Login Register Cart 0
General Review Article

Neutrophilic Asthma and Potentially Related Target Therapies

Author(s): Pranav Nair* and Kedar S. Prabhavalkar

Volume 21, Issue 4, 2020

Page: [374 - 388] Pages: 15

DOI: 10.2174/1389450120666191011162526

Price: $65

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.

« Previous Next »
Graphical Abstract

[1]
Loerbroks A, Bosch JA, Sheikh A, Yamamoto S, Herr RM. Reports of wheezing and of diagnosed asthma are associated with impaired social functioning: Secondary analysis of the cross-sectional World Health Survey data. J Psychosom Res 2018; 105(105): 52-7.
[http://dx.doi.org/10.1016/j.jpsychores.2017.12.008] [PMID: 29332634]
[2]
Nakagome K, Matsushita S, Nagata M. Neutrophilic inflammation in severe asthma. Int Arch Allergy Immunol 2012; 158(Suppl. 1): 96-102.
[http://dx.doi.org/10.1159/000337801] [PMID: 22627375]
[3]
Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology 2006; 11(1): 54-61.
[http://dx.doi.org/10.1111/j.1440-1843.2006.00784.x] [PMID: 16423202]
[4]
Norzila MZ, Fakes K, Henry RL, Simpson J, Gibson PG. interleukin-8 secretion and neutrophil recruitment accompanies induced sputum eosinophil activation in children with acute asthma. Am J Respir Crit Care Med 2000; 161(31): 769-74.
[http://dx.doi.org/10.1164/ajrccm.161.3.9809071]
[5]
Uddin M, Lau LC, Seumois G, et al. EGF-induced bronchial epithelial cells drive neutrophil chemotactic and anti-apoptotic activity in asthma. PLoS One 2013; 8(9)e72502
[http://dx.doi.org/10.1371/journal.pone.0072502] [PMID: 24039773]
[6]
Yang X, Jiang Y, Wang C. Does IL-17 Respond to the Disordered Lung Microbiome and Contribute to the Neutrophilic Phenotype in Asthma 2016; 2016
[http://dx.doi.org/10.1155/2016/6470364]
[7]
Uddin M, Nong G, Ward J, et al. Prosurvival activity for airway neutrophils in severe asthma. Thorax 2010; 65(8): 684-9.
[http://dx.doi.org/10.1136/thx.2009.120741] [PMID: 20685741]
[8]
Louis R, Djukanovic R. Is the Neutrophil a Worthy Target in Severe Asthma and Chronic Obstructive Pulmonary Disease? Clin Exp Allergy. Journal of the British Society for Allergy and Clinical Immunology 2006; 36(5): 563-7.
[http://dx.doi.org/10.1111/j.1365-2222.2006.02493.x]
[9]
Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax 2002; 57(7): 643-8.
[http://dx.doi.org/10.1136/thorax.57.7.643] [PMID: 12096210]
[10]
McGrath KW, Icitovic N, Boushey HA, et al. Asthma Clinical Research Network of the National Heart, Lung, and Blood Institute. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med 2012; 185(6): 612-9.
[http://dx.doi.org/10.1164/rccm.201109-1640OC] [PMID: 22268133]
[11]
Thomson NC. Novel approaches to the management of noneosinophilic asthma. Ther Adv Respir Dis 2016; 10(3): 211-34.
[http://dx.doi.org/10.1177/1753465816632638] [PMID: 26929306]
[12]
Brooks CR, Gibson PG, Douwes J, Van Dalen CJ, Simpson JL. Relationship between airway neutrophilia and ageing in asthmatics and non-asthmatics. Respirology 2013; 18(5): 857-65.
[http://dx.doi.org/10.1111/resp.12079] [PMID: 23490307]
[13]
Svenningsen S, Nair P. Asthma endotypes and an overview of targeted therapy for asthma. Front Med (Lausanne) 2017; 4(September): 158.
[http://dx.doi.org/10.3389/fmed.2017.00158] [PMID: 29018800]
[14]
Bandyopadhyay A, Roy PP, Saha K, Chakraborty S, Jash D, Saha D. Usefulness of induced sputum eosinophil count to assess severity and treatment outcome in asthma patients. Lung India 2013; 30(2): 117-23.
[http://dx.doi.org/10.4103/0970-2113.110419] [PMID: 23741092]
[15]
Pabreja K, Gibson P, Lochrin AJ, Wood L, Baines KJ, Simpson JL. Sputum colour can identify patients with neutrophilic inflammation in asthma. BMJ Open Respir Res 2017; 4(1) e000236
[http://dx.doi.org/10.1136/bmjresp-2017-000236] [PMID: 29071085]
[16]
Haldar P, Pavord ID. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J Allergy Clin Immunol 2007; 119(5): 1043-52.
