Abstract
Background: Neutrophilic asthma is generally associated with the absence of eosinophils and activation of non- predominant type 2 immunological pathways. It involves bronchial inflammation followed by different degrees of airway remodeling. Neutrophilic inflammation activates specific cellular and molecular pathways due to inhalation of environmental trigger factors such as exhaust fumes, cigarette smoke, occupation-related agents, and infections.
Objective: This review discusses the involvement of neutrophils in asthma and potentially related target therapies.
Results: Corticosteroid resistance is the hallmark of neutrophilic asthma which increases disease severity and leads to difficult-to-control asthma. Patients with neutrophil-dominant asthma are characterized by low levels of (or absence of) Th2 cytokines. Due to the shortage of effective treatments for neutrophilic asthma newer biologics are being developed that target type 2 asthma symptoms and phenotypes. Understanding different biomarkers, inflammatory pathways and treatment strategies involved in neutrophilic asthma will help to decrease adverse effects related to corticosteroid insensitivity. Better insight of targets involved in neutrophilic inflammation can lead to improved therapies.
Conclusion: Further evaluation and clinical trials of emerging biologics involved in neutrophilic asthma needs to be performed before bringing them into clinical practice.
Keywords: Neutrophilic asthma, targets, non-eosinophilic, cytokines, airway hyperreactivity, inflammation.
Graphical Abstract
[http://dx.doi.org/10.1016/j.jpsychores.2017.12.008] [PMID: 29332634]
[http://dx.doi.org/10.1159/000337801] [PMID: 22627375]
[http://dx.doi.org/10.1111/j.1440-1843.2006.00784.x] [PMID: 16423202]
[http://dx.doi.org/10.1164/ajrccm.161.3.9809071]
[http://dx.doi.org/10.1371/journal.pone.0072502] [PMID: 24039773]
[http://dx.doi.org/10.1155/2016/6470364]
[http://dx.doi.org/10.1136/thx.2009.120741] [PMID: 20685741]
[http://dx.doi.org/10.1111/j.1365-2222.2006.02493.x]
[http://dx.doi.org/10.1136/thorax.57.7.643] [PMID: 12096210]
[http://dx.doi.org/10.1164/rccm.201109-1640OC] [PMID: 22268133]
[http://dx.doi.org/10.1177/1753465816632638] [PMID: 26929306]
[http://dx.doi.org/10.1111/resp.12079] [PMID: 23490307]
[http://dx.doi.org/10.3389/fmed.2017.00158] [PMID: 29018800]
[http://dx.doi.org/10.4103/0970-2113.110419] [PMID: 23741092]
[http://dx.doi.org/10.1136/bmjresp-2017-000236] [PMID: 29071085]
[http://dx.doi.org/10.1016/j.jaci.2007.02.042] [PMID: 17472810]
[http://dx.doi.org/10.5114/ada.2017.71428] [PMID: 30429702]
[http://dx.doi.org/10.1016/j.it.2017.07.003] [PMID: 28784414]
[http://dx.doi.org/10.2500/aap.2016.37.3944] [PMID: 27401308]
[http://dx.doi.org/10.18176/jiaci.0114] [PMID: 28211346]
[http://dx.doi.org/10.1155/2011/920734] [PMID: 21369545]
[http://dx.doi.org/10.1186/1471-2466-14-207] [PMID: 25526871]
