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J Zhejiang Univ (Med Sci)  2021, Vol. 50 Issue (1): 123-130    DOI: 10.3724/zdxbyxb-2021-0030
The role of neutrophils in asthma
CHEN Fei(),YU Min,ZHONG Yonghong,HUA Wen,HUANG Huaqiong()
Department of Respiratory and Critical Care Medicine,the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China
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Bronchial asthma is a chronic respiratory disease,characterized by airway inflammation,airway hyperresponsiveness,reversible airway obstruction and airway remodeling,in which a variety of cells including airway inflammatory cells and structural cells are involved. Previous studies have shown that asthma is mainly driven by Th2 cytokines IL-4,IL-5,and IL-13,leading to airway eosinophil inflammation. With further research,however,it has been found that neutrophils are also closely related to asthma. Numbers of neutrophils are elevated in airway through increased chemotaxis and decreased apoptosis,which is earlier than eosinophils,leading to airway neutrophilic inflammation. Neutrophils can produce elastase,myeloperoxidase,neutrophil extra- cellular traps,chemokines and cytokines,participating in the occurrence and development of asthma. The antagonists against these molecules,such as anti-IL-8 receptor antibody,anti-IL-17 antibody,and DNase,have shown positive effects on neutrophilic asthma,but further studies are needed to support their clinical application. This article mainly reviews the role of neutrophils in asthma and related mechanisms.

Key wordsNeutrophils      Asthma      Neutrophilic asthma      Therapy; Review     
Received: 14 September 2020      Published: 14 May 2021
CLC:  R562.1  
Corresponding Authors: HUANG Huaqiong     E-mail:;
Cite this article:

CHEN Fei,YU Min,ZHONG Yonghong,HUA Wen,HUANG Huaqiong. The role of neutrophils in asthma. J Zhejiang Univ (Med Sci), 2021, 50(1): 123-130.

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关键词: 中性粒细胞,  哮喘,  中性粒细胞哮喘,  治疗; 综述 
Figure 1 Molecular mechanisms of neutrophils in asthma
[1]   PETERS M C, WENZEL S E . Intersection of biology and therapeutics:type 2 targeted therapeutics for adult asthma[J]. Lancet, 2020, 395(10221): 371-383.
doi: 10.1016/S0140-6736(19)33005-3
[2]   ZHANG J, ZHU Z, ZUO X, et al. The role of NTHi colonization and infection in the pathogenesis of neutrophilic asthma[J]. Respir Res, 2020, 21(1): 170.
doi: 10.1186/s12931-020-01438-5
[3]   GRUNWELL J R, STEPHENSON S T, TIROUVAN- ZIAM R, et al. Children with neutrophil-predominant severe asthma have proinflammatory neutrophils with enhanced survival and impaired clearance[J]. J Allergy Clin Immunol-Practice, 2019, 7(2): 516-525.e6.
doi: 10.1016/j.jaip.2018.08.024
[4]   KHAN M A, ALI Z S, SWEEZEY N, et al. Progression of cystic fibrosis lung disease from childhood to adulthood:neutrophils,neutrophil extracellular trap (NET) formation,and net degradation[J]. Genes, 2019, 10(3): 183.
doi: 10.3390/genes10030183
[5]   MANTOVANI A, CASSATELLA M A, COSTANTINI C, et al. Neutrophils in the activation and regulation of innate and adaptive immunity[J]. Nat Rev Immunol, 2011, 11(8): 519-531.
doi: 10.1038/nri3024
[6]   RADERMECKER C,LOUIS R,BUREAU F,et al. Role of neutrophils in allergic asthma[J]. Curr Opin Immunol,2018,54:28–34.DOl:10.1016/j.coi. 2018.05.006 .
[7]   LIU W, CHEN H, ZHANG D, et al. A retrospective study of clinical features of cough variant asthma in Chinese adults[J]. Allergy Asthma Clin Immunol, 2019, 15(1): 3.
doi: 10.1186/s13223-019-0318-5
[8]   SIMPSON J L, SCOTT R, BOYLE M J, et al. Inflamma- tory subtypes in asthma:Assessment and identification using induced sputum[J]. Respirology, 2006, 11(1): 54-61.
doi: 10.1111/j.1440-1843.2006.00784.x
[9]   TAYLOR S L,LEONG L E X,CHOO J M,et al. Inflam- matory phenotypes in patients with severe asthma are associated with distinct airway microbiology[J]. J Allergy Clin Immunol,2018,141(1):94–103.e115.DOl:10.1016/j.jaci.2017.03.044 .