[http://dx.doi.org/10.1016/j.jaci.2007.02.042] [PMID: 17472810]
[17]
Paplińska-Goryca M, Grabczak EM, Dąbrowska M, et al. Sputum interleukin-25 correlates with asthma severity: a preliminary study. Postepy Dermatol Alergol 2018; 35(5): 462-9.
[http://dx.doi.org/10.5114/ada.2017.71428] [PMID: 30429702]
[18]
Ray A, Kolls JK. Neutrophilic Inflammation in Asthma and Association with Disease Severity. Trends Immunol 2017; 38(12): 942-54.
[http://dx.doi.org/10.1016/j.it.2017.07.003] [PMID: 28784414]
[19]
Shimoda T, Obase Y, Kishikawa R, Iwanaga T. Influence of cigarette smoking on airway inflammation and inhaled corticosteroid treatment in patients with asthma. Allergy Asthma Proc 2016; 37(4): 50-8.
[http://dx.doi.org/10.2500/aap.2016.37.3944] [PMID: 27401308]
[20]
Cabrera M, Ortiz-Menéndez JC, Garzón B, Barrios L. Need for Emergency Epinephrine to Treat Food Allergy Reactions in Schools in the Hortaleza District in Madrid. J Investig Allergol Clin Immunol 2017; 27(1): 58-60.
[http://dx.doi.org/10.18176/jiaci.0114] [PMID: 28211346]
[21]
Wallace J, D’silva L, Brannan J, Hargreave FE, Kanaroglou P, Nair P. Association between proximity to major roads and sputum cell counts. Can Respir J 2011; 18(1): 13-8.
[http://dx.doi.org/10.1155/2011/920734] [PMID: 21369545]
[22]
Simpson JL, Guest M, Boggess MM, Gibson PG. Occupational exposures, smoking and airway inflammation in refractory asthma. BMC Pulm Med 2014; 14(1): 207.
[http://dx.doi.org/10.1186/1471-2466-14-207] [PMID: 25526871]
[23]
Veres TZ, Rochlitzer S, Braun A. The role of neuro-immune cross-talk in the regulation of inflammation and remodelling in asthma. Pharmacol Ther 2009; 122(2): 203-14.
[http://dx.doi.org/10.1016/j.pharmthera.2009.02.007] [PMID: 19292991]
[24]
Pembrey L, Barreto ML, Douwes J, et al. Understanding asthma phenotypes: the World Asthma Phenotypes (WASP) international collaboration. ERJ Open Res 2018; 4(3): 13-2018.
[http://dx.doi.org/10.1183/23120541.00013-2018] [PMID: 30151371]
[25]
Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 2008; 28(4): 454-67.
[http://dx.doi.org/10.1016/j.immuni.2008.03.004] [PMID: 18400188]
[26]
Xu L, Sun WJ, Jia AJ, et al. MBD2 regulates differentiation and function of Th17 cells in neutrophils- dominant asthma via HIF-1α. J Inflamm (Lond) 2018; 15(1): 15.
[http://dx.doi.org/10.1186/s12950-018-0191-x] [PMID: 30150897]
[27]
Hernandez-pando R, Ph D, Vega MI, et al. NIH Public Access 2012; 66(7): 909-18.
[http://dx.doi.org/10.1111/j.1398- 9995.2011.02594.x.HypoxiaInducible]
[28]
Garth J, Barnes JW, Krick S. Targeting Cytokines as Evolving Treatment Strategies in Chronic Inflammatory Airway Diseases. Int J Mol Sci 2018; 19(11)E3402
[http://dx.doi.org/10.3390/ijms19113402] [PMID: 30380761]
[29]
Liu L, Zhang X, Liu Y, et al. Chitinase-like protein YKL-40 correlates with inflammatory phenotypes, anti-asthma responsiveness and future exacerbations. Respir Res 2019; 20(1): 95.
[http://dx.doi.org/10.1186/s12931-019-1051-9] [PMID: 31113430]
[30]
Pham DL, Ban GY, Kim SH, et al. Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma. Clin Exp Allergy 2017; 47(1): 57-70.
[http://dx.doi.org/10.1111/cea.12859] [PMID: 27883241]
[31]
Pham DL, Kim SH, Losol P, et al. Association of autophagy related gene polymorphisms with neutrophilic airway inflammation in adult asthma. Korean J Intern Med (Korean Assoc Intern Med) 2016; 31(2): 375-85.