[http://dx.doi.org/10.1016/j.pharmthera.2009.02.007] [PMID: 19292991]
[http://dx.doi.org/10.1183/23120541.00013-2018] [PMID: 30151371]
[http://dx.doi.org/10.1016/j.immuni.2008.03.004] [PMID: 18400188]
[http://dx.doi.org/10.1186/s12950-018-0191-x] [PMID: 30150897]
[http://dx.doi.org/10.1111/j.1398- 9995.2011.02594.x.HypoxiaInducible]
[http://dx.doi.org/10.3390/ijms19113402] [PMID: 30380761]
[http://dx.doi.org/10.1186/s12931-019-1051-9] [PMID: 31113430]
[http://dx.doi.org/10.1111/cea.12859] [PMID: 27883241]
[http://dx.doi.org/10.3904/kjim.2014.390] [PMID: 26701229]
[http://dx.doi.org/10.1136/thx.2010.157719] [PMID: 21785157]
[http://dx.doi.org/10.1164/ajrccm.159.3.9709083] [PMID: 10051240]
[http://dx.doi.org/10.2147/JAA.S85615] [PMID: 27445499]
[http://dx.doi.org/10.1016/j.jaci.2013.03.037] [PMID: 23683514]
[http://dx.doi.org/10.1002/14651858.CD011511.pub2] [PMID: 27595415]
[http://dx.doi.org/10.1111/j.1398-9995.2011.02711.x] [PMID: 21933195]
[http://dx.doi.org/10.1016/S2213-2600(17)30306-5]
[http://dx.doi.org/10.1016/S2213-2600(14)70107-9] [PMID: 24948430]
[http://dx.doi.org/10.1136/thoraxjnl-2014-206067] [PMID: 25746630]
[http://dx.doi.org/10.4046/trd.2017.0108] [PMID: 29332324]
[http://dx.doi.org/10.1136/thoraxjnl-2012-202698] [PMID: 23291349]
[http://dx.doi.org/10.1136/thoraxjnl-2011-200160] [PMID: 22387445]
[http://dx.doi.org/10.1016/S0140-6736(17)31281-3] [PMID: 28687413]
[http://dx.doi.org/10.1159/000449062] [PMID: 27603525]
[http://dx.doi.org/10.1165/rcmb.2010-0052OC] [PMID: 20463291]
[http://dx.doi.org/10.1378/chest.14-3138] [PMID: 26043025]
[http://dx.doi.org/10.3892/etm.2017.4576] [PMID: 28810543]
[http://dx.doi.org/10.1080/17476348.2018.1457437] [PMID: 29575963]
[http://dx.doi.org/10.1007/s11095-015-1766-3] [PMID: 26238046]
[http://dx.doi.org/10.2147/DDDT.S118485] [PMID: 28176948]
[http://dx.doi.org/10.1183/09031936.00158208] [PMID: 19196814]
[http://dx.doi.org/10.1016/j.pupt.2018.09.007] [PMID: 30219705]
[http://dx.doi.org/10.1165/rcmb.2013-0247OC] [PMID: 24188042]
[http://dx.doi.org/10.1378/chest.07-0019] [PMID: 18628217]
[http://dx.doi.org/10.11131/2018/101306] [PMID: 29450204]
[http://dx.doi.org/10.1016/j.imlet.2013.11.004] [PMID: 24269293]
[http://dx.doi.org/10.1189/jlb.0208125] [PMID: 19564575]
[http://dx.doi.org/10.1159/000211379] [PMID: 19494512]
[http://dx.doi.org/10.1124/jpet.106.119040] [PMID: 17496165]
[http://dx.doi.org/10.1007/s00018-011-0870-8] [PMID: 22045556]
[http://dx.doi.org/10.1097/MCP.0000000000000120] [PMID: 25415406]
[http://dx.doi.org/10.4049/jimmunol.1301538] [PMID: 24446518]
[http://dx.doi.org/10.1016/j.pupt.2017.05.012] [PMID: 28549850]
[http://dx.doi.org/10.1016/S2213-2600(16)30227-2]
[http://dx.doi.org/10.1016/j.pupt.2016.09.005] [PMID: 27640067]
[http://dx.doi.org/10.1186/1465-9921-14-137]
[http://dx.doi.org/10.1111/j.1365- 2125.2011.03968.x.]