[10]   NAIR P, PRABHAVALKAR K S . Neutrophilic asthma and potentially related target therapies[J]. Curr Drug Targets, 2020, 21(4): 374-388.
doi: 10.2174/1389450120666191011162526
[11]   NAIR P, AZIZ-UR-REHMAN A, RADFORD K . Therapeutic implications of ‘neutrophilic asthma’ [J]. Curr Opin Pulmonary Med, 2015, 21(1): 33-38.
doi: 10.1097/MCP.0000000000000120
[12]   PANETTIERI JR. R A . Neutrophilic and pauci-immune phenotypes in severe asthma[J]. Immunol Allergy Clinics North Am, 2016, 36(3): 569-579.
doi: 10.1016/j.iac.2016.03.007
[13]   SEYS S F, LOKWANI R, SIMPSON J L, et al. New insights in neutrophilic asthma[J]. Curr Opin Pulmonary Med, 2019, 25(1): 113-120.
doi: 10.1097/MCP.0000000000000543
[14]   PATEL K K, WEBLEY W C . Respiratory chlamydia infection induce release of hepoxilin A3 and histamine production by airway neutrophils[J]. Front Immunol, 2018,
doi: 10.3389/fimmu.2018.02357
[15]   WANG G, PANG Z, CHEN-YU HSU A, et al. Combined treatment with SB203580 and dexamethasone suppresses non-typeable Haemophilus influenzae-induced Th17 inflammation response in murine allergic asthma[J]. Eur J Pharmacol, 2019, 172623.
doi: 10.1016/j.ejphar.2019.172623
[16]   RADERMECKER C, SABATEL C, VANWINGE C, et al. Locally instructed CXCR4hi neutrophils trigger environment-driven allergic asthma through the release of neutrophil extracellular traps[J]. Nat Immunol, 2019, 20(11): 1444-1455.
doi: 10.1038/s41590-019-0496-9
[17]   GENG X, WANG X, LUO M, et al. Induction of neutrophil apoptosis by a Bcl-2 inhibitor reduces particulate matter-induced lung inflammation[J]. Aging, 2018, 10(6): 1415-1423.
doi: 10.18632/aging.101477
[18]   PANG L,ZOU S,SHI Y,et al. Apigenin attenuates PM2.5-induced airway hyperresponsiveness and inflammation by down-regulating NF-κB in murine model of asthma[J]. Int J Clin Exp Pathol,2019,12(10):3700–3709 .
[19]   SHORE S A . Mechanistic basis for obesity-related increases in ozone-induced airway hyperresponsi- veness in mice[J]. Ann ATS, 2017, 14(Supplement_5): S357-S362.
doi: 10.1513/AnnalsATS.201702-140AW
[20]   RAY A, KOLLS J K . Neutrophilic inflammation in asthma and association with disease severity[J]. Trends Immunol, 2017, 38(12): 942-954.
doi: 10.1016/
[21]   MATSUSHIMA H, GENG S, LU R, et al. Neutrophil differentiation into a unique hybrid population exhibiting dual phenotype and functionality of neutrophils and dendritic cells[J]. Blood, 2013, 121(10): 1677-1689.
doi: 10.1182/blood-2012-07-445189
[22]   ZHAN C, XU R, LIU J, et al. Increased sputum IL-17A level in non-asthmatic eosinophilic bronchitis[J]. Lung, 2018, 196(6): 699-705.
doi: 10.1007/s00408-018-0166-y
[23]   WHITEHEAD G S,KANG H S,THOMAS S Y,et al. Therapeutic suppression of pulmonary neutrophilia and allergic airway hyperresponsiveness by a RORγt inverse agonist[J/OL]. JCI Insight,2019,5(14):e125528.DOl:10.1172/jci.insight.125528 .
