气道上皮细胞及相关细胞因子在哮喘中作用研究进展

doi:10.12372/jcp.2025.24e1083

摘要/Abstract

摘要：

哮喘是一种常见的慢性气道炎症性疾病，其主要特点是气道的非特异性炎症、气道结构重塑及气道高反应性。多年来关于哮喘的发病机制主要集中于过敏反应导致的免疫失衡，而近年来针对气道上皮损伤在哮喘发生发展中的作用及机制受到重视，认为它可能是哮喘发病与控制的关键因素。气道上皮是人体呼吸系统抵御外界环境有害刺激的第一道屏障，也是气道最为重要的结构细胞。当哮喘患者吸入外界有害物质及过敏原时，气道上皮细胞首先受到侵犯并出现损伤，合成和释放多种炎性介质和细胞因子激活免疫细胞，诱导哮喘发生发展。本文旨在对目前有关哮喘气道上皮损伤的发生机制以及哮喘患者气道上皮的病理变化及其关键细胞因子进行综述，以发现潜在的生物标记物与治疗靶点，为哮喘的早期预测和精准防治提供依据。

关键词: 哮喘, 气道上皮细胞, 细胞因子

Abstract:

Asthma is a common chronic airway inflammatory disease, which is characterized by non-specific airway inflammation, airway remodeling and airway hyperresponsiveness. For many years, the pathogenesis of asthma has mainly focused on immune imbalance caused by allergic reaction, but in recent years, attention has been paid to the role and mechanism of airway epithelial injury in the occurrence and development of asthma, which may be a key factor in the pathogenesis and control of asthma. Airway epithelium is the first barrier of human respiratory system to resist the harmful stimulation of external environment, and it is also the most important structural cell of airway. When asthma patients inhale harmful substances and allergens, airway epithelial cells are first invaded and damaged, and a variety of inflammatory mediators and cytokines are synthesized and released to activate immune cells, inducing the occurrence and development of asthma. This paper aims to review the pathogenesis of airway epithelial injury in asthma, the pathological changes of airway epithelial in asthma patients and its key cytokines, in order to find potential biomarkers and therapeutic targets, and provide basis for early prediction and accurate prevention and treatment of asthma.

Key words: asthma, airway epithelial cell, cytokine

中图分类号:

赵宇, 邹文静, 符州. 气道上皮细胞及相关细胞因子在哮喘中作用研究进展[J]. 临床儿科杂志, 2025, 43(8): 635-642.

ZHAO Yu, ZOU Wenjing, FU Zhou. Research progress on the role of airway epithelial cells and related cytokines in asthma[J]. Journal of Clinical Pediatrics, 2025, 43(8): 635-642.

参考文献 47

[1]	Stern J, Pier J, Litonjua AA. Asthma epidemiology and risk factors[J]. Semin Immunopathol, 2020, 42(1): 5-15. doi: 10.1007/s00281-020-00785-1 pmid: 32020334
[2]	陈少甜, 杨男. 脂质代谢在哮喘中作用机制的研究进展[J]. 临床儿科杂志, 2024, 42(5): 461-466.
	Chen ST, Yang N. Research progress on mechanism of lipid metabolism in asthma[J]. Linchuang Erke Zazhi, 2024, 42(5): 461-466.
[3]	李丹, 张睿, 刘峰, 等. 超重和肥胖与哮喘患儿肺功能的相关性研究[J]. 临床儿科杂志, 2024, 42(5): 429-433.
	Li D, Zhang R, Liu F, et al. Correlation between overweight and obesity and lung function in children with asthma[J]. Linchuang Erke Zazhi, 2024, 42(5): 429-433.
[4]	Hellings PW, Steelant B. Epithelial barriers in allergy and asthma[J]. J Allergy Clin Immunol, 2020, 145(6): 1499-1509. doi: S0091-6749(20)30553-4 pmid: 32507228
[5]	Frey A, Lunding LP, Ehlers JC, et al. More than just a barrier: the immune functions of the airway epithelium in asthma pathogenesis[J]. Front Immunol, 2020, 11: 761. doi: 10.3389/fimmu.2020.00761 pmid: 32411147
[6]	Cumplido-Laso G, Benitez DA, Mulero-Navarro S, et al. Transcriptional regulation of airway epithelial cell differentiation: insights into the notch pathway and beyond[J]. Int J Mol Sci, 2023, 24(19): 14789.
[7]	Gomi K, Arbelaez V, Crystal RG, et al. Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway[J]. PloS one, 2015, 10(2): e0116507.
[8]	Raby KL, Michaeloudes C, Tonkin J, et al. Mechanisms of airway epithelial injury and abnormal repair in asthma and COPD[J]. Front Immunol, 2023, 14: 1201658.
[9]	Popov G, Aleksandrov R, Petkova V, et al. Analysis of bacterial biofilm formation and MUC5AC and MUC5B expression in chronic rhinosinusitis patients[J]. J Clin Med, 2023, 12(5): 1808.
[10]	Reid AT, Nichol KS, Chander Veerati P, et al. Blocking notch3 signaling abolishes MUC5AC production in airway epithelial cells from individuals with asthma[J]. Am J Respir Cell Mol Biol, 2020, 62(4): 513-523.
[11]	Xu J, Yu H, Sun X. Less is more: rare pulmonary neuroendocrine cells function as critical sensors in lung[J]. Dev Cell, 2020, 55(2): 123-132. doi: 10.1016/j.devcel.2020.09.024 pmid: 33108755
[12]	Sui P, Wiesner DL, Xu J, et al. Pulmonary neuroendocrine cells amplify allergic asthma responses[J]. Science, 2018, 360(6393): eaan8546.
[13]	Zhu L, An L, Ran D, et al. The club cell marker SCGB1A1 downstream of FOXA2 is reduced in asthma[J]. Am J Respir Cell Mol Biol, 2019, 60(6): 695-704.
[14]	Singh S, Dutta J, Ray A, et al. Airway epithelium: a neglected but crucial cell type in asthma pathobiology[J]. Diagnostics (Basel), 2023, 13(4): 808.
[15]	Busse WW, Kraft M, Rabe KF, et al. Understanding the key issues in the treatment of uncontrolled persistent asthma with type 2 inflammation[J]. Eur Respir J, 2021, 58(2): 2003393.
[16]	Kim HY, Jeong D, Kim JH, et al. Innate type-2 cytokines: from immune regulation to therapeutic targets[J]. Immune Netw, 2024, 24(1): e6.
[17]	Hamilton D, Lehman H. Asthma phenotypes as a guide for current and future biologic therapies[J]. Clin Rev Allergy Immunol, 2020, 59(2): 160-174.
[18]	Bachert C, Hicks A, Gane S, et al. The interleukin-4/interleukin-13 pathway in type 2 inflammation in chronic rhinosinusitis with nasal polyps[J]. Front Immunol, 2024, 15: 1356298.
[19]	Tubau C, Puig L. Therapeutic targeting of the IL-13 pathway in skin inflammation[J]. Expert Rev Clin Immunol, 2021, 17(1): 15-25.
[20]	Ji T, Li H. T-helper cells and their cytokines in pathogenesis and treatment of asthma[J]. Front Immunol, 2023, 14: 1149203.
[21]	Xing Z, Liu S, He X. Critical and diverse role of alarmin cytokines in parasitic infections[J]. Front Cell Infect Microbiol, 2024, 14: 1418500.
[22]	Jin J, Chen X, Zhao Y, et al. The role and its regulatory significance of interleukin-25 in ovalbumin induced atopic dermatitis of mice[J]. Beijing Da Xue Xue Bao Yi Xue Ban, 2024, 56(5): 756-762.
[23]	Porsbjerg CM, Sverrild A, Lloyd CM, et al. Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics[J]. Eur Respir J, 2020, 56(5): 2000260.
[24]	Gauvreau GM, Hohlfeld JM, FitzGerald JM, et al. Inhaled anti-TSLP antibody fragment, ecleralimab, blocks responses to allergen in mild asthma[J]. Eur Respir J, 2023, 61(3): 2201193.
[25]	Wechsler ME, Ruddy MK, Pavord ID, et al. Efficacy and safety of itepekimab in patients with moderate-to-severe asthma[J]. N Engl J Med, 2021, 385(18): 1656-1668.
[26]	Mosbech CH, Godtfredsen NS, Ulrik CS, Westergaard CG. Biomarker-guided withdrawal of inhaled corticosteroids in asthma patients with a non-T2 inflammatory phenotype - a randomized controlled trial study protocol[J]. BMC Pulm Med, 2023, 23(1): 372.
[27]	Jeong J, Lee HK. The role of CD4+ T cells and microbiota in the pathogenesis of asthma[J]. Int J Mol Sci, 2021, 22(21): 11822.
[28]	Yang Y, Jia M, Ou Y, et al. Mechanisms and biomarkers of airway epithelial cell damage in asthma: a review[J]. Clin Respir J, 2021, 15(10): 1027-1045.
[29]	Tota M, Łacwik J, Laska J, et al. The role of eosinophil-derived neurotoxin and vascular endothelial growth factor in the pathogenesis of eosinophilic asthma[J]. Cells, 2023, 12(9): 1326.
[30]	Cao L, Liu F, Liu Y, et al. TSLP promotes asthmatic airway remodeling via p38-STAT3 signaling pathway in human lung fibroblast[J]. Exp Lung Res, 2018, 44(6): 288-301. doi: 10.1080/01902148.2018.1536175 pmid: 30428724
[31]	Jin A, Tang X, Zhai W, et al. TSLP-induced collagen type-I synthesis through STAT3 and PRMT1 is sensitive to calcitriol in human lung fibroblasts[J]. Biochim Biophys Acta Mol Cell Res, 2021, 1868(10): 119083.
[32]	Braile M, Fiorelli A, Sorriento D, et al. Human lung-resident macrophages express and are targets of thymic stromal lymphopoietin in the tumor microenvironment[J]. Cells, 2021, 10(8): 2012.
[33]	Gomułka K, Tota M, Brzdąk K. Effect of VEGF stimulation on CD11b receptor on peripheral eosinophils in asthmatics[J]. Int J Mol Sci, 2023, 24(10): 8880.
[34]	Xu X, Luo S, Li B, et al. IL-25 contributes to lung fibrosis by directly acting on alveolar epithelial cells and fibroblasts[J]. Exp Biol Med (Maywood), 2019, 244(9): 770-780.
[35]	Gauvreau GM, Bergeron C, Boulet LP, et al. Sounding the alarmins-The role of alarmin cytokines in asthma[J]. Allergy, 2023, 78(2): 402-417.
[36]	Tan QY, Cheng ZS. TGFβ1-smad signaling pathway participates in interleukin-33 induced epithelial-to-mesenchymal transition of A549 cells[J]. Cell Physiol Biochem, 2018, 50(2):757-767.
[37]	Oda N, Miyahara N, Taniguchi A, et al. Requirement for neuropeptide Y in the development of type 2 responses and allergen-induced airway hyperresponsiveness and inflammation[J]. Am J Physiol Lung Cell Mol Physiol, 2019, 316(3): L407-L417.
[38]	Arzola-Martínez L, Benavente R, Vega G, et al. Blocking ATP-releasing channels prevents high extracellular ATP levels and airway hyperreactivity in an asthmatic mouse model[J]. Am J Physiol Lung Cell Mol Physiol, 2021, 321(2): L466-L476.
[39]	Tang S, Du X, Yuan L, et al. Airway epithelial ITGB4 deficiency in early life mediates pulmonary spontaneous inflammation and enhanced allergic immune response[J]. J Cell Mol Med, 2020, 24(5): 2761-2771. doi: 10.1111/jcmm.15000 pmid: 31970850
[40]	Yuan L, Liu H, Du X, et al. Airway epithelial ITGB4 deficiency induces airway remodeling in a mouse model[J]. J Allergy Clin Immunol, 2023, 151(2): 431-446.
[41]	Liu P, Li S, Tang L. Nerve growth factor: a potential therapeutic target for lung diseases[J]. Int J Mol Sci, 2021, 22(17): 9112.
[42]	Ogawa H, Azuma M, Umeno A, et al. Singlet oxygen -derived nerve growth factor exacerbates airway hyperresponsiveness in a mouse model of asthma with mixed inflammation[J]. Allergol Int, 2022, 71(3): 395-404.
[43]	王植嘉, 尚云晓. 神经激肽1受体拮抗剂对哮喘小鼠气道炎症和高反应性的影响[J]. 中国小儿急救医学, 2020, 27(2): 105-109.
	Wang ZJ, Shang YX. Effect of neurokinin-1 receptor antagonists on airway inflammation and hyperresponsiveness in asthma mice[J]. Zhongguo Xiaoer Jijiu Yixue, 2020, 27(2): 105-109.
[44]	Hur J, Rhee CK, Lee SY, et al. MicroRNA-21 inhibition attenuates airway inflammation and remodelling by modulating the transforming growth factor β-Smad7 pathway[J]. Korean J Intern Med, 2021, 36(3): 706-720. doi: 10.3904/kjim.2020.132 pmid: 33601867
[45]	Bradding P, Porsbjerg C, Côté A, et al. Airway hyperresponsiveness in asthma: the role of the epithelium[J]. J Allergy Clin Immunol, 2024, 153(5): 1181-1193. doi: 10.1016/j.jaci.2024.02.011 pmid: 38395082
[46]	Temann UA, Geba GP, Rankin JA, et al. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness[J]. J Exp Med, 1998, 188(7): 1307-1320. doi: 10.1084/jem.188.7.1307 pmid: 9763610
[47]	McKnight CG, Potter C, Finkelman FD. IL-4Rα expression by airway epithelium and smooth muscle accounts for nearly all airway hyperresponsiveness in murine allergic airway disease[J]. Mucosal Immunol, 2020, 13(2): 283-292. doi: 10.1038/s41385-019-0232-7 pmid: 31745261