Journal of Pulmonary Medicine & Respiratory Research Category: Medical Type: Review Article

Mechanisms of Interleukin -17 in the Pathogenesis of Neutrophilic Asthma

Nightingale Syabbalo1*
1 Professor of Medicine and Physiology, Copperbelt University, Kitwe, Zambia

*Corresponding Author(s):
Nightingale Syabbalo
Professor Of Medicine And Physiology, Copperbelt University, Kitwe, Zambia
Tel:+260 966486117,

Received Date: May 15, 2020
Accepted Date: May 22, 2020
Published Date: May 30, 2020


Asthma is a complex chronic airway disease with several distinct phenotypes characterized by different immunopathological pathways, clinical presentation, physiology, comorbidities, biomarker of allergic inflammation, and response to treatment. Approximately 10% of patients with asthma have severe refractory disease, which is difficult to control on high doses of inhaled corticosteroids, and long-acting β2-agonists. About 50% of these individuals suffer from neutrophilic asthma. Neutrophilic asthma is a phenotype of asthma that is severe and persistent, with frequent exacerbations, and is characterized by fixed airway obstruction. It is associated with comorbidities such as respiratory infections, obesity, gastroesophageal reflux disease, and obstructive sleep apnea. Immunopathologically, it is characterized by the presence of high levels of neutrophils in the lungs and airways. Interleukin-17 secreted by Th17 cells, plays a key role in the pathogenesis of neutrophilic asthma by expressing the secretion of chemoattractant cytokines, and chemokines for the recruitment and activation of neutrophils. Activated neutrophils produce oxidative bursts, releasing multiple proteinases, cytokines, chemokines, and reactive oxygen species which cause airway epithelial cell injury, inflammation, and hyperresponsiveness. During respiratory infections, and allergic inflammation, neutrophils can release neutrophil extracellular traps and cytoplasts, which can damage epithelial cells leading to further airway inflammation. Neutrophilic asthma is unresponsive to high dose inhaled corticosteroids, and probably to precision novel anti-IgE, interleukin and interleukin monoclonal antibody therapies. There is need for targeted precision biologics, and other treatment modalities for these patients.


Chemokines; Cytokines; Interleukin-17; Monoclonal antibodies; Neutrophilic asthma


Act1: adaptor protein nuclear factor (NF)-κ activator

AHR: airway hyperresponsiveness

ARDS: adult respiratory distress syndrome

BAL: bronchoalveolar lavage

CF: cystic fibrosis

COPD: Chronic obstructive pulmonary disease

CXCL: C-X-C motif chemokine ligand

DPP-4: dipeptidyl peptidase-4

FEF 25-75%: forced expiratory flow at 25% to 75% points

FeNO: fractional expired nitric oxide

FEV1: forced expiratory volume in 1 sec

FVC: forced vital capacity

GERD: gastroeosophageal reflux disease

GM-CSF: granulocyte/monocyte colony-stimulating factor

GRO-α: growth-related oncogene α

ICS: inhaled corticosteroids

IFN-γ: interferon-γ

LABA: long acting beta-adrenoceptor agent

LAMA: long acting muscarinic antagonist

IL: interleukin

ILC-3: type 3 innate lymphoid cell

LTB4: leukotriene B4

MAP: mitogen-activated protein

MIP-1α: macrophage inflammatory protein 1-α

MMP: matrix metalloproteinases

MPO: myeloperoxidase

NETS: neutrophil extracellular traps

NF-?B: nuclear factor-?B

NO: nitric oxide

OCS: oral corticosteroids

OSA: obstructive sleep apnoea

PAF: platelet activating factor

PGE2: prostaglandin E2

RORγt: retinoic acid-related orphan receptor γ, thymus specific

ROS: reactive oxygen species

RV: rhinoviruses

SABA: short acting beta-adrenoceptor agent

TGF-β: transforming growth factor-β

Th2: T-helper type 2 cells

Th17: T-helper type 17 cells

TNF-α: tumour necrosis factor-α

TSLP: Thymic stromal lymphopoietin

TXB2: thromboxane B2


Asthma is a significant public health problem, affecting more than 300 million individuals globally [1]. It is a complex chronic airway disease with several distinct phenotypes, characterized by different immunopathological pathways, clinical features, physiology, comorbidities, biomarker of allergic inflammation, and response to treatment [1-4]. It has now become common practice to phenotype asthma for precision and targeted therapies, because asthmatic patients respond to the standard treatment differently. There are several proposed distinct clinical phenotypes of asthma, such as childhood-onset allergic asthma, adult-onset eosinophilic asthma, neutrophilic asthma, Exercise-Induced Asthma (EIA), obesity-related asthma, and Aspirin-Exacerbated Respiratory Disease (AERD) [5-12]. Among these phenotypes of asthma, are patients with severe persistent asthma whose disease is refractory to the standard treatment, including high doses of Inhaled Corticosteroids (ICS), Long-Acting β2-Agonists (LABA), and Leukotriene Receptor Antagonists (LTRA) [5,7,9,14]. Severe asthma is a debilitating form of asthma, which afflicts about 10% of asthma patients [13]. It has a late-onset, and is related to respiratory infections, hormonal changes, or environmental exposures, but it can develop in childhood, often associated with allergies [13]. Patients with severe asthma typically have the lowest quality of life [14] the highest risk for morbidity and mortality [13-15] and consume the majority of healthcare resources [13].

Severe refractory asthma encompasses several cellular and molecular phenotypes of asthma, including eosinophilic, neutrophilic, paucigranulocytic, and mixed granulocytic asthma phenotypes [6]. Eosinophilic asthma is a very well defined and established phenotype of asthma [5,6,9,10] whereas, neutrophilic asthma is less defined, and has a complex pathogenesis.

Approximately 50% of patients with asthma have an eosinophilic inflammatory type [16], whereas the remaining patients show a non-eosinophilic phenotype, which include neutrophilic, paucigranulocytic, and mixed granulocytic. McGrath et al [17] have reported that non-eosinophilic asthma, including neutrophilic asthma can be observed in patients with severe asthma, but also in approximately half of patients with mild-to-moderate asthma.

Neutrophilic asthma is characterized by severe persistent disease, frequent exacerbations, and fixed airway obstruction. It is associated with comorbidities such as respiratory infections, obesity, Gastroesophageal Reflux Disease (GERD), and Obstructive Sleep Apnea (OSA) [14], which require treatment in order to achieve asthma control. Neutrophilic asthma is unresponsive to standard treatment with Inhaled Corticosteroids (ICS), Long-Acting β2-Agonists (LABA), Leukotriene Receptor Antagonists (LTRA), mast cell stabilizing agents [7,14,18,19] and probably to the new biologics [20]. The clinical, and diagnostic features of neutrophilic asthma are summarized in table 1.

Adult on-set, most cases after 20 years

Less atopic

Less severe exacerbations compared to eosinophilic asthma

Co-morbidities: obesity, smoking, GERD, OSA

Sputum neutrophil count, 40-70%; eosinophil count <2-3%

Low FeNO <30 ppb - biomamarker of eosinophilic asthma

Low periostin levels - indicator of IL-13 inflammatory activity

High hydrogen sulfide levels

Less subepithelial basement membrane thickness - indicator of IL-13 and IL-25 inflammatory activity

Fixed airway obstruction (low FEV1)

Low post-bronchodilator response to β2-gonists

Less responsive to methacholine bronchoprovocation tests

Corticosteroid unresponsiveness

Table 1: Clinical and diagnostic characteristics of neutrophilic asthma

Abbreviations: GRD, gastroeosophageal reflux disease; OSA, obstructive sleep apnoea; FeNO, fractional expired nitric oxide; FEV1, forced expired volume in 1 sec.

Interleukin-17 (IL-17 also termed IL-17A) plays a key role in the pathophysiology of neutrophilic asthma. IL-17 and other family members are produced mainly by Th17 cells, but other cell can also secrete IL-17 in the lungs. IL-17 induces the transcription of several cytokines, chemokines, adhesion molecules, and growth factors. Chemoattractant cytokines, and chemokines recruit and activate neutrophils into the airways leading to neutrophilic asthma.

The major role of neutrophils in the lung is respiratory defense against bacterial and fungi, but unfortunately, activated neutrophils can produce proteases, Reactive Oxygen Species (ROS), cytokines, and chemokines which can lead to epithelial injury, airway inflammation and hyperresponsiveness, culminating to severe neutrophilic asthma. Neutrophils upon provocation by viral and bacterial infections or allergic inflammation, can generate Neutrophils Extracellular Traps (NETs), inflammasomes, and cytoplasts, which can further orchestrate airway injury, hyperreactivity, and can lead to severe obstructive disease [21].

This review discusses the production of IL-17 and other IL-17 family members by Th17 cells; IL-17 immunopathological roles; IL-17 signaling pathways; and IL-17 collaborating cytokines (IL-1β, IL-6, IL-8, IL-21, and IL-23) in the pathophysiology of severe neutrophilic asthma.


T helper 17 (Th17) cells were first identified in 2005 as the main producer of the IL-17 [22,23]. Th17 cells also produce IL-17F, IL-22, IL-21 and IL-26, and to a lesser extent IL-6, GM-CSF, and TNF-β [24-30]. The differentiation of Th17 cells from naïve T cells is regulated by the combination of IL-6 and Transforming Growth Factor (TGF)-β [31-37]. The presence of both IL-6 and TGF-β is required for the upregulation of a specific Th17 cell transcription factor, retinoic acid Receptor-related Orphan Receptor (ROR)-γt [33,34]. The transcription factor RORγt is necessary for Th17 cytokine production and for the expression of the IL-23 receptor complex [34]. Interleukin-23 is required for expansion, stabilization, and proliferation of Th17 cells in order to produce chemoattractant cytokines, and chemokines [38,39]. In addition, IL-23 prolongs the expression of Th17 cells signature cytokines, such as IL-17, IL-22, and GM-CSF that induce tissue pathology and mediates chronic inflammation. It also promotes the survival, and maintenance of Th17 cells [38,39]. Interleukin-21 produced by Th17 cells themselves, acts in a positive feedback loop to differentiate more Th17 cells [40]. Signal Transducer and Activator of Transcription 3 (STAT 3) appears to be essential for the differentiation of Th17 cells [40,41]. Interleukin-1β is essential in the early differentiation and conversion of Fox3+ T cells into IL-17-producing cells [42,43].


Interleukin-17 is also secreted by other activated immune cells, such as dendritic cells, CD8+ T cells, δγ T cells, natural killer cells, invariant natural killer T cells, lymphoid tissue inducer cells, and type 3 innate lymphoid cells [44-50]. Additionally, haematopoietic and non-haematopoietic cells, such as eosinophils, neutrophils, monocytes, macrophages, and bronchial fibroblasts can secrete IL-17, under certain circumstances [51-54]. Because of the large number of cells producing IL-17, it becomes very difficult to target any specific cell type. Moreover, most of these cells produce a plethora of inflammatory mediators, which could make precision therapeutic targeting difficult.


Interleukin-17 (IL-17) plays a key role in the pathogenesis of neutrophilic asthma, via induction and expression of cytokines, chemokines, adhesion molecule, and growth factors which propagate neutrophil recruitment and activation into the airways. Interleukin-17, synonymous to IL-17A was initially identified as Cytotoxic T-Lymphocyte-associated Antigen 8 (CTLA-8) in 1993 by Rouvier and colleagues [55]. Subsequent characterization revealed that this cytokine was produced by a special type of T helper cells different from Th1 and Th2 known as Th17 cells, and thus renamed as IL-17 [56-58]. Latter genomic sequencing led to the discovery of additional IL-17 family members totaling six, namely IL-17A (synonymous to IL-17), IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25), and IL-17F [59-63].

IL-17 is disulfide-linked homodimeric glycoprotein consisting of 155 amino acids with a molecular weight of 35 kDa; but heterodimers composed of IL-17A and IL-17F, as well as IL-17F homodimers exist [64,65]. IL-17A homodimer produce more pathophysiologic responses than the heterodimer or the IL-17F homodimer [62,64, 65]. Among the IL-17 family members, IL-17F has the highest homology (55%) with IL-17A [62,66,67] and IL-25 has the least homology (17%) [62,67]. Moreover, IL-25 immunopathologically behaves as a Th2 cytokine similar to the other “alarmin” cytokines, such as IL33 and TSLP. IL-17A and IL-17F have similar pathophysiological roles, although IL-17 is about 10-30 times as potent as IL-17F [64]. IL-17 is the most studied family member [59,62] particularly in the pathogenesis of rheumatoid arthritis [67-69] and psoriasis [70-73] and to a lesser extent in the immunopathology of neutrophilic asthma [6,9,10,16,20].

Interleukin-17 signaling 

Interleukin-17 family cytokines signal via a receptor family that is distinct from other known cytokine receptors [57,74]. There are five IL-17 family member receptors, namely IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE, all of which are single-transmembrane receptors with conserved structural features [59]. Structurally, all the receptors have two extracellular fibronectin II-like domains, and a conserved cytoplasmic motif “SEFIR” domain. The SEFIR (similar expression to fibroblast growth factor genes and IL-17Rs protein family) is critical for triggering downstream signaling events [59]. 

Interleukin-17 acts by stimulating a heterodimer receptor complex constituted by an IL-17 receptor A (IL-17RA), and IL-17 receptor C (IL-17RC) receptor sub-units [62,75-80]. The signaling is via the adaptor protein nuclear factor (NF)-κ activator (Act1), and downstream to more generic intracellular signaling proteins [81-83]. The signaling compounds may include tumor necrosis factor receptor associated factor -2, -3, and -6; TGF-activated kinase-1 and mitogen-activated protein kinases, such as c-jun N-terminal kinase, extracellular-regulated kinase, and p38 [80,82-84]. Tumor-necrosis factor receptor associated factor (TRAF6) is critical for the activation of the NF-?B, and MAPK pathways [85]. The signaling adaptor Act1, which also contains the SEFIR domain, is essential for mediating IL-117R signaling [86,87]. Further downstream signaling pathways finally result in the induction of expression of cytokines, chemokines, and growth factors by IL-17.

The major role of IL-17 and IL-17F in the pathogenesis of neutrophilic asthma is to induce the expression of chemokines, cytokines, and growth factors, which recruit, activate and promote neutrophil degranulation in the airways [88,89]. Some of these mediators cause airway epithelial injury, goblet metaplasia and mucus hypersecretion, hyperresponsiveness, airway smooth muscle proliferation [90] and airway remodeling, which lead to severe airway obstruction and corticosteroid resistance. IL-17 per se plays a role in subepithelial fibrosis, and airway remodeling [91]. Table 2 shows the list of cytokines, chemokines, and lipid mediators induced by interleukin-17. 





Interleukin-6 (IL-6)

CXCL1 (Gro-α)

Leukotriene B4

Prostaglandin E2

IL-8 (CXCL8)

CXCL2 (Gro-β)















Tumor necrosis factor-α (TNF-α)




Transforming growth factor-β (TGF-β)




Granulocyte colony-stimulating factor (G-CSF)




Granulocyte macrophage colony-stimulating factor (GM-CSF)




Table 2: Cytokines, and chemokines expressed by interleukin-17


Neutrophils are polymorphonuclear leukocytes that have a fundamental role to play in innate immune response [88,92]. Neutrophils act as the first line of defense against pathogens, such as bacteria, fungi and perhaps viruses, and participate in the resolution of inflammation. However, neutrophils also contribute to immunopathology of many diseases including respiratory diseases, such as cystic fibrosis, Adult Respiratory Distress Syndrome (ARDS), and neutrophilic asthma.

Activated neutrophils produce oxidative bursts, releasing multiple proteases, cytokines, chemokines, lipid mediators, cathepsin G, myeloperoxidase, and cytotoxic Reactive Oxygen Species (ROS) that lead to airway epithelial cell injury, inflammation, and hyperresponsiveness. The mediators are also responsible for goblet cell hyperplasia and mucus hypersecretion, airway smooth muscle proliferation and remodeling [93]. The chemoattractant mediators, such as CXCL1, CXCL2, CXCL6, CXCL8 (IL-8), LTB4, PAF, thromboxane’s further orchestrate neutrophil recruitment, migration and activation, thus amplifying the neutrophilic airway inflammation [94]. Neutrophils produce ROS which lead to an increase in transcription of IL-8 by epithelial cells, further propagating the chemoattractant neutrophilic response [95]. Inflammatory mediators, such as neutrophil proteases (elastase, cathepsin G, metalloproteinase-9, proteinase-3), and ROS act synergistically to cause the immunopathological features of neutrophilic asthma outlined in table 3.



Lipid derivatives

Interleukin 1α (IL-1α)


Leukotriene B4 (LTB4)



Prostaglandin E2 (PGE2)



Platelet activating factor

IL-8 (CXCL8)


Thromboxane B2 (TXB2)

IL-17 and IL-17F



Interferon-γ (IFN-γ)



Tumor necrosis factor-α (NF-α)



Macrophage inflammatory protein 1-α (MIP-1α)



Table 3: Chemoattractant mediators associated with neutrophilic airway inflammation

There is sufficient evidence to support the roles of mediators secreted by neutrophils in the pathogenesis of severe neutrophilic asthma. Several studies have documented increased concentrations of neutrophil active mediators, such as IL-8, elastase, Matrix Metalloproteinase-9 (MMP-9), Leukotriene B4 (LTB4), IL-17A, TNF-α, and GM-CSF in plasma, BAL fluid, and bronchial epithelial-conditioned media derived from patients with severe neutrophilic asthma [6,96-103]. In an elegant study, Grunwell et al [104] have demonstrated that children with neutrophilic-predominant asthma have proinflammatory neutrophils with enhanced survival. They have also reported that, children with neutrophilic asthma have quantitatively significantly increased levels of a wide variety of cytokines (IL-1β, IL-6, IL-8); chemokines (CXCL2, CXCL3, CXCL4), myeloperoxidase, and elastase in their BAL fluid.

a. Metalloproteases

Metalloprotease-9 is one of the most investigated inflammatory mediators in asthma. Elevated levels of MMP-9 have been found in induced sputum, and BAL fluid from patients with asthma, and the levels correlated with neutrophil numbers [104] and the severity of asthma [105] Wenzel et el [106] have suggested that localized tissue MMP-9 deposition in the lungs may lead to subepithelial basement membrane thickening, fixed airflow obstruction, and severe asthma.

b. Neutrophil elastase

Neutrophil elastase is one of the most cytotoxic proteins produced by activated neutrophils forms the primary granules. It has been implicated in all the pathophysiological aspects of severe neutrophilic asthma. The immunopathological roles of elastase include airway epithelial injury, increased vascular permeability, hyperplasia of bronchial sub mucus glands and hypersecretion of mucus, bronchoconstriction, and hyperresponsiveness [107]. Neutrophil elastase can induce goblet cell metaplasia, mucus hypersecretion, which is a hallmark of severe asthma. It can also induce airway smooth muscle proliferation [108] and has been implicated in airway remodeling [109].

Neutrophil elastase level has been shown to be elevated in bronchial secretions, and in induced sputum in asthmatic patients compared to healthy controls, especially during exacerbations [110,111].

c. Myeloperoxidase

Myeloperoxidase (MPO) released from neutrophil primary granules can react with hydrogen peroxide (H2O2) generated during respiratory bursts, producing hypochlorous acid (HOCl), and other reactive oxygen species [112]. The ROS are crucial for microbial activity, and antigen presentation, but play deleterious role in causing injury to lung tissue during neutrophilic inflammatory process [89,90]. MPO levels have been shown to be elevated in the BAL fluid of patients with asthma compared to healthy subjects [113,114].

d. Lipid mediators

Neutrophils can synthesize lipid mediators such as and leukotrienes (LTB4), and platelet activating factor (PAF). They are also able to produce prostaglandins (PGE2), and thromboxane’s (TXB2) via cyclooxygenase enzyme systems [115,116]. Lipid mediators play an important role in neutrophil migration and activation in the airway inflammation process.

e. Reactive oxygen species 

Activated neutrophils are the major source of reactive oxygen species, such as hydrogen peroxide (H2O2), hypochlorous acid (HOCl), and superoxide radical (O2-) in allergic inflammation. ROS act synergistically with neutrophil proteases to cause lung tissue damage, sub mucus gland hyperplasia and mucus secretion, and airway hyperreactivity [117-121].