[24]   WITOWSKI J, KSI??EK K, J?RRES A . Interleukin-17:a mediator of inflammatory responses[J]. Cell Mol Life Sci, 2004, 61(5): 567-579.
doi: 10.1007/s00018-003-3228-z
[25]   LUCHERINI O M, LOPALCO G, CANTARINI L, et al. Critical regulation of Th17 cell differentiation by serum amyloid-A signalling in Behcet’s disease[J]. Immunol Lett, 2018, 38-44.
doi: 10.1016/j.imlet.2018.10.013
[26]   DIMITROVA D, YOUROUKOVA V, IVANOVA-TODOROVA E, et al. Serum levels of IL-5,IL-6,IL-8,IL-13 and IL-17A in pre-defined groups of adult patients with moderate and severe bronchial asthma[J]. Respiratory Med, 2019, 144-154.
doi: 10.1016/j.rmed.2019.06.024
[27]   PAL K, FENG X, STEINKE J W, et al. Leukotriene A4 hydrolase activation and leukotriene B4 production by eosinophils in severe asthma[J]. Am J Respir Cell Mol Biol, 2019, 60(4): 413-419.
doi: 10.1165/rcmb.2018-0175OC
[28]   ELLER M C N, VERGANI K P, SARAIVA-ROMANHOLO B M, et al. Can inflammatory markers in induced sputum be used to detect phenotypes and endotypes of pediatric severe therapy-resistant asthma?[J]. Pediatr Pulmonol, 2018, 53(9): 1208-1217.
doi: 10.1002/ppul.24075
[29]   PINTARD C, BEN KHEMIS M, LIU D, et al. Apocynin prevents GM-CSF-induced-ERK1/2 activation and -neutrophil survival independently of its inhibitory effect on the phagocyte NADPH oxidase NOX2[J]. Biochem Pharmacol, 2020, 113950.
doi: 10.1016/j.bcp.2020.113950
[30]   HILLIARD K A, BLAHO V A, JACKSON C D, et al. Leukotriene B4 receptor BLT1 signaling is critical for neutrophil apoptosis and resolution of experimental Lyme arthritis[J]. FASEB J, 2020, 34(2): 2840-2852.
doi: 10.1096/fj.201902014R
[31]   MCCRACKEN J M, ALLEN L A H . Regulation of human neutrophil apoptosis and lifespan in health and disease[J]. J Cell Death, 2014, JCD.S11038.
doi: 10.4137/JCD.S11038
[32]   BARCELLOS-DE-SOUZA P,CANETTI C,BARJA-FIDALGO C,et al. Leukotriene B(4) inhibits neutrophil apoptosis via NADPH oxidase activity: redox control of NF-κB pathway and mitochondrial stability[J]. Biochim Biophys Acta,2012,1823(10):1990–1997.DOl:10.1016/j.bbamcr.2012. 07.012 .
[33]   顾晓菲,陈鑫淼,陈慧君,等. S100A8/RAGE、Caveolin-1在中性粒细胞性支气管哮喘大鼠中的作用及罗红霉素对其表达的影响[J]. 中华结核和呼吸杂志,2019,42(11):845–851. DOI: 10.3760/cma.j.issn.1001-0939.2019.11.012 .
[34]   KIM D H, CHOI E, LEE J S, et al. House dust mite allergen regulates constitutive apoptosis of normal and asthmatic neutrophils via toll-like receptor 4 [J/OL]. PLoS One, 2015, 10(5): e0125983.
doi: 10.1371/journal.pone.0125983
[35]   KIM D H, GU A, LEE J S, et al. Suppressive effects of S100A8 and S100A9 on neutrophil apoptosis by cytokine release of human bronchial epithelial cells in asthma[J]. Int J Med Sci, 2020, 17(4): 498-509.
doi: 10.7150/ijms.37833
[36]   WENG Q, ZHU C, ZHENG K, et al. Early recruited neutrophils promote asthmatic inflammation exacerbation by release of neutrophil elastase[J]. Cellular Immunol, 2020, 104101.
doi: 10.1016/j.cellimm.2020.104101
[37]   TOUSSAINT M,JACKSON D J,SWIEBODA D,et al. Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation[J]. Nat Med,2017,23(6):681–691.DOl:10.1038/nm. 4332 .
[38]   WEERAPPULI P D, LOUTTIT C, KOJIMA T, et al. Extracellular trap-mimicking DNA‐histone mesostructures synergistically activate dendritic cells[J/OL]. Adv Healthcare Mater, 2019, 8(22): 1900926.
doi: 10.1002/adhm.201900926
[39]   MONTESEIRíN J. Neutrophils and asthma[J]. J Investig Allergol Clin Immunol,2009,19(5):340–354 .