[http://dx.doi.org/10.3904/kjim.2014.390] [PMID: 26701229]
[32]
Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG. Systemic upregulation of neutrophil α-defensins and serine proteases in neutrophilic asthma. Thorax 2011; 66(11): 942-7.
[http://dx.doi.org/10.1136/thx.2010.157719] [PMID: 21785157]
[33]
Salvi S, Blomberg A, Rudell B, et al. Acute inflammatory responses in the airways and peripheral blood after short-term exposure to diesel exhaust in healthy human volunteers. Am J Respir Crit Care Med 1999; 159(3): 702-9.
[http://dx.doi.org/10.1164/ajrccm.159.3.9709083] [PMID: 10051240]
[34]
Perret JL, Bonevski B, McDonald CF, Abramson MJ. Smoking cessation strategies for patients with asthma: improving patient outcomes. J Asthma Allergy 2016; 9: 117-28.
[http://dx.doi.org/10.2147/JAA.S85615] [PMID: 27445499]
[35]
Nanzer AM, Chambers ES, Ryanna K, et al. Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion. J Allergy Clin Immunol 2013; 132(2): 297-304.e3.
[http://dx.doi.org/10.1016/j.jaci.2013.03.037] [PMID: 23683514]
[36]
Martineau AR, Cates CJ, Urashima M, et al. Vitamin D for the management of asthma. Cochrane Database Syst Rev [Review] 2016; 9(9) CD011511
[http://dx.doi.org/10.1002/14651858.CD011511.pub2] [PMID: 27595415]
[37]
Bozzetto S, Carraro S, Giordano G, Boner A, Baraldi E. Asthma, allergy and respiratory infections: the vitamin D hypothesis. Allergy 2012; 67(1): 10-7.
[http://dx.doi.org/10.1111/j.1398-9995.2011.02711.x] [PMID: 21933195]
[38]
Jolliffe DA, Greenberg L, Hooper RL, et al. Articles Vitamin D Supplementation to Prevent Asthma Exacerbations: A Systematic Review and Meta-Analysis of Individual Participant Data. Lancet Respiratory 2017; 2600(17): 1-10.
[http://dx.doi.org/10.1016/S2213-2600(17)30306-5]
[39]
Wong EHC, Porter JD, Edwards MR, Johnston SL. The role of macrolides in asthma: current evidence and future directions. Lancet Respir Med 2014; 2(8): 657-70.
[http://dx.doi.org/10.1016/S2213-2600(14)70107-9] [PMID: 24948430]
[40]
Essilfie AT, Horvat JC, Kim RY, et al. Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma. Thorax 2015; 70(5): 458-67.
[http://dx.doi.org/10.1136/thoraxjnl-2014-206067] [PMID: 25746630]
[41]
An TJ, Rhee CK, Kim JH, et al. Effects of Macrolide and Corticosteroid in Neutrophilic Asthma Mouse Model. Tuberc Respir Dis (Seoul) 2018; 81(1): 80-7.
[http://dx.doi.org/10.4046/trd.2017.0108] [PMID: 29332324]
[42]
Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013; 68(4): 322-9.
[http://dx.doi.org/10.1136/thoraxjnl-2012-202698] [PMID: 23291349]
[43]
Essilfie AT, Simpson JL, Dunkley ML, et al. Combined Haemophilus influenzae respiratory infection and allergic airways disease drives chronic infection and features of neutrophilic asthma. Thorax 2012; 67(7): 588-99.
[http://dx.doi.org/10.1136/thoraxjnl-2011-200160] [PMID: 22387445]
[44]
Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet 2017; 390(10095): 659-68.
[http://dx.doi.org/10.1016/S0140-6736(17)31281-3] [PMID: 28687413]
[45]
Al-Sawalha NA, Knoll BJ. Statins in Asthma: A Closer Look into the Pharmacological Mechanism of Action. Pharmacology 2016; 98(5-6): 279-83.
[http://dx.doi.org/10.1159/000449062] [PMID: 27603525]
[46]
Schaafsma D, Dueck G, Ghavami S, et al. The mevalonate cascade as a target to suppress extracellular matrix synthesis by human airway smooth muscle. Am J Respir Cell Mol Biol 2011; 44(3): 394-403.
[http://dx.doi.org/10.1165/rcmb.2010-0052OC] [PMID: 20463291]
[47]
Maneechotesuwan K, Wongkajornsilp A, Adcock IM, Barnes PJ. simvastatin suppresses airway il-17 and upregulates il-10 in patients with stable COPD. Chest 2015; 148(5): 1164-76.