In vitro stimulation of neutrophils from atopic asthmatic patients with inophore A2318, and the chemoattractant fMLP have been shown to produce higher level of ROS compared to non-atopic subjects [117,119]. Tanazawa et al [120] have reported that the production of free oxygen radicals was inversely proportional to measures of airway obstruction, e.g., FEV1. The levels of O2-, however, are related to bronchial hyperresponsiveness to methacholine challenge [120]. Furthermore, higher levels of ROS have been reported during asthma attacks and exacerbations, thus implicating ROS in the pathogenesis of severe neutrophilic asthma, and in promoting exacerbations. Loukides and colleagues [121] have reported an increase in hydrogen peroxide in expired breath condensates from patients with asthma, which correlated with airway inflammation and asthma severity.

Neutrophil proteases, such as elastase, cathepsin G, and protease-3 may induce airway inflammation through activation of eosinophils to produce superoxide’s, cytokines, and chemokines, thus aggravating neutrophilic asthma [122]. Thus, during neutrophilic asthma, there is collaborative cross-talk between neutrophils and eosinophils, leading to more severe neutrophilic airway inflammation.

f. Treatment options for neutrophilic asthma

Neutrophilic asthma is a very difficult phenotype of asthma to treat. It is unresponsive to high dose inhaled corticosteroids, and to the new biologics targeted at IgE (omalizumab), and Th2 cytokines, such as IL-5 (mepolizumab, reslizumab, benralizumab), and IL-4/IL-13 (dupilumab), which are effective in the treatment of eosinophilic asthma, and are steroid-sparing [123-127].

Neutrophilic asthma is characterized by chronic neutrophilic airway inflammation, frequent exacerbation and fixed airflow obstruction. It is therefore, logical to add-on treatment with long-acting drug with broad pharmacodynamic and therapeutic actions, such as Long-acting Muscarinic Antagonists (LAMA), and selective long-acting theophyllines (Table 4).





IL-7R, IL-17 mAbs

Brodalumab, secukinumab


p19 subunit of IL-23


IL-8 (CXCL8)

CXCLR2 blockade

AZD5069, SCH527123


IL-1β blockade

Anakinra, canakinumab


TNF-β blockade

Etanercept, golimumab


p38 kinase blockade


Phosphodiesterase 4

Phosphodiesterase 4 inhibition


Macrolide antibiotics


Azithromycin, clarithromycin


Muscarinic receptor blockade


Table 4: Pharmacological interventions in neutrophilic asthma

Abbreviations: IL, interleukin; mAb, monoclonal antibody; CXC, C-X-C chemokine motif ligand; GRO-α: growth-related oncogene α; TNF-β, tumor necrosis factor-β; TK, tyrosine kinase receptor cKit (KIT).


Tiotropium bromide is a Long-acting Muscarinic Antagonist (LAMA) that cause bronchodilation by blocking the actions of cholinergic muscarinic receptors in the airway [128]. It is a selective LAMA, and antagonizes only M1 and M3 muscarinic subtypes, and has a 20-fold higher affinity than the nonselective LAMAs, such as ipratropium [128]. It slowly dissociates from M3 receptors, which confers it a half-life of approximately 35 hours and thus permits once-daily dosing [128-130]. Tiotropium has demonstrated clinical efficacy in patients with neutrophilic asthma [131], and other phenotypes of asthma [132]. Itis the only LAMA recommended as an add-on therapy to ICS in patients with severe refractory asthma [132-134], particularly patients with neutrophilic asthma [131].

a. Theophyllines

Theophyllines have a long noble history in the management of patients with asthma because of their broad pharmacological effects and immunomodulatory actions. Selective phosphodiesterase 4 inhibitors such as roflumilast have been shown to decrease the levels of the key cytokines involved in the pathogenesis of neutrophilic asthma, such as TNF-α, IL-6, IL-8, and IL-17. Roflumilast treatment has been shown to decrease levels of IL-6 in patients with Asthma-COPD Overlap Syndrome (ACOS) [135], and IL-8 in patients with mild asthma [136]. Similarly, roflumilast has been shown to decrease IL-17 levels in patient with asthma [137]. 

Clinical studies have demonstrated the beneficial and efficacy of roflumilast in the treatment of neutrophilic asthma [136,138-142]. Themechanisms of theophyllines in relieving bronchoconstriction in patients with neutrophilic asthma are summarized in table 5.

Reduces airway inflammation

Reduces airway hyperresponsiveness

Reduces bronchochonstriction

Enhances mucociliary clearance

Prevents excessive airway remodeling with persistent airflow obstruction

Decreases the levels of Th17 associated cytokines, and chemokines

Indirectly decreases airway neutrophilia

Table 5: Pharmacological mechanisms of theophyllines in patients with neutrophilic asthma

b. Macrolides

Macrolide antibiotics have been demonstrated to be effective as add-on therapy for neutrophilic asthma [143-146]. In the AMAZES (Asthma and Macrolide: Azithromycin Efficacy and Safety) study, azithromycin reduced asthma exacerbations, and significantly improved asthma-related quality of life [145]. The mechanism of macrolides in neutrophilic asthma is related to their immunomodulatory and anti-inflammatory effects [145]. Macrolides have been shown to reduce neutrophil migration, and to decrease airway neutrophilia, and IL-8 levels [145, 146]. Macrolides have also been reported to inhibit NF-?B, and other transcription factors [146,147] and attenuate TNF-α, and IL-17 immune responses [146]. Cigana et al [148] have shown that azithromycin significantly reduces NF-?B expression, TNF-α mRNA levels and TNF-α secretion in cystic fibrosis-derived cell line. Marjanovi? and colleagues [147] have reported that macrolide antibiotics inhibit cytokine, and chemokine production, including IL-1β, IL-6, TNF-α, CXCL1, CXCL5, and CXCL8. This would of course, reduce neutrophil recruitment and influx into the asthmatic airways. Additionally, macrolides have antiviral action [149] and solithromycin has been reported to have the ability to restore corticosteroid sensitivity by inhibiting the phosphoinositide 3-kinase pathway [150]. In a pilot randomized, double-blind, placebo-controlled study in premature infants, azithromycin prophylaxis reduced postnatal steroid requirements, and duration of mechanical ventilation, although the incidence of bronchopulmonary dysplasia, and mortality were unaffected [151]. Short courses of macrolide antibiotics are useful during bacterial and viral-exacerbated asthma, and in patients with neutrophilic asthma, particularly with steroid- resistance asthma. However, long-term macrolide therapy for severe asthma should be avoided due to the risk of increased carriage of macrolide, and tetracycline resistance by airway microbiomes [152]. 

c. Bronchial thermoplasty

Severe neutrophilic asthma is characterized by airway smooth muscle hypertrophy and hyperplasia. Patients with severe refractory asthma who are not responsive to precise personalized anti-eosinophilic asthma biologics targeted at specific Th2 interleukins [153], may benefit from bronchial thermoplasty. Bronchial thermoplasty utilizes radio frequency thermal energy to reduce airway smooth muscle mass [154,155]. Thermoplasty improves symptoms control, and reduces exacerbation, emergency room visits, and hospitalization in patients with severe uncontrolled asthma and chronic airway obstruction. The procedure also improves the quality of life for the patients [156-160].