[40]   GRZELA K, LITWINIUK M, ZAGORSKA W, et al. Airway remodeling in chronic obstructive pulmonary disease and asthma:the role of matrix metallopro- teinase-9[J]. Arch Immunol Ther Exp, 2016, 64(1): 47-55.
doi: 10.1007/s00005-015-0345-y
[41]   SIMPSON J L, SCOTT R J, BOYLE M J, et al. Differential proteolytic enzyme activity in eosinophilic and neutrophilic asthma[J]. Am J Respir Crit Care Med, 2005, 172(5): 559-565.
doi: 10.1164/rccm.200503-369OC
[42]   CUI H, HUANG J, LU M, et al. Antagonistic effect of vitamin E on nAl2O3-induced exacerbation of Th2 and Th17-mediated allergic asthma via oxidative stress[J]. Environ Pollut, 2019, 1519-1531.
doi: 10.1016/j.envpol.2019.06.092
[43]   LI Y, ZHANG L, WANG X, et al. Effect of Syringic acid on antioxidant biomarkers and associated inflam- matory markers in mice model of asthma[J]. Drug Dev Res, 2019, 80(2): 253-261.
doi: 10.1002/ddr.21487
[44]   KIM S H, UUGANBAYAR U, TRINH H K T, et al. Evaluation of neutrophil activation status according to the phenotypes of adult asthma[J]. Allergy Asthma Immunol Res, 2019, 11(3): 381.
doi: 10.4168/aair.2019.11.3.381
[45]   KEATINGS V M, BARNES P J . Granulocyte activation markers in induced sputum:comparison between chronic obstructive pulmonary disease,asthma,and normal subjects[J]. Am J Respir Crit Care Med, 1997, 155(2): 449-453.
doi: 10.1164/ajrccm.155.2.9032177
[46]   ALI I, KHAN S N, CHATZICHARALAMPOUS C, et al. Catalase prevents myeloperoxidase self-destruction in response to oxidative stress[J]. J Inorg Biochem, 2019, 110706.
doi: 10.1016/j.jinorgbio.2019.110706
[47]   MOSCHONAS I C, TSELEPIS A D . The pathway of neutrophil extracellular traps towards atherosclerosis and thrombosis[J]. Atherosclerosis, 2019, 9-16.
doi: 10.1016/j.atherosclerosis.2019.06.919
[48]   LACHOWICZ-SCROGGINS M E, DUNICAN E M, CHARBIT A R, et al. Extracellular DNA,neutrophil extracellular traps,and inflammasome activation in severe asthma[J]. Am J Respir Crit Care Med, 2019, 199(9): 1076-1085.
doi: 10.1164/rccm.201810-1869OC
[49]   MURCIA R Y, VARGAS A, LAVOIE J P . The interleukin-17 induced activation and increased survival of equine neutrophils is insensitive to glucocorticoids [J/OL]. PLoS One, 2016, 11(5): e0154755.
doi: 10.1371/journal.pone.0154755
[50]   张星慧,常晓悦. 中性粒细胞性哮喘与其相关细胞因子[J]. 国际呼吸杂志,2017,37(23):1815–1818. DOI:10.3760/cma.j.issn.1673-436X.2017.23.011 .
[51]   RODRíGUEZ-CERDEIRA C,GONZáLEZ-CESPóN J L,MARTíNEZ-HERRERA E,et al. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management[J]. G Ital Dermatol Venereol,2020. DOI: 10.23736/S0392-0488.20. 06580-3 .
[52]   LIANG L, HUR J, KANG J Y, et al. Effect of the anti-IL-17 antibody on allergic inflammation in an obesity-related asthma model[J]. Korean J Intern Med, 2018, 33(6): 1210-1223.
doi: 10.3904/kjim.2017.207
[53]   BUSSE W W, HOLGATE S, KERWIN E, et al. Randomized,double-blind,placebo-controlled study of brodalumab,a human anti–IL-17 receptor monoclonal antibody,in moderate to severe asthma[J]. Am J Respir Crit Care Med, 2013, 188(11): 1294-1302.
doi: 10.1164/rccm.201212-2318OC
[54]   STATON T L, PENG K, OWEN R, et al. A phase I,randomized,observer-blinded,single and multiple ascending-dose study to investigate the safety,phar- macokinetics,and immunogenicity of BITS7201A,a bispecific antibody targeting IL-13 and IL-17,in healthy volunteers[J]. BMC Pulm Med, 2019, 19(1): 5.
doi: 10.1186/s12890-018-0763-9
[55]   TODD C M, SALTER B M, MURPHY D M, et al. The effects of a CXCR1/CXCR2 antagonist on neutrophil migration in mild atopic asthmatic subjects[J]. Pulm Pharmacol Ther, 2016, 34-39.
doi: 10.1016/j.pupt.2016.09.005
[56]   NAIR P,GAGA M,ZERVAS E,et al. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized,placebo-controlled clinical trial[J]. Clin Exp Allergy,2012,42(7):1097–1103. DOl:10.1111/j.1365-2222.2012.04014.x .