[http://dx.doi.org/10.1378/chest.14-3138] [PMID: 26043025]
[48]
Liu MW, Liu R, Wu HY, et al. Atorvastatin has a protective effect in a mouse model of bronchial asthma through regulating tissue transglutaminase and triggering receptor expressed on myeloid cells-1 expression. Exp Ther Med 2017; 14(2): 917-30.
[http://dx.doi.org/10.3892/etm.2017.4576] [PMID: 28810543]
[49]
Zeki AA, Elbadawi-Sidhu M. Innovations in asthma therapy: is there a role for inhaled statins? Expert Rev Respir Med 2018; 12(6): 461-73.
[http://dx.doi.org/10.1080/17476348.2018.1457437] [PMID: 29575963]
[50]
Tulbah AS, Ong HX, Lee WH, Colombo P, Young PM, Traini D. Biological Effects of Simvastatin Formulated as pMDI on Pulmonary Epithelial Cells. Pharm Res 2016; 33(1): 92-101.
[http://dx.doi.org/10.1007/s11095-015-1766-3] [PMID: 26238046]
[51]
Gallelli L, Falcone D, Cannataro R, et al. Theophylline action on primary human bronchial epithelial cells under proinflammatory stimuli and steroidal drugs: a therapeutic rationale approach. Drug Des Devel Ther 2017; 11: 265-72.
[http://dx.doi.org/10.2147/DDDT.S118485] [PMID: 28176948]
[52]
Hagan A O, Bickel S, Morton R, Jacobson S, Myers J A. Anti-Inflammatory Dosing of Theophylline in the Treatment of Status Asthmaticus in Children 2016; 183-9.
[53]
Spears M, Donnelly I, Jolly L, et al. Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study. Eur Respir J 2009; 33(5): 1010-7.
[http://dx.doi.org/10.1183/09031936.00158208] [PMID: 19196814]
[54]
Calzetta L, Hanania NA, Dini FL, et al. Impact of doxofylline compared to theophylline in asthma: A pooled analysis of functional and clinical outcomes from two multicentre, double-blind, randomized studies (DOROTHEO 1 and DOROTHEO 2). Pulm Pharmacol Ther 2018; 53: 20-6.
[http://dx.doi.org/10.1016/j.pupt.2018.09.007] [PMID: 30219705]
[55]
Bourke JE, Bai Y, Donovan C, Esposito JG, Tan X, Sanderson MJ. Novel small airway bronchodilator responses to rosiglitazone in mouse lung slices. Am J Respir Cell Mol Biol 2014; 50(4): 748-56.
[http://dx.doi.org/10.1165/rcmb.2013-0247OC] [PMID: 24188042]
[56]
Belvisi MG, Hele DJ. Peroxisome proliferator-activated receptors as novel targets in lung disease. Chest 2008; 134(1): 152-7.
[http://dx.doi.org/10.1378/chest.07-0019] [PMID: 18628217]
[57]
Banno A, Reddy AT, Lakshmi SP, Reddy RC. PPARs: key regulators of airway inflammation and potential therapeutic targets in asthma. Nucl Receptor Res 2018; 5: 1-17.
[http://dx.doi.org/10.11131/2018/101306] [PMID: 29450204]
[58]
Zhao Y, Huang Y, He J, et al. Rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, attenuates airway inflammation by inhibiting the proliferation of effector T cells in a murine model of neutrophilic asthma. Immunol Lett 2014; 157(1-2): 9-15.
[http://dx.doi.org/10.1016/j.imlet.2013.11.004] [PMID: 24269293]
[59]
Holden N S, George T, Rider C F, et al. Induction of Regulator of G-Protein Signaling 2 Expression by Long- Acting b 2 - Adrenoceptor Agonists and Glucocorticoids in Human Airway Epithelial Cells S 1-24 2014.
[60]
Stillie R, Farooq SM, Gordon JR, Stadnyk AW. The functional significance behind expressing two IL-8 receptor types on PMN. J Leukoc Biol 2009; 86(3): 529-43.
[http://dx.doi.org/10.1189/jlb.0208125] [PMID: 19564575]
[61]
Kikuchi S, Kikuchi I, Takaku Y, et al. Neutrophilic inflammation and CXC chemokines in patients with refractory asthma. Int Arch Allergy Immunol 2009; 149(Suppl. 1): 87-93.
[http://dx.doi.org/10.1159/000211379] [PMID: 19494512]
[62]
Chapman RW, Minnicozzi M, Celly CS, et al. A novel, orally active CXCR1/2 receptor antagonist, Sch527123, inhibits neutrophil recruitment, mucus production, and goblet cell hyperplasia in animal models of pulmonary inflammation. J Pharmacol Exp Ther 2007; 322(2): 486-93.