[http://dx.doi.org/10.1165/rcmb.2015-0044OC]
[http://dx.doi.org/10.1016/j.pupt.2013.11.007] [PMID: 24333186]
[http://dx.doi.org/10.1111/cea.12002] [PMID: 23331559]
[http://dx.doi.org/10.1517/13543784.16.1.109] [PMID: 17155857]
[http://dx.doi.org/10.1021/jm040217u] [PMID: 15887951]
[http://dx.doi.org/10.1021/jm800582j] [PMID: 18686943]
[PMID: 11259554]
[http://dx.doi.org/10.1164/ajrccm.157.2.9708012] [PMID: 9476844]
[http://dx.doi.org/10.1186/s40364-018-0128-9] [PMID: 29651336]
[http://dx.doi.org/10.1177/1535370216685006] [PMID: 28056550]
[http://dx.doi.org/10.1016/j.pupt.2004.10.001] [PMID: 15649851]
[http://dx.doi.org/10.1016/j.pupt.2010.03.011] [PMID: 20381629]
[http://dx.doi.org/10.21037/jtd.2017.03.116] [PMID: 28523172]
[http://dx.doi.org/10.1186/1471-2466-14-166] [PMID: 25351474]
[http://dx.doi.org/10.1124/jpet.114.220558] [PMID: 25576073]
[http://dx.doi.org/10.1124/jpet.114.220541] [PMID: 25576075]
[http://dx.doi.org/10.1124/jpet.110.173690] [PMID: 21205923]
[http://dx.doi.org/10.1186/s13578-015-0063-5] [PMID: 26697166]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00767] [PMID: 26301626]
[http://dx.doi.org/10.1124/jpet.118.249516] [PMID: 30217958]
[http://dx.doi.org/10.1038/s41467-018-07698-6] [PMID: 30542075]
[http://dx.doi.org/10.1186/s12931-016-0436-2] [PMID: 27716212]
[http://dx.doi.org/10.1124/pr.116.012518] [PMID: 27363440]
[http://dx.doi.org/10.1016/j.coi.2013.08.002] [PMID: 24035139]
[http://dx.doi.org/10.1186/s40413-018-0208-1] [PMID: 30386455]
[http://dx.doi.org/10.1164/rccm.201212-2318OC] [PMID: 24200404]
[http://dx.doi.org/10.1165/rcmb.4832] [PMID: 12495931]
[http://dx.doi.org/10.1183/09031936.00114212] [PMID: 23277521]
[http://dx.doi.org/10.1186/2050-6511-15-60]
[http://dx.doi.org/10.1016/j.cyto.2015.12.001] [PMID: 26717421]
[http://dx.doi.org/10.1038/ni.3049]
[http://dx.doi.org/10.1016/j.cyto.2014.07.060]
[http://dx.doi.org/10.1126/scitranslmed.aab3142]
[http://dx.doi.org/10.1080/14712598.2017.1387245] [PMID: 28990423]
[http://dx.doi.org/10.1016/j.jaci.2015.01.018] [PMID: 25769911]
[http://dx.doi.org/10.1016/j.jaci.2014.07.039] [PMID: 25195169]
[http://dx.doi.org/10.7573/dic.212561] [PMID: 30534175]
[http://dx.doi.org/10.1159/000484873] [PMID: 29306942]
[http://dx.doi.org/10.1097/MCP.0000000000000372] [PMID: 28319473]
[http://dx.doi.org/10.1159/000488291] [PMID: 29669351]
[http://dx.doi.org/10.1016/S2213-2600(16)30018-2] [PMID: 27230825]
[http://dx.doi.org/10.1097/ACI.0000000000000148] [PMID: 25961390]
[http://dx.doi.org/10.1183/09031936.00105013] [PMID: 24136334]
[http://dx.doi.org/10.14814/phy2.12352] [PMID: 25969462]
[http://dx.doi.org/10.2147/COPD.S150887] [PMID: 29255355]
[http://dx.doi.org/10.2165/00003495-200363230-00002] [PMID: 14636078]
[http://dx.doi.org/10.1016/S2213-2600(13)70187-5] [PMID: 24429275]
[http://dx.doi.org/10.1016/j.coph.2019.05.005] [PMID: 31229937]
[http://dx.doi.org/10.1016/j.jaip.2017.04.038] [PMID: 28689841]
[http://dx.doi.org/10.1056/NEJMoa1704064] [PMID: 28877011]
[http://dx.doi.org/10.1016/S2213-2600(18)30184-X] [PMID: 29792288]
[http://dx.doi.org/10.1136/thoraxjnl-2014-206719] [PMID: 26001563]
[http://dx.doi.org/10.1016/j.alit.2019.01.004] [PMID: 30792118]