[57]   WATZ H,UDDIN M,PEDERSEN F,et al. Effects of the CXCR2 antagonist AZD5069 on lung neutrophil recruitment in asthma[J]. Pulm Pharmacol Ther,2017,45:121–123. DOl:10.1016/j.pupt.2017.05.012 .
[58]   O’BYRNE P M, METEV H, PUU M, et al. Efficacy and safety of a CXCR2 antagonist,AZD5069,in patients with uncontrolled persistent asthma:a randomised,double-blind,placebo-controlled trial[J]. Lancet Respiratory Med, 2016, 4(10): 797-806.
doi: 10.1016/S2213-2600(16)30227-2
[59]   AN T J, RHEE C K, KIM J H, et al. Effects of macrolide and corticosteroid in neutrophilic asthma mouse model[J]. Tuberc Respir Dis, 2018, 81(1): 80.
doi: 10.4046/trd.2017.0108
[60]   PANETTIERI R A JR. The role of neutrophils in asthma[J]. Immunol Allergy Clin North Am,2018,38(4):629–638. DOl:10.1016/j.iac.2018.06.005 .
[61]   LOVERDOS K, BELLOS G, KOKOLATOU L, et al. Lung microbiome in asthma:current perspectives[J]. JCM, 2019, 8(11): 1967.
doi: 10.3390/jcm8111967
[1] HUA Wen, HUANG Huaqiong, SHEN Huahao. Interpretation of 2016 asthma management and prevention guideline[J]. J Zhejiang Univ (Med Sci), 2016, 45(5): 447-452.
[2] LI Tingting, KE Yuehai, CHENG Hongqiang. Reasearch progress on the role of neutrophils in asthma[J]. J Zhejiang Univ (Med Sci), 2016, 45(5): 544-549.
[3] SONG Shun-de, TANG Hui-fang . Progress in PDE4 targeted therapy for inflammatory diseases[J]. J Zhejiang Univ (Med Sci), 2014, 43(3): 353-358.
[4] . Preventive effect of IL-18 gene modified mature dendritic cells vaccine on airway inflammation in mouse asthma model[J]. J Zhejiang Univ (Med Sci), 2011, 40(2): 176-183.
[5] . CRTH2 antagonist ameliorates airway inflammation in rats with asthma [J]. J Zhejiang Univ (Med Sci), 2010, 39(1): 64-70.
[6] . Identification of differentially expressed genes in rat asthma model by suppression subtractive hybridization technology[J]. J Zhejiang Univ (Med Sci), 2009, 38(4): 362-369.
[7] Zheng Yixiong, Xie Qiangmin, Yang Qiuhuo. Effects of Bambuterol on Pulmonary Mechanical Function in Sensitized Guinea Pigs[J]. J Zhejiang Univ (Med Sci), 1998, 27(6): 241-244.
[8] Zhao Menghui, Zhang Lifen, Zhang Weiping. A MODEL OF AIRWAY ALLERGIC INFLAMMATION IN THE SD RATS[J]. J Zhejiang Univ (Med Sci), 1997, 26(3): 100-102,121.
[9] Zhang Weiping, Lu Zhiyong, Wu Renyi, et al. CHARACTERISTICS OF AIRWAY REACTIVITY IN CONSCIOUS AND UNRESTRAINED GUINEA PIGS[J]. J Zhejiang Univ (Med Sci), 1997, 26(1): 1-5.
[10] Zhang Lifen and Bian Rulian. EFFECT OF PLATELETS ON HYPERREACTIVITY OF ISOLATED AIRWAY IN GUINEA PIGS[J]. J Zhejiang Univ (Med Sci), 1996, 25(3): 97-99.
[11] Chen Xiaoyou, Tiang Peiwen, Kao Yan, et al. ADRENAL CORTEX FUNCTION INASTHMATIC CHILDREN[J]. J Zhejiang Univ (Med Sci), 1995, 24(3): 122-123,125.
[12] Pan Cunmei, Wang Xu, Lu Hang, et al. INCREASED SUPEROXIDE ANION IN THE PERIPHERAL NEUTROPHILS OF ASTHMATIC CHILDREN[J]. J Zhejiang Univ (Med Sci), 1994, 23(6): 244-245,264.