Neutrophilic asthma is a complex phenotype of asthma that is severe and persistent, with frequent exacerbations, and is characterized by fixed airway obstruction. Immunopathologically, it is characterized by the presence of high levels of neutrophils in the lungs and airways. Interleukin-17 secreted by Th17 cells, plays a key role in the pathogenesis of neutrophilic asthma by expressing the secretion of chemoattractant cytokines, and chemokines for the recruitment, and activation of neutrophils. Activated neutrophils produce oxidative bursts, releasing multiple proteinases, cytokines, chemokines, and reactive oxygen species which cause airway epithelial cell injury, inflammation, hyperresponsiveness, and airway remodeling. Neutrophilic asthma is unresponsive to high dose inhaled corticosteroids, and probably to precision novel anti-IgE, interleukin and interleukin monoclonal antibody therapies. There is need for targeted precision biologics and other treatment modalities for these patients, such as LAMA, long-acting phosphodiesterase inhibitors, and bronchial thermoplasty.


  1. Global Initiative for Asthma. Global Strategy for Asthma management and Prevention [updated 2018]. Available from. Accessed December 2, 2018.
  2. The Global Asthma Network. The Global Asthma Report 2014 [Last accessed 07 August 2018].
  3. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and Management of Asthma – A Summary Report 2007. J Allergy Clin Immunol 2007; 120: S94-S138.
  4. Asher MI, Montefort S, Bjorksten B (2006) worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phase One and Three repeat multi-country cross-sectional surveys. Lancet 368: 733-743.
  5. Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudue JB, et al. (1999) Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 160: 1001-1008.
  6. Simpson JL, Scott R, Boyle MJ, Gibson PG (2006) inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology 1: 54-61.
  7. Moore W, Bleecker E, Curren-Everett D, Erzurum S, Ameredes BT, et al. (2007) National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. Characterization of the severe asthma phenotypes by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J Allergy Clin Immunol 119: 405-413.
  8. Anderson GP (2008) Endotypying asthma: new insights into key pathogenic mechanism in a heterogenous disease. Lancet 372: 1107-1119.
  9. Moore WC, Meyer DA, Wenzel SE, Teague WG, Li H, et al. (2009) Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 181: 315-323.
  10. Wenzel SE (2012) Asthma phenotypes: the evolution from clinical to molecular approach. Nat Med 18: 716-725.
  11. Siroux V, González JR, Bouzigon E, Curjuric I, Boudier A, et al. (2014) Genetic heterogenicity of asthma phenotypes identified by a clustering approach. Eur Resp J 43: 439-452.
  12. Sutherland ER, Basagana X, Boudier A, Goleva E, King TS (2012) Cluster analysis of obesity and asthma. Phenotypes. PLOS One 7. e36631.
  13. Severe Asthma Research Program. A National Institute of Health/National Heart, Lung & Blood Institute sponsored network. 2019.
  14. McDonald VM, Hiles SA, Jones KA, Clark VL, Yorke J (2018) Health-related quality of life burden in severe asthma. Med J Aust 209: S28-S33.
  15. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, et al. (2014) International ERS/ATS Guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 43: 343-373.
  16. Douwes J, Gibson P, Pekkanen J, Pearce N (2002) Non-eosinophilic asthma: importance and possible mechanisms. Thorax 57: 643-648.
  17. McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland E R, et al. (2012) A large subgroup of mild-to-moderate asthma is persistently non eosinophilic. Am J Respir Crit Care Med 185: 612-619.
  18. Bel EH, Sousa A, Fleming L, Bush A, Chung KF, et al. (2011) Diagnosis of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (AMI). Thorax 66: 910-917.
  19. Wener RL, Bel EH (2013) Severe refractory asthma: an update. Eur Respir Rev 22: 196-201.
  20. Syabbalo N (2020) Neutrophilic asthma: a complex phenotype of asthma. J Lung Pulm Respir Res 7: 18-24.
  21. Lachowicz-Scroggins ME, Duncan EM, Charbit AR, Raymond W, Looney MR, et al. (2019) Neutrophils extracellular traps, and inflammasome activation in severe asthma. Am J Respir Crit Care Med 199: 1076-1085.
  22. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, et al. (2005) Interleukin 17-producing CD4+ effector T cell develop via a lineage distinct from the T helper type 1 and type 2 lineages. Immunology 6: 1123-1132.
  23. Park H, Li Yang XO, Chang SH, Nurieva R, Wang Y, et al. (2005) A distinct lineage of CD+ T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6: 1133-1141.
  24. Korn T, Betteli E, Oukka M, Kuchroo VK (2009) IL-17 and 17 cells. Annu Rev Immunol 27: 485-517.
  25. Wilson NJ, Boniface K, Chan JR, Mckenzie BS, Blumenschein WM, et al. (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8: 950-957.
  26. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joanopoulos K, et al. (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th7 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203: 2271-2279.
  27. Chung Y, Yang X, Chang SH, Ma L, Tian Q, et al. (2006) Expression and regulation of IL-22 in the IL-17-producing CD41 T lymphocytes. Cell Res 16: 902-907.
  28. Zheng Y, Danilenko DM, Valdez P, Kasman I, Wu J, et al. (2007) cytokine mediates IL-23-induced dermal inflammation and acanthosis. Nature 445: 648-651.
  29. Tesmer LA, Lundy SK, Sarkar S, Fox DA (2008) Th17 cells in human disease. Immunol Rev 223: 87-113.
  30. Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction of effector functions of T(H)17 cells. Nature 453: 1051-1057.
  31. Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, et al. (2006) Transforming growth factor-β induces development of TH17 lineage. Nature 441: 231-234.
  32. Veldeon M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing cells. Immunity 24: 179-189.
  33. McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, et al. (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)17- cell-mediated pathology. Nat Immunol 8: 1390-1397.
  34. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, et al. (2006) The orphan nuclear receptor RORgammat directs differentiation program of proinflammatory IL-17+ T helper cells. Cell 1262: 1121-1133.
  35. Zú?iga LA, Jain R, Haines C, Cua DJ (2013) Th17 cell development: from cradle to grave. Immunol Rev 252: 78-88.
  36. Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 19: 281-286.
  37. Gaffen SL, Jain R, Garg AV, Cua DJ (2014) The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 14: 585-600.