[http://dx.doi.org/10.1124/jpet.106.119040] [PMID: 17496165]
[63]
Day RB, Link DC. Regulation of neutrophil trafficking from the bone marrow. Cell Mol Life Sci 2012; 69(9): 1415-23.
[http://dx.doi.org/10.1007/s00018-011-0870-8] [PMID: 22045556]
[64]
Nair P, Aziz-Ur-Rehman A, Radford K. Therapeutic implications of ‘neutrophilic asthma’. Curr Opin Pulm Med 2015; 21(1): 33-8.
[http://dx.doi.org/10.1097/MCP.0000000000000120] [PMID: 25415406]
[65]
Mizutani N, Nabe T, Yoshino S. IL-17A promotes the exacerbation of IL-33-induced airway hyperresponsiveness by enhancing neutrophilic inflammation via CXCR2 signaling in mice. J Immunol 2014; 192(4): 1372-84.
[http://dx.doi.org/10.4049/jimmunol.1301538] [PMID: 24446518]
[66]
Watz H, Uddin M, Pedersen F, et al. Effects of the CXCR2 antagonist AZD5069 on lung neutrophil recruitment in asthma. Pulm Pharmacol Ther 2017; 45: 121-3.
[http://dx.doi.org/10.1016/j.pupt.2017.05.012] [PMID: 28549850]
[67]
Byrne PMO, 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. Lancet Respir Med 2016; 4(10): 797-806.
[http://dx.doi.org/10.1016/S2213-2600(16)30227-2]
[68]
Todd CM, Salter BM, Murphy DM, et al. The effects of a CXCR1/CXCR2 antagonist on neutrophil migration in mild atopic asthmatic subjects. Pulm Pharmacol Ther 2016; 41: 34-9.
[http://dx.doi.org/10.1016/j.pupt.2016.09.005] [PMID: 27640067]
[69]
Leaker B R, Barnes P J, Connor B O. Inhibition of LPS-Induced Airway Neutrophilic Inflammation in Healthy Volunteers with an Oral CXCR2 Antagonist 2013; 1-9.
[http://dx.doi.org/10.1186/1465-9921-14-137]
[70]
Lazaar A L, Sweeney L E, Macdonald A J, Alexis N E, Chen C, Tal-singer R. SB-656933, a Novel CXCR2 Selective Antagonist, Inhibits Ex Vivo Neutrophil Activation and Ozone-Induced Airway Inflammation in Humans WHAT IS ALREADY KNOWN ABOUT 2011.
[http://dx.doi.org/10.1111/j.1365- 2125.2011.03968.x.]
[71]
Hosoki K, Aguilera-Aguirre L, Brasier AR, Kurosky A, Boldogh I, Sur S. Facilitation of allergic sensitization and allergic airway inflammation by pollen-induced innate neutrophil recruitment. Am J Respir Cell Mol Biol 2016; 54(1): 81-90.
[http://dx.doi.org/10.1165/rcmb.2015-0044OC]
[72]
Chaudhuri R, Norris V, Kelly K, et al. Effects of a FLAP inhibitor, GSK2190915, in asthmatics with high sputum neutrophils. Pulm Pharmacol Ther 2014; 27(1): 62-9.
[http://dx.doi.org/10.1016/j.pupt.2013.11.007] [PMID: 24333186]
[73]
Kent SE, Boyce M, Diamant Z, et al. The 5-lipoxygenase-activating protein inhibitor, GSK2190915, attenuates the early and late responses to inhaled allergen in mild asthma. Clin Exp Allergy 2013; 43(2): 177-86.
[http://dx.doi.org/10.1111/cea.12002] [PMID: 23331559]
[74]
Kroegel C, Foerster M. Phosphodiesterase-4 inhibitors as a novel approach for the treatment of respiratory disease: cilomilast. Expert Opin Investig Drugs 2007; 16(1): 109-24.
[http://dx.doi.org/10.1517/13543784.16.1.109] [PMID: 17155857]
[75]
Manallack DT, Hughes RA, Thompson PE. The next generation of phosphodiesterase inhibitors: structural clues to ligand and substrate selectivity of phosphodiesterases. J Med Chem 2005; 48(10): 3449-62.
[http://dx.doi.org/10.1021/jm040217u] [PMID: 15887951]
[76]
Kodimuthali A, Jabaris SSL, Pal M. Recent advances on phosphodiesterase 4 inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. J Med Chem 2008; 51(18): 5471-89.
[http://dx.doi.org/10.1021/jm800582j] [PMID: 18686943]
[77]
Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 2001; 297(1): 267-79.
[PMID: 11259554]
[78]
TORPHY. T. J. Phosphodiesterase Isozymes. Am J Respir Crit Care Med 1998; 157(2): 351-70.
[http://dx.doi.org/10.1164/ajrccm.157.2.9708012] [PMID: 9476844]
[79]
Southworth T, Mason S, Bell A, et al. PI3K, p38 and JAK/STAT signalling in bronchial tissue from patients with asthma following allergen challenge. Biomark Res 2018; 6(1): 14.
[http://dx.doi.org/10.1186/s40364-018-0128-9] [PMID: 29651336]
[80]
Murad HA, Habib HS, Rafeeq MM, Sulaiman MI, Abdulrahman AS, Khabaz MN. Co-inhalation of roflumilast, rather than formoterol, with fluticasone more effectively improves asthma in asthmatic mice. Exp Biol Med (Maywood) 2017; 242(5): 516-26.
[http://dx.doi.org/10.1177/1535370216685006] [PMID: 28056550]
[81]
Jones NA, Boswell-Smith V, Lever R, Page CP. The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro. Pulm Pharmacol Ther 2005; 18(2): 93-101.
[http://dx.doi.org/10.1016/j.pupt.2004.10.001] [PMID: 15649851]
[82]
Hatzelmann A, Morcillo EJ, Lungarella G, et al. Pulmonary pharmacology & therapeutics the preclinical pharmacology of ro fl umilast e a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2010; 23(4): 235-56.
[http://dx.doi.org/10.1016/j.pupt.2010.03.011] [PMID: 20381629]
[83]
Kawamatawong T. Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway diseases. J Thorac Dis 2017; 9(4): 1144-54.
[http://dx.doi.org/10.21037/jtd.2017.03.116] [PMID: 28523172]
[84]
Leaker BR, Singh D, Ali FY, Barnes PJ, O’Connor B. The effect of the novel phosphodiesterase-4 inhibitor MEM 1414 on the allergen induced responses in mild asthma. BMC Pulm Med 2014; 14(1): 166.
[http://dx.doi.org/10.1186/1471-2466-14-166] [PMID: 25351474]
[85]
Villetti G, Carnini C, Battipaglia L, et al. CHF6001 II: a novel phosphodiesterase 4 inhibitor, suitable for topical pulmonary administration--in vivo preclinical pharmacology profile defines a potent anti-inflammatory compound with a wide therapeutic window. J Pharmacol Exp Ther 2015; 352(3): 568-78.
[http://dx.doi.org/10.1124/jpet.114.220558] [PMID: 25576073]
[86]
Moretto N, Caruso P, Bosco R, et al. CHF6001 I: a novel highly potent and selective phosphodiesterase 4 inhibitor with robust anti-inflammatory activity and suitable for topical pulmonary administration. J Pharmacol Exp Ther 2015; 352(3): 559-67.
[http://dx.doi.org/10.1124/jpet.114.220541] [PMID: 25576075]
[87]
Tralau-Stewart CJ, Williamson RA, Nials AT, et al. GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: in vitro, kinetic, and in vivo characterization. J Pharmacol Exp Ther 2011; 337(1): 145-54.
[http://dx.doi.org/10.1124/jpet.110.173690] [PMID: 21205923]
[88]
Lin CH, Hong YC, Kao SH. Aeroallergen Der p 2 induces apoptosis of bronchial epithelial BEAS-2B cells via activation of both intrinsic and extrinsic pathway. Cell Biosci 2015; 5(1): 71.
[http://dx.doi.org/10.1186/s13578-015-0063-5] [PMID: 26697166]
[89]
Down K, Amour A, Baldwin IR, et al. optimization of novel indazoles as highly potent and selective inhibitors of phosphoinositide 3-kinase δ for the treatment of respiratory disease. J Med Chem 2015; 58(18): 7381-99.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00767] [PMID: 26301626]
[90]
Khindri S, Cahn A, Begg M, et al. A multicentre, randomized, double-blind, placebo-controlled, crossover study to investigate the efficacy, safety, tolerability, and pharmacokinetics of repeat doses of inhaled nemiralisib in adults with persistent, uncontrolled asthma. J Pharmacol Exp Ther 2018; 367(3): 405-13.
[http://dx.doi.org/10.1124/jpet.118.249516] [PMID: 30217958]
[91]
Campa CC, Silva RL, Margaria JP, et al. Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis. Nat Commun 2018; 9(1): 5232.
[http://dx.doi.org/10.1038/s41467-018-07698-6] [PMID: 30542075]
[92]
Southworth T, Plumb J, Gupta V, et al. Anti-inflammatory potential of PI3Kδ and JAK inhibitors in asthma patients. Respir Res 2016; 17(1): 124.
[http://dx.doi.org/10.1186/s12931-016-0436-2] [PMID: 27716212]
[93]
Barnes PJ. Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease. Pharmacol Rev 2016; 68(3): 788-815.
[http://dx.doi.org/10.1124/pr.116.012518] [PMID: 27363440]
[94]
Newcomb DC, Peebles RS Jr. Th17-mediated inflammation in asthma. Curr Opin Immunol 2013; 25(6): 755-60.
[http://dx.doi.org/10.1016/j.coi.2013.08.002] [PMID: 24035139]
[95]
Zhu L, Ciaccio CE, Casale TB. Potential new targets for drug development in severe asthma. World Allergy Organ J 2018; 11(1): 30.
[http://dx.doi.org/10.1186/s40413-018-0208-1] [PMID: 30386455]
[96]
Busse WW, 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. Am J Respir Crit Care Med 2013; 188(11): 1294-302.https://doi.org/10.10.1164/rccm.201212-2318OC
[http://dx.doi.org/10.1164/rccm.201212-2318OC] [PMID: 24200404]
[97]
Hellings PW, Kasran A, Liu Z, et al. Interleukin-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma. Am J Respir Cell Mol Biol 2003; 28(1): 42-50.
[http://dx.doi.org/10.1165/rcmb.4832] [PMID: 12495931]
[98]
Lévy M, Celermajer D, Szezepanski I, Boudjemline Y, Bonnet D. Do tertiary paediatric hospitals deal with the same spectrum of paediatric pulmonary hypertension as multicentre registries? Eur Respir J 2013; 41(1): 236-9.
[http://dx.doi.org/10.1183/09031936.00114212] [PMID: 23277521]
[99]
Dejager L, Dendoncker K, Eggermont M, et al. Neutralizing tnf α restores glucocorticoid sensitivity in a mouse model of neutrophilic airway inflammation No. January 2015; 1-14.
[100]
Michel O, Huy P, Dinh D, Doyen V, Corazza F. Anti-tnf inhibits the airways neutrophilic inflammation induced by inhaled endotoxin in human. BMC Pharmacol Toxicol 2014; 15: 60.
[http://dx.doi.org/10.1186/2050-6511-15-60]
[101]
Lee HS, Park HW, Song WJ, et al. TNF-α enhance Th2 and Th17 immune responses regulating by IL23 during sensitization in asthma model. Cytokine 2016; 79: 23-30.
[http://dx.doi.org/10.1016/j.cyto.2015.12.001] [PMID: 26717421]
[102]
Holgate ST, Noonan M, Chanez P, et al. Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised. Controlled Trial 2011; pp. 1352-9.
[103]
Lambrecht BN, Hammad H. The Immunology of Asthma. Nat Immunol 2015; 16(1): 45-56.
[http://dx.doi.org/10.1038/ni.3049]
[104]
Ullah MA, Sukkar M, Ferreira M, Phipps S. 53. Cytokine 2014; 70(1): 40.
[http://dx.doi.org/10.1016/j.cyto.2014.07.060]
[105]
Choy D F, Hart K M, Borthwick L A, et al. T H 2 and T H 17 Inflammatory pathways are reciprocally regulated in Asthma 2015; 5(301)
[http://dx.doi.org/10.1126/scitranslmed.aab3142]
[106]
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 , pharmacokinetics , and immunogenicity of bits7201a , a bispecific antibody targeting IL-13 and IL- 17 in Healthy Volunteers 2019; 1-16.
[107]
Pelaia C, Vatrella A, Gallelli L, et al. Dupilumab for the treatment of asthma. Expert Opin Biol Ther 2017; 17(12): 1565-72.
[http://dx.doi.org/10.1080/14712598.2017.1387245] [PMID: 28990423]
[108]
Krueger JG, Ferris LK, Menter A, et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2015; 136(1): 116-124.e7.
[http://dx.doi.org/10.1016/j.jaci.2015.01.018] [PMID: 25769911]
[109]
Hernandez ML, Mills K, Almond M, et al. IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers. J Allergy Clin Immunol 2015; 135(2): 379-85.
[http://dx.doi.org/10.1016/j.jaci.2014.07.039] [PMID: 25195169]
[110]
Menzella F, Bertolini F, Biava M, Galeone C, Scelfo C, Caminati M. Severe refractory asthma: current treatment options and ongoing research. Drugs Context 2018; 7 212561
[http://dx.doi.org/10.7573/dic.212561] [PMID: 30534175]
[111]
Chen Z, Bai FF, Han L, et al. Targeting Neutrophils in Severe Asthma via Siglec-9. Int Arch Allergy Immunol 2018; 175(1-2): 5-15.
[http://dx.doi.org/10.1159/000484873] [PMID: 29306942]
[112]
Oberle AJ, Mathur P. Precision medicine in asthma: the role of bronchial thermoplasty. Curr Opin Pulm Med 2017; 23(3): 254-60.
[http://dx.doi.org/10.1097/MCP.0000000000000372] [PMID: 28319473]
[113]
Bonta PI, Chanez P, Annema JT, Shah PL, Niven R. Bronchial Thermoplasty in Severe Asthma: Best Practice Recommendations from an Expert Panel. Respiration 2018; 95(5): 289-300.
[http://dx.doi.org/10.1159/000488291] [PMID: 29669351]
[114]
Trivedi A, Pavord ID, Castro M. Bronchial thermoplasty and biological therapy as targeted treatments for severe uncontrolled asthma. Lancet Respir Med 2016; 4(7): 585-92.
[http://dx.doi.org/10.1016/S2213-2600(16)30018-2] [PMID: 27230825]
[115]
Wesolowska-Andersen A, Seibold MA. Airway molecular endotypes of asthma: dissecting the heterogeneity. Curr Opin Allergy Clin Immunol 2015; 15(2): 163-8.
[http://dx.doi.org/10.1097/ACI.0000000000000148] [PMID: 25961390]
[116]
Simpson JL, Phipps S, Baines KJ, Oreo KM, Gunawardhana L, Gibson PG. Elevated expression of the NLRP3 inflammasome in neutrophilic asthma. Eur Respir J 2014; 43(4): 1067-76.
[http://dx.doi.org/10.1183/09031936.00105013] [PMID: 24136334]
[117]
Zeki AA, Bratt JM, Chang KY, et al. Intratracheal instillation of pravastatin for the treatment of murine allergic asthma: a lung-targeted approach to deliver statins. Physiol Rep 2015; 3(5): 1-22.
[http://dx.doi.org/10.14814/phy2.12352] [PMID: 25969462]
[118]
Matera MG, Page C, Cazzola M. Doxofylline is not just another theophylline! Int J Chron Obstruct Pulmon Dis 2017; 12: 3487-93.
[http://dx.doi.org/10.2147/COPD.S150887] [PMID: 29255355]
[119]
Spina D. Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease. Drugs 2003; 63(23): 2575-94.
[http://dx.doi.org/10.2165/00003495-200363230-00002] [PMID: 14636078]
[120]
Franciosi LG, Diamant Z, Banner KH, et al. Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med 2013; 1(9): 714-27.
[http://dx.doi.org/10.1016/S2213-2600(13)70187-5] [PMID: 24429275]
[121]
Eger KA, Bel EH. The emergence of new biologics for severe asthma. Curr Opin Pharmacol 2019; 46: 108-15.
[http://dx.doi.org/10.1016/j.coph.2019.05.005] [PMID: 31229937]
[122]
Pepper AN, Renz H, Casale TB, Garn H. Biologic Therapy and Novel Molecular Targets of Severe Asthma. J Allergy Clin Immunol Pract 2017; 5(4): 909-16.
[http://dx.doi.org/10.1016/j.jaip.2017.04.038] [PMID: 28689841]
[123]
Corren J, Parnes JR, Wang L, et al. Tezepelumab in Adults with Uncontrolled Asthma. N Engl J Med 2017; 377(10): 936-46.
[http://dx.doi.org/10.1056/NEJMoa1704064] [PMID: 28877011]
[124]
Panettieri RA Jr, Sjöbring U, Péterffy A, et al. Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials. Lancet Respir Med 2018; 6(7): 511-25.
[http://dx.doi.org/10.1016/S2213-2600(18)30184-X] [PMID: 29792288]
[125]
Hanania NA, Noonan M, Corren J, et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax 2015; 70(8): 748-56.
[http://dx.doi.org/10.1136/thoraxjnl-2014-206719] [PMID: 26001563]
[126]
Busse WW. Biological treatments for severe asthma: A major advance in asthma care. Allergol Int 2019; 68(2): 158-66.
[http://dx.doi.org/10.1016/j.alit.2019.01.004] [PMID: 30792118]

Rights & Permissions Print Cite
Article Metrics
95
6
1
World Malaria Day
© 2024 Bentham Science Publishers | Privacy Policy