosal Immunol, 2022, 15(6): 1158-1169. |
31 | SAIKUMAR JAYALATHA A K, HESSE L, KETELAAR M E, et al. The central role of IL-33/IL-1RL1 pathway in asthma: from pathogenesis to intervention[J]. Pharmacol Ther, 2021, 225: 107847. |
32 | HUANG R F, MAO W, WANG G L, et al. Synergistic relationship between TSLP and IL-33/ST2 signaling pathways in allergic rhinitis and the effects of hypoxia[J]. Int Forum Allergy Rhinol, 2020, 10(4): 511-520. |
33 | YAO X J, LIU X F, WANG X D. Potential role of interleukin-25/interleukin-33/thymic stromal lymphopoietin-fibrocyte axis in the pathogenesis of allergic airway diseases[J]. Chin Med J (Engl), 2018, 131(16): 1983-1989. |
34 | AKAR-GHIBRIL N, CASALE T, CUSTOVIC A, et al. Allergic endotypes and phenotypes of asthma[J]. J Allergy Clin Immunol Pract, 2020, 8(2): 429-440. |
35 | MENZIES-GOW A, CORREN J, BOURDIN A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma[J]. N Engl J Med, 2021, 384(19): 1800-1809. |
36 | BACHARIER L B, JACKSON D J. Biologics in the treatment of asthma in children and adolescents[J]. J Allergy Clin Immunol, 2023, 151(3): 581-589. |
37 | WECHSLER M E, RUDDY M K, PAVORD I D, et al. Efficacy and safety of itepekimab in patients with moderate-to-severe asthma[J]. N Engl J Med, 2021, 385(18): 1656-1668. |
38 | AnaptysBio, Inc. Efficacy, safety, and pharmacokinetic profile of etokimab (ANB020) in adult participants with moderate-to-severe atopic dermatitis (ATLAS)[EB/OL]. [2022-11-20]. https://clinicaltrials.gov/ct2/show/NCT03533751. |
/
〈 |
|
〉 |