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Immