哮喘儿童小气道功能障碍的再认识

doi:10.3969/j.issn.1674-8115.2023.04.014

摘要/Abstract

摘要：

小气道功能障碍（small airway dysfunction，SAD）广泛存在于儿童哮喘的多个阶段，以气道炎症、气道重塑、气道高反应性为基础，其中气道炎症是SAD的主要病理特征。近年来研究发现，参与小气道病变进展的免疫细胞，如2型固有淋巴细胞（type 2 innate lymphoid cell，ILC2）、巨噬细胞、粒细胞等，在哮喘相关的临床控制和靶向治疗中发挥重要的作用。同时，随着脉冲振荡技术和呼出气一氧化氮检测等临床检测技术的不断完善，SAD与儿童哮喘早期发生和发展有关的证据也越来越多。针对小气道的超细颗粒气雾剂和单克隆抗体靶向药物研制为哮喘精准控制提供了新的手段。因此，小气道在哮喘等慢性呼吸系统疾病中的功能近年来受到广泛关注。既往研究表明，SAD会增加儿童哮喘不受控制的风险，但往往易被忽视。该文从发病机制、诊断评估和治疗3个方面阐述SAD及儿童哮喘的最新研究进展，希冀为以小气道为治疗靶点的长期哮喘管理提供新的视角及认识。

关键词: 小气道功能障碍, 气道炎症, 气道重塑, 儿童, 哮喘, 哮喘控制

Abstract:

Small airway dysfunction (SAD) widely exists in different stages of childhood asthma, which is based on airway inflammation, airway remodeling and airway hyperresponsiveness. Among them, airway inflammation is the main pathological feature of SAD. It has been recently found that immune cells involved in the progression of the disease, such as type 2 innervate lymphoid cells (ILC2s), macrophages, and granulocyte, played an important role in clinical control and targeted therapy of asthma. At the same time, with continuous improvement of clinical detection technologies such as impulse oscillometry and exhaled nitric oxide detecting, more and more evidence suggests that SAD is associated with the early occurrence and development of pediatric asthma. The development of ultra-fine particle aerosol and monoclonal antibody targeting small airways has provided a new means for the precise control of asthma. Therefore, the function of small airways in chronic respiratory diseases, including asthma, has received extensive attention in recent years. Previous studies have shown that SAD increases the risk of uncontrolled asthma in children, but it is often ignored. This article describes the latest research progress of SAD and childhood asthma from the aspects of pathogenesis, diagnostic evaluation and treatment, so as to provide a new perspective and understanding for long-term asthma management targeting small airways.

Key words: small airway dysfunction (SAD), airway inflammation, airway remodeling, child, asthma, asthma control

中图分类号:

R725.6

朱思宇, 董晓艳. 哮喘儿童小气道功能障碍的再认识[J]. 上海交通大学学报（医学版）, 2023, 43(4): 500-506.

ZHU Siyu, DONG Xiaoyan. New insights in small airway dysfunction of childhood asthma[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(4): 500-506.

参考文献 55

1	DHARMAGE S C, PERRET J L, CUSTOVIC A. Epidemiology of asthma in children and adults[J]. Front Pediatr, 2019, 7: 246.
2	RAMRATNAM S K, BACHARIER L B, GUILBERT T W. Severe asthma in children[J]. J Allergy Clin Immunol Pract, 2017, 5(4): 889-898.
3	USMANI O S, SINGH D, SPINOLA M, et al. The prevalence of small airways disease in adult asthma: a systematic literature review[J]. Respir Med, 2016, 116: 19-27.
4	ABDO M, TRINKMANN F, KIRSTEN A M, et al. Small airway dysfunction links asthma severity with physical activity and symptom control[J]. J Allergy Clin Immunol Pract, 2021, 9(9): 3359-3368.e1.
5	KOEFOED H J L, ZWITSERLOOT A M, VONK J M, et al. Asthma, bronchial hyperresponsiveness, allergy and lung function development until early adulthood: a systematic literature review[J]. Pediatr Allergy Immunol, 2021, 32(6): 1238-1254.
6	朱蕾. 临床呼吸生理学[M]. 上海: 上海科学技术出版社, 2020: 96-97.
	ZHU L. Clinical respiratory physiology[M]. Shanghai: Shanghai Scientific & Technical Publishers, 2020: 96-97.
7	徐康乔, 夏元旦, 徐丽, 等. 嗜酸性粒细胞及中性粒细胞型哮喘患者炎症特点与小气道功能变化分析[J]. 中国综合临床, 2022, 38(3): 256-261.
	XU K J, XIA Y D, XU L, et al. Analysis of inflammatory characteristics and changes in small airway function in patients with eosinophil and neutrophilic asthma[J]. Clinical Medicine of China, 2022, 38(3): 256-261.
8	HE X Y, SIMPSON J L, WANG F. Inflammatory phenotypes in stable and acute childhood asthma[J]. Paediatr Respir Rev, 2011, 12(3): 165-169.
9	HAMMAD H, LAMBRECHT B N. The basic immunology of asthma[J]. Cell, 2021, 184(6): 1469-1485.
10	ZINELLU E, PIRAS B, RUZITTU G G M, et al. Recent advances in inflammation and treatment of small airways in asthma[J]. Int J Mol Sci, 2019, 20(11): 2617.
11	ABDO M, TRINKMANN F, KIRSTEN A M, et al. The relevance of small airway dysfunction in asthma with nocturnal symptoms[J]. J Asthma Allergy, 2021, 14: 897-905.
12	NAGAKUMAR P, DENNEY L, FLEMING L, et al. Type 2 innate lymphoid cells in induced sputum from children with severe asthma[J]. J Allergy Clin Immunol, 2016, 137(2): 624-626.e6.
13	LIU T, WU J, ZHAO J, et al. Type 2 innate lymphoid cells: a novel biomarker of eosinophilic airway inflammation in patients with mild to moderate asthma[J]. Respir Med, 2015, 109(11): 1391-1396.
14	KATO A. Group 2 innate lymphoid cells in airway diseases[J]. Chest, 2019, 156(1): 141-149.
15	SUI P F, WIESNER D L, XU J H, et al. Pulmonary neuroendocrine cells amplify allergic asthma responses[J]. Science, 2018, 360(6393): eaan8546.
16	ZHU X Y, CUI J, YI L, et al. The role of T cells and macrophages in asthma pathogenesis: a new perspective on mutual crosstalk[J]. Mediators Inflamm, 2020, 2020: 7835284.
17	AKTAR A, SHAN L Y, KOUSSIH L, et al. PlexinD1 deficiency in lung interstitial macrophages exacerbates house dust mite-induced allergic asthma[J]. J Immunol, 2022, 208(5): 1272-1279.
18	CUI Z, FENG Y, LI D Q, et al. Activation of aryl hydrocarbon receptor (AhR) in mesenchymal stem cells modulates macrophage polarization in asthma[J]. J Immunotoxicol, 2020, 17(1): 21-30.
19	ALOBAIDI A H, ALSAMARAI A M, ALSAMARAI M A. Inflammation in asthma pathogenesis: role of T cells, macrophages, epithelial cells and type 2 inflammation[J]. Antiinflamm Antiallergy Agents Med Chem, 2021, 20(4): 317-332.
20	ABDELAZIZ M H, ABDELWAHAB S F, WAN J, et al. Alternatively activated macrophages; a double-edged sword in allergic asthma[J]. J Transl Med, 2020, 18(1): 58.
21	HASTIE A T, MAUGER D T, DENLINGER L C, et al. Baseline sputum eosinophil + neutrophil subgroups' clinical characteristics and longitudinal trajectories for NHLBI Severe Asthma Research Program (SARP 3) cohort[J]. J Allergy Clin Immunol, 2020, 146(1): 222-226.
22	BU T, WANG L F, YIN Y Q. How do innate immune cells contribute to airway remodeling in COPD progression?[J]. Int J Chron Obstruct Pulmon Dis, 2020, 15: 107-116.
23	HABENER A, GRYCHTOL R, GAEDCKE S, et al. IgA⁺ memory B-cells are significantly increased in patients with asthma and small airway dysfunction[J]. Eur Respir J, 2022, 60(5): 2102130.
24	FANG L, ROTH M. Airway wall remodeling in childhood asthma: a personalized perspective from cell type-specific biology[J]. J Pers Med, 2021, 11(11): 1229.
25	JOHNSON M T, BENSON J C, PATHAK T, et al. The airway smooth muscle sodium/calcium exchanger NCLX is critical for airway remodeling and hyperresponsiveness in asthma[J]. J Biol Chem, 2022, 298(8): 102259.
26	DOLHNIKOFF M, DA SILVA L F, DE ARAUJO B B, et al. The outer wall of small airways is a major site of remodeling in fatal asthma[J]. J Allergy Clin Immunol, 2009, 123(5): 1090-1097.e1.
27	SUN Y, SHI Z Q, LIU B, et al. YKL-40 mediates airway remodeling in asthma via activating FAK and MAPK signaling pathway[J]. Cell Cycle, 2020, 19(11): 1378-1390.
28	O'REILLY R, ULLMANN N, IRVING S, et al. Increased airway smooth muscle in preschool wheezers who have asthma at school age[J]. J Allergy Clin Immunol, 2013, 131(4): 1024-1032, 1032.e1-1032.e16.
29	LI J, WANG X Y, SU Y F, et al. TRIM33 modulates inflammation and airway remodeling of PDGF-BB-induced airway smooth-muscle cells by the Wnt/β-catenin pathway[J]. Int Arch Allergy Immunol, 2022, 183(10): 1127-1136.
30	THAKORE P, EARLEY S. STIM1 is the key that unlocks airway smooth muscle remodeling and hyperresponsiveness during asthma[J]. Cell Calcium, 2022, 104: 102589.
31	MANSON M L, SÄFHOLM J, JAMES A, et al. IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways[J]. J Allergy Clin Immunol, 2020, 145(3): 808-817.e2.
32	GEBSKI E B, ANASPURE O, PANETTIERI R A, et al. Airway smooth muscle and airway hyperresponsiveness in asthma: mechanisms of airway smooth muscle dysfunction[J]. Minerva Med, 2022, 113(1): 4-16.
33	CHIBA Y, SUTO W, SAKAI H. Augmented Pla2g4c/Ptgs2/Hpgds axis in bronchial smooth muscle tissues of experimental asthma[J]. PLoS One, 2018, 13(8): e0202623.
34	苗青, 张静. 生后早期过敏原暴露对哮喘小鼠气道炎症及气道高反应性的影响[J]. 中华微生物学和免疫学杂志, 2021, 41(12): 927-933.
	MIAO Q, ZHANG J. Effects of early postnatal allergen exposure on airway inflammation and airway hyperresponsiveness in asthmatic mice[J]. Chinese Journal of Microbiology and Immunology, 2021, 41(12): 927-933.
35	KOZIOL-WHITE C J, GHOSH A, SANDNER P, et al. Soluble guanylate cyclase agonists induce bronchodilation in human small airways[J]. Am J Respir Cell Mol Biol, 2020, 62(1): 43-48.
36	CHEN Y L, HUANG H Y, LEE C C, et al. Small interfering RNA targeting nerve growth factor alleviates allergic airway hyperresponsiveness[J]. Mol Ther Nucleic Acids, 2014, 3: e158.
37	ALMESHARI M A, ALOBAIDI N Y, SAPEY E, et al. Small airways response to bronchodilators in adults with asthma or COPD: a systematic review[J]. Int J Chron Obstruct Pulmon Dis, 2021, 16: 3065-3082.
38	赵珊, 王浩彦. 小气道功能与气道高反应性的相关性分析[J]. 国际呼吸杂志, 2016, 36(12): 930-935.
	ZHAO S, WANG H Y. Correlation between small airway function and airway hyperresponsiveness[J]. International Journal of Respiration, 2016, 36(12): 930-935.
39	RAJI H, HADDADZADEH SHOUSHTARI M, IDANI E, et al. Forced expiratory flow at 25‒75% as a marker for airway hyper responsiveness in adult patients with asthma-like symptoms[J]. Tanaffos, 2018, 17(2): 90-95.
40	曹菊英, 杨希晨, 刘桂华, 等. 支气管哮喘儿童肺功能检测与评价[J]. 临床肺科杂志, 2011, 16(11): 1703-1704.
	CAO J Y, YANG X C, LIU G H, et al. Pulmonary function testing and evaluation in children with bronchial asthma[J]. Journal of Clinical Pulmonary Medicine, 2011, 16(11): 1703-1704.
41	QIN R, AN J, XIE J, et al. FEF_25-75% is a more sensitive measure reflecting airway dysfunction in patients with asthma: a comparison study using FEF_25‒75% and FEV₁%[J]. J Allergy Clin Immunol Pract, 2021, 9(10): 3649-3659.e6.
42	柴小艺, 冯雍, 蔡栩栩. 肺功能小气道功能评价在儿童哮喘中的应用进展[J]. 国际儿科学杂志, 2022, 49(4): 254-257.
	CHAI X Y, FENG Y, CAI X X. Advances in the evaluation of small airway function of lung function in childhood asthma[J]. International Journal of Pediatrics, 2022, 49(4): 254-257.
43	CALVERLEY P M A, FARRÉ R. Oscillometry: old physiology with a bright future[J]. Eur Respir J, 2020, 56(3): 2001815.
44	LAUHKONEN E, RIIKONEN R, TÖRMÄNEN S, et al. Impulse oscillometry at preschool age is a strong predictor of lung function by flow-volume spirometry in adolescence[J]. Pediatr Pulmonol, 2018, 53(5): 552-558.
45	上海市医学会儿科学分会呼吸学组, 上海儿童医学中心儿科医疗联合体(浦东), 上海智慧儿科临床诊治技术工程技术研究中心. 儿童哮喘小气道功能障碍评估及治疗专家共识[J]. 中华实用儿科临床杂志, 2021, 36(23): 1761-1768.
	Respiratory Group of Pediatric Branch of Shanghai Medical Association, Shanghai Children's Medical Center Pediatric Medical Complex (Shanghai), Pediatric Artificial Intelligence Clinical Application and Research Center, Shanghai Children's Medical Center. Expert consensus on the evaluation and treatment of small airway dysfunction in childhood with asthma[J]. Chinese Journal of Applied Clinical Pediatrics, 2021, 36(23): 1761-1768.
46	LIN L M, CHANG Y J, YANG K D, et al. Small airway dysfunction measured by impulse oscillometry and fractional exhaled nitric oxide is associated with asthma control in children[J]. Front Pediatr, 2022, 10: 877681.
47	FUJISAWA T, YASUI H, AKAMATSU T, et al. Alveolar nitric oxide concentration reflects peripheral airway obstruction in stable asthma[J]. Respirology, 2013, 18(3): 522-527.
48	BARRIOS J, AI X B. Neurotrophins in asthma[J]. Curr Allergy Asthma Rep, 2018, 18(2): 10.
49	ROBINSON P D, SALIMI F, COWIE C T, et al. Ultrafine particle exposure and biomarkers of effect on small airways in children[J]. Environ Res, 2022, 214(Pt 1): 113860.
50	BERRY M, HARGADON B, MORGAN A, et al. Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma[J]. Eur Respir J, 2005, 25(6): 986-991.
51	HOPP R J, WILSON M C, PASHA M A. Small airway disease in pediatric asthma: the who, what, when, where, why, and how to remediate. A review and commentary[J]. Clin Rev Allergy Immuno, 2022, 62(1): 145-159.
52	WANG T Y, ZHOU Q L, SHANG Y X. MiRNA-451a inhibits airway remodeling by targeting cadherin 11 in an allergic asthma model of neonatal mice[J]. Int Immunopharmacol, 2020, 83: 106440.
53	YANG Z C, QU Z H, YI M J, et al. MiR-448-5p inhibits TGF-β1-induced epithelial-mesenchymal transition and pulmonary fibrosis by targeting Six1 in asthma[J]. J Cell Physiol, 2019, 234(6): 8804-8814.
54	JIA Y, FANG X, ZHU X H, et al. IL-13⁺ type 2 innate lymphoid cells correlate with asthma control status and treatment response[J]. Am J Respir Cell Mol Biol, 2016, 55(5): 675-683.
55	AKKOC T. Mesenchymal stem cells in asthma[J]. Adv Exp Med Biol, 2020, 1247: 101-108.

[1]	姜静, 卞勇, 郑吉建, 黄悦. 狭颅症儿童颅骨修补术中出血量的影响因素[J]. 上海交通大学学报（医学版）, 2023, 43(4): 453-458.
[2]	邓云天, 熊文魁, 朱芮, 刘恩梅, 李雪梅, 钟朝晖. 生命早期环境因素暴露与儿童哮喘关系的病例对照研究[J]. 上海交通大学学报（医学版）, 2023, 43(1): 44-51.
[3]	罗雯懿, 陈琳, 袁理, 倪平, 蔡小满, 章雅青. 3~6岁先天性心脏病患儿术后心脏康复水平及其相关因素的Rasch分析[J]. 上海交通大学学报（医学版）, 2022, 42(9): 1303-1310.
[4]	李雯, 李苑, 叶海昀, 张笑笑, 乔彤, 李嫔. 1型糖尿病儿童眼底黄斑区早期微血管变化的观察[J]. 上海交通大学学报（医学版）, 2022, 42(9): 1311-1314.
[5]	户宜, 丁国栋. 上海地区学龄前儿童对羟基苯甲酸酯类物质暴露与肺功能的相关性研究[J]. 上海交通大学学报（医学版）, 2022, 42(8): 1103-1109.
[6]	邢正文, 吴滢, 王雪莉, 王庆煜, 王文婷, 李治, 张彬, 金晶. 儿童CIC重排肉瘤的临床病理特征[J]. 上海交通大学学报（医学版）, 2022, 42(8): 1151-1157.
[7]	康文慧, 陈仪婷, 赵安达, 李荣, 李生慧. 褪黑素在哮喘发病和病程中的作用机制研究进展[J]. 上海交通大学学报（医学版）, 2022, 42(5): 667-672.
[8]	陈仪婷, 赵安达, 李荣, 康文慧, 李生慧. 循环外泌体微RNA在支气管哮喘中的作用综述[J]. 上海交通大学学报（医学版）, 2022, 42(3): 375-380.
[9]	邢正文, 吴滢, 王雪莉, 王庆煜, 王文婷, 李治, 张彬, 金晶. 8例儿童卵巢颗粒细胞瘤临床病理特征及预后分析[J]. 上海交通大学学报(医学版), 2022, 42(2): 192-196.
[10]	林艳艳, 许岩, 李慧. 儿童急性淋巴细胞白血病化学治疗常规药物耐药机制的研究进展[J]. 上海交通大学学报(医学版), 2022, 42(2): 211-217.
[11]	李波, 朱明, 郑吉建. 利多卡因联用对行包皮环切术患儿所需艾司氯胺酮半数有效量的影响[J]. 上海交通大学学报（医学版）, 2022, 42(12): 1706-1711.
[12]	魏逸凡, 朱月钮, 孔祥莓, 许雅雅, 朱晓东. 早期机械通气对小儿膈肌形态与功能的影响[J]. 上海交通大学学报（医学版）, 2022, 42(12): 1712-1719.
[13]	李爱求, 张潇潇, 姜允丽, 肖艳赏, 丁国栋, 吴蓓蓉, 董晓艳. 学龄前儿童反复喘息的相关危险因素分析[J]. 上海交通大学学报（医学版）, 2022, 42(10): 1435-1440.
[14]	刘青, 张娜, 邵静波, 李红, 陈凯, 杜成坎, 王真, 蒋慧. MLL基因重排阳性的儿童急性白血病患者的临床特点及预后分析[J]. 上海交通大学学报(医学版), 2021, 41(7): 903-909.
[15]	刘子豪, 唐文芳, 王辉. 儿童脑肿瘤氨基酸PET显像的研究进展[J]. 上海交通大学学报(医学版), 2021, 41(7): 949-952.