  38. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, et al. (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421: 744-748.
  39. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, et al. (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathway. Nat Immunol 8: 967-974.
  40. Korn T, Betteli E, Gao W, Awasthi A, Jäger A, et al. (2007) IL-21 initiates alternative pathway to induce T(H)17 cells. Nature 448:484-487.
  41. Wei L, Laurence A, Elias KM, O’Shea JJ (2007) IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 282: 34605-34610.
  42. Acosta-Rodriguez EV, Napolitani G, Lanzaveocchia A, Sallusto F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing cells. Nat Immunol 8: 942-949.
  43. Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, et al. (2009) Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30: 576-587.
  44. Michel ML, Mendes-da-Cruz D, Keller AC, Lochner M, Schneider E, et al. (2008) Critical role of ROR-gammat in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation. Proc Natl Acad Sci 105: 19845-19850.
  45. Zhao Y, Yang J, Gao YD (2011) Altered expression of T cell (Th)1, Th2, and Th17 cytokines in CD8+ and Υδ T cells in patients with allergic asthma. J Asthma 48: 429-436.
  46. Roark CL, Simonian PL, Fontenot AP, Born WK, O’Brien RL (2008) gammadelta T cells: an important source of IL-17. Curr Opin Immunol 20: 353-357.
  47. Rachitskaya AV, Hansen AM, Horai R, Li Z, Villasmil R, et al. (2008) Cutting edge: NKT cells constitutively express IL-23 receptor and RORgammat and rapidly produce IL-17 upon receptor ligation in an IL-6-induced fashion. J Immunol 180: 5167-5171.
  48. Coquet JM, Chakravarti S, Kyparissoudis K, McNab FW, Pitt LA, et al. (2008) Diverse cytokine production by NTK cell subsets and identification of an IL-17-producing D4- NK1.1-NKT cell population. Proc Natl Acad Sci 105: 11287-11292.
  49. Takatori H, Kunno Y, Watford WT, Tato CM, Weiss G, et al. (2009) Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med 206: 35-41.
  50. Cua DJ, Tato CM (2010) Innate IL-17 producing cells: the sentinel of the immune system. Nat Rev Immunol 10: 479-489.
  51. Brodlie M, McKean MC, Johnston GE, Anderson AE, Hilkens CM (2011) Fisher. Raised interleukin-17 is immunolocalized to neutrophils in cystic fibrosis. Eur Respir J 37: 1378-1385.
  52. Ramirez-Velazquez C, Castillo EC, Guido-Bayardo L, Ortiz-Navarrete V (2013) IL-17-producing peripheral blood CD177+ neutrophils increase in allergic subjects. Allergy Asthma Clin Immunol 9: 23.
  53. Song C, Luo L, Lei Z, Li B, Liu G, et al. (2008). IL-17A-producing alveolar macrophages mediate allergic lung inflammation related to asthma. J Immunol 181: 6117-6124.
  54. Molet S, Hamid Q, Davoine F, Nutku E. Taha R, et al. (2001) IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol 108: 430-438.
  55. Rouvier E, Luciani MF, Mattéi MG, Denoit F, Golstein P (1993) CTLA-8, cloned from activated T cell, bearing AU-rich messenger RNA instability sequences, homologous to a herpesvirus saimari J Immunol 150: 5445-5456.
  56. Yao Z, Maraskovsky E, Spriggs MK, Cohen JI, Armitage RJ, et al. (1996) Herpesvirus saimari open reading frame 14, a protein encoded by T lymphotropic herpes virus, binds to MHC class II molecules and stimulates T cell proliferation. J Immunol 156: 3260-3266.
  57. Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, et al. (1995) Herpes saimari encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3: 811-821.
  58. Moseley TA, Haudenschild DR, Rose L, Reddi AH (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14: 155-174.
  59. Aggarwal S, Gurney AL (2002) IL-17: prototype member of an emerging cytokine family. J Leukoc Biol 71: 1-8.
  60. Gaffen SL (2004) Biology of recently discovered cytokines: interleukin-17 - a unique inflammatory cytokine with roles in bone biology and arthritis. Arthritis Res Ther 6: 240-247.
  61. Kolls JK, Lindén A (2004) Interleukin-17 family members and inflammation. Immunity 21: 467-476.
  62. Pappu BP, Angkasekwinai P, Dong C (2008) Regulatory mechanisms of helper T cell differentiation: new lesson learned from interleukin 17 family cytokines. Pharmacol Ther 117: 374-384.
  63. Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25: 821-852.
  64. Chung S, Dong CA (2007) novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell Res 17: 435-440.
  65. Gaffen S (2009) Structure and signaling of the IL-17 receptor family. Nat Immunol 9: 556-567.
  66. Kuestner RE, Taft DW, Haran A, Bradt Cs, Blender T, et al. (2007) Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. J Immunol 179: 5462-5473.
  67. Hu Y, Shen F, Crellin NK, Ouyang W (2011) IL-17 pathway as a major therapeutic target in autoimmune diseases. Ann NY Acad Sci 1217: 60-76.
  68. Lubbert E, Joosten LA, Oppers B, van den Bersselaar L, Coenen-de Roo CJ, et al. (2001) IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J Immunol 167: 1004-1013.
  69. Metawi S, Abbas D, Kamal M, Ibrahim M (2011) Serum and synovial fluid levels of interleukin-17 in correlation with disease activity in patients with RA. Clin Rheumatol 30: 1201-1207.
  70. Park J, Park M, Lee S, Oh H, Lim M, et al. (2012) TWEAK promotes the production of interleukin-17 in rheumatoid arthritis. Cytokine 60: 143-149.
  71. Arican OAM, Sasmaz S, Ciragil P (2005) Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm 2005: 273-279.
  72. Martin DA, Toune JE, Kricorian G, Klekotka P, Gudjonsson JE, et al. (2013) The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings. J Invest Dermatol 133: 17-26.
  73. Papp KA, Leonardi C, Menter A, Ortonne J-P, Kruger JG, et al. (2012) Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med 366: 1181-1189.
  74. Moseley TA, Haudenchild DR, Rose L, Reddi AH (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14: 155-174.
  75. Gaffen SL (2004) Biology of recently discovered cytokines: interleukin-17 - a unique inflammatory cytokine with roles in bone biology and arthritis. Arthritis Res Ther 6: 240-247.
  76. Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25: 821-852.
  77. Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, et al. (2006) Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol 177: 36-39.
  78. Chang SH, Dong C (2011) Signaling of interleukin-17 family cytokine in immunity and inflammation. Cell Signal 23: 1069-1075.
  79. Iwakara Y, Ishigame H, Saijo S, Nakae S (2011) Functional specialization of interleukin-17 family members. Immunity 34: 149-162.
  80. Ivanov S, Lindén A (2009) Interleukin-17A as a drug target in human disease. Trends Pharmacol Sci; 30: 95-103.
  81. Chang Y, Al-Alwan L, Risse PA (2012) Th17-associated cytokines promote human airway smooth muscle cell proliferation. FASEB J 26: 5152-5160.
  82. Wilson NJ, Boniface K, Chan JR, (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol8: 950-957.
  83. Shen F, Gaffen SL (2008) Structure-function relationships in IL-17A receptor: implications for signal transduction and therapy. Cytokine 41: 92-104.
  84. Gaffen SL (2009) Structure and signaling in the IL-17 receptor family. Nat Rev Immunol 9: 556-567.
  85. Schwandner R, Yamaguchi K, Cao Z (2000) Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J Exp Med 191: 1233-1240.
  86. Lindén A (2007) A role for the cytoplasmic adaptor protein act1 in mediating IL-17 signaling. Sci STKE 398: re4.
  87. Qian Y, Liu C, Hartupee J (2007) The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol 8: 247-256.
  88. Bruijnzeel PL, Uddin M, Koenderman L (2015) Targeting neutrophil inflammation in severe neutrophilic asthma: can we target the disease-relevant neutrophil type? J Leukoc Biol 98: 549-556.
  89. Cowburn AS, Condliffe AM, Farahi N, Summers C, Chilvers ER (2008) Advances in neutrophil biology: clinical implication. Chest 134: 606-612.
  90. Chang Y, Al-Alwan L, Risse PA (2012) Th17-associated cytokine promote human airway smooth muscle cell proliferation. FASEB J 26: 5152-5160.
  91. Al-Ramli W, Préfontaine D, Chouiali F (2009) T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol 123: 1185-1187.
  92. Summers C, Ranklin SM, Condliffe AM, Singh N, Peters AM, et al. (2010) Neutrophil kinetics in health and disease. Trends Immunol 31: 318-324.
  93. Woodruff PG, Fahy JV (2002) A role for neutrophil in asthma. Am J Med 112: 498-500.
  94. Nakagome K, Matsushita S, Nagata M (2012) Neutrophil inflammation in severe asthma. Int Arch Allergy 158: 96-102.
  95. Lindén A (2001) Role of interleukin-17 and the neutrophil in asthma. In Arch Allergy Immunol 126: 179-184.
  96. Teran LM, Campos MG, Begishvilli BT, Schröder JM, Djukanovic R, et al. (1997) Identification of neutrophil chemotactic factors in bronchoalveolar lavage fluid of asthmatic patients. Clin Exp Allergy 27:396-405.
  97. Wenzel SE, Larsen GL, Johnston K, Voelkel NF, Westcott JY (1990) Elevated levels of leukotriene C4 in brronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge. Am Rev Respir Dis 142: 112-119.
  98. Brown PH, Crompton GK, Greening AP (1991) Proinflammatory cytokines in asthma. Lancet 338: 590-593.
  99. Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, et al. (2005) Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 60: 1012-1018.
  100. Morishima Y, Ano S, Ishii Y, Ohtsuka S, Matsuyama M, Kawaguchi M, et al. (2013) Th17-associated cytokines as a therapeutic target for steroid-insensitive asthma. Clin Dev Immunol 2013: 609395.
  101. Cundall M, Sun Y, Miranda C, Trudeau JB, Barnes S, et al. (2003) Neutrophil-derived metalloproteinase-9 is increased in severe asthma and poorly inhibited by glucocorticoids. J Allergy Clin Immunol 112: 1064-1071.
  102. Hoshino M, Nakamura Y, Sim J, Shimojo J, Isogai S (1998) Bronchial subepithelial fibrosis and expression of metalloproteinase-9 in asthmatic airway inflammation. J Allergy Clin Immunol 102: 783-788.
  103. Panettieri RA Jr (2018) The role of neutrophils in asthma. Immunol Allergy Clin North Am 38: 629-638.
  104. Grunwell JR, Stephenson ST, Tirouvanzian R, Brown LAS, Brown MR, et al. (2019) Children with neutrophil-predominant severe asthma have proinflammatory neutrophils with enhanced survival and impaired clearance. J Allergy Clin Immnol 7: 516-525.
  105. Hoshino M, Nakamura Y, Sim J, Shimojo J, Isogai S (1998) Bronchial subepithelial fibrosis and expression of metalloproteinase-9 in asthmatic airway inflammation. J Allergy Clin Immunol 102: 783-788.
  106. Wenzel SE, Balzar S, Cundall M, Chu HW (2003) Subepithelial basement membrane immunoreactivity for metalloprotease-9: association with asthma severity, neutrophilic inflammation, and wound repair. J Allergy Clin Immunol 111: 1345-1352.
  107. Amitani R, Wilson R, Rutman A, Read R, Ward C, et al. (1999) Effects of human neutrophil elastase and Pseudomonas aeruginosa proteases on human respiratory epithelium. Am J Respir Cell Mol Biol 4: 26-32.
  108. Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG (2011) Systemic upregulation of neutrophil α-defensins and serine proteases in neutrophilic asthma. Thorax 66: 942-947.
  109. Vargas A, Roux-Dalvai F, Droit A, Lavoie JP (2016) Neutrophil-derived exosomes: a new mechanism contributing to airway smooth muscle remodeling. Am J Respir Cell Mol Biol 55: 450-46.
  110. Nadel JA (1991) Role of enzymes from inflammatory cells on submucosal gland secretion. Respiration 58: 3-5.
  111. Monteseirín J, Bonella I, Camacho MJ, Chacón P, Vega A, et al. (2003) Specific allergens enhance elastase release in stimulated neutrophils from asthma patients. Int Arch Allergy Immunol 131: 174-181.
  112. Monteseirín J (2009) Neutrophil in asthma. J Investig Allergol Clin Immunol 19: 340-354.
  113. Hood PP, Cotter TP, Costello JF, Simpson AP (1999) Effect of intravenous corticosteroid on ex vivo leukotriene generation by blood leucocytes of normal and asthmatic patients. Thorax 54: 1075-1082.
  114. Keating VM, Barnes PJ (1997) Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects. Am J Respir Crit Care Med 155: 449-453.
  115. Chabannes B, Hosni R, Moliere P, Croset M, Pacheco Y, et al. (1991) Leukotriene B4 levels in neutrophils from allergic and healthy subjects stimulated by low concentration of calcium ionophore A23187. Effect of exogenous arachidonic acid and possible endogenous source. Biochim Biophys Acta 1093: 47-54.
  116. Maloney CG, Kutchara WA, Albertine KH, McIntyre TM, Prescott SM, et al. (1998) Inflammatory agonist induce cyclooxygenase type 2 expression by human neutrophils. J Immunol 160: 1402-1410.
  117. Kato M, Nakano M, Morikawe A, Kimura H, Shigata M, et al. (1991) Ability of polymorphonuclear leukocytes to generate active oxygen species in children with bronchial asthma. Int Arch Allergy Appl Immunol 95: 17-22.
  118. Styrt B, Rockling RE, Klempner MS (1988) Characterization of the neutrophil respiratory burst in atopy. J Allergy Clin Immunol 81: 20-26.
  119. Meltzer S, Goldberg B, Lad P, Easton J (1989) Superoxide generation and its modulation by adenosine in the neutrophils of subjects with asthma. J Allergy Clin Immunol 83: 960-966.
  120. Tanazawa H, Kurihara N, Hirata K, Takeda T (1991) The role of free radicals in airway obstruction in asthmatic patients. Chest 100: 1319-1322.
  121. Loukides S, Buoros D, Papatheodorou G, Siafakas NM (2002) The relationships among hydrogen peroxide in expired breathe condensate, airway inflammation, and asthma severity. Chest 121: 338-346.
  122. Hiraguchi Y, Nagao M, Hosoki K, Okuda R, Fujisawa T (2008) Neutrophil proteases activate eosinophil function in vitro. In Arch Allergy Immunol 146: 16-21.
  123. de Groot JC, ten Brinke A, Bel EHD (2015) Management of the patient with eosinophilic asthma: a new era begins. ERJ Open Res 1: 0024-2016.
  124. McCraken J, Tripple J, Calhoun WJ (2016) Biological therapy in the management of asthma. Curr Opin Allergy Clin Immunol 16: 375-382.
  125. Zhu L, Ciaccio C, Casale TB (2018) Potential new targets for drug development in severe asthma. World Allergy Org J 11: 13.
  126. Busse WW (2019) Biological treatment for severe asthma: A major advance in asthma care. Allergol Int 68: 158-166.
  127. Syabbalo N (2020) Clinical features and management of eosinophilic asthma. J Respir Dis Treat 1: 105.
  128. Quirce S, Dominguez-Ortega J, Barranco P (2015) Anticholinergics for treatment of asthma. J Invest Allergol Clin Immunol 25: 85-94.
  129. Chari VM, Mclvor RA (2018) Tiotropium for the treatment of asthma: patient selection and perspectives. Can Respir J ID 3464960.
  130. Timmer W, Moroni-Zentgraft P, Cornelissen P, Unseld A, Pizzichini E, et al. (2015) Once-daily tiotropium Respimat® 5 μg is an efficacy 24-h bronchodilator in adults with asthma. Respir Med 109: 329-338.
  131. Radovanovic D, Santus P, Mantero M (2017) The evidence on tiotropium in asthma: from rational to bedside. Multidiscip Respir Med 12: 12.
  132. Fardon T, Haggart K, Lee DK, Liporth BJ (2007) A proof of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma. Respir Med 101: 1218-1228.
  133. Kertjens HA, Angel M, Dahl R, Paggiaro P, Beck E, et al. (2012) Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 367: 1198-1203.
  134. Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, et al. (2010) Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 363:1715-1726.
  135. Barnes NC, Saetta M, Rabe KF (2014) Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast. BMC Pulm Med 14: 9.
  136. Gauvreau GM, Boulet LP, Schmid-Wirlitsch D, Côté J, Duong M, et al. (2011) Roflumilast attenuates allergen induced inflammation in mild asthmatic subjects. Respir Res 12: 140.
  137. Barnes NC (2007) The properties of inhaled corticosteroids: similarities and differences. Prim Care Respir J 16: 149-154.
  138. Bardin P, Kanniess F, Gauvreau G, Bredenbröker D, Rabe KF (2015) Roflumilast for asthma: Efficacy findings in mechanism of action studies. Pulm Pharmacol Ther 35: S4-S10.
  139. Bateman ED, Bousquet J, Aubier M, Bredenbröker D, O’Byrne PM (2015) Roflumilast for asthma: efficacy findings in non-placebo-controlled comparator and dosing studies. Pulm Pharmacol Ther; 35: S11-S19.
  140. Meltzer EO, Chervinsky P, Busse W, Ohta K, Bardin P, et al (2015) Roflumilast for asthma: Efficacy findings in placebo-controlled studies. Pulm Pharmacol Ther 35: S20-S27.
  141. Xang X, Chen Y, Fan L, Xu X, You D, et al. (2018) Pharmacological mechanism of roflumilast in the treatment of asthma-COPD overlap. Drug Res Dev Ther 12: 2371-2379.
  142. Kawamatawong T (2017) Roles of roflumilast, a selective phosphodiesterase 4 inhibitor, in airway disease. Thorac Dis 9: 1144-1154.
  143. Idris SD, Chilvers ER, Haworth C, Mckeon D, Condliffe AM (2008) Azithromycin therapy for neutrophilic airway disease: myth or magic? Thorax 64:3.
  144. Simpson JL, Powell H, Boyles MJ, Scott RJ, Gibson PG (2008) Clarithromycin targets neutrophil airway inflammation in refractory asthma. Am J Respir Crit Care Med 177: 148-155.
  145. Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, et al. (2017) Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomized, double-blind, placebo-controlled trial. Lancet 390: 659-668.
  146. Kobayashi Y, Wada H, Rossios C, Takagi D, Higaki M, et al. (2013) A novel macrolide solithromycin exert superior anti-inflammatory effect via NF-?B inhibition. J Pharmacol Exp Ther 345: 76-84.
  147. Marjanovi? N, Bosnan M, Michielin F, Willé DR, Ani?-Mili? T, et al. (2011) Macrolide antibiotics broadly and distinctively inhibit cytokine and chemokine production by COPD sputum cells in vitro. Pharmacol Res 63: 389-397.
  148. Cigana C, Assael BM, Meloli P (2007) Azithromycin selectively reduces tumor necrosis factor alpha levels in cystic fibrosis airway epithelial line. Antimicrob Agents Chemother 51: 975-981.
  149. Schögler A, Kopf BS, Edwards MR (2015) Novel antiviral properties of azithromycin in cystic fibrosis airway epithelial cells. Eur Respir J 45: 428-439.
  150. Kobayashi Y, Wada H, Rossios C (2013) A novel macrolide/fluoketolide, solithromycin (CEM-101), reverses corticosteroid insensitivity via phosphoinositide 3-kinase. Br J Pharmacol 169: 1024-1034.
  151. Ballard HO, Anstead MJ, Shook AL (2007) Azithromycin in the extremely birth weight infants for prevention of bronchopulmonary dysplasia: a pilot study. Resp Rev 8: 41-50.
  152. Taylor SL, Leong LEX, Mobegi FM (2019) Long-term azithromycin reduces Haemophilus influenzae and increases antibiotic resistance in severe asthma. Am J Respir Crit Care Med 200: 309-317.
  153. Thomson NC, Bicknell, S, Chaudhri R (2012) Bronchial thermoplasty for severe asthma. Curr Opin Allergy Clin Immunol 12: 241-248.
  154. Dombret M-C, Alagha K, Boulet LP, Brillet PY, Joos G, et al. (2014) Bronchial thermoplasty: a new therapeutic option for the treatment of severe uncontrolled asthma in adults. Eur Respir J 23: 510-518.
  155. Wechsler ME, Laviolette M, Rubin AS, Fiterman J (2013) Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe asthma. J Allergy Clin Immunol 132: 1295-1302.
  156. Trivedi A, Pavord ID, Castro M (2016) Bronchial thermoplasty and biological therapy as a targeted treatment for severe uncontrolled asthma. Lancet Respir Med 4: 585-592.
  157. Laxmanan B, Hogarth DK (2015) Bronchial thermoplasty: current perspective. J Asthma Allergy 8: 37-49.
  158. Oberle AJ, Mathur P (2017) Precision medicine in asthma: the role of bronchial thermoplasty. Curr Opin Pulm Med 23: 254-260.
  159. Chupp G, Laviolette M, Cohn L, McEvoy C, Bansal S, et al. (2017) Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: a comparison of 3-year follow-up results from two prospective multicentre studies. Eur Respir J 50: 1700017.
  160. Thomson NC, Chanez P (2017) How effective is bronchial thermoplasty for severe asthma in clinical practice? Eur Respir J 5: 1701140.

Citation: Syabbalo N (2020) Mechanisms of Interleukin -17 in The Pathogenesis of Neutrophilic Asthma. J Pulm Med Respir Res 6: 032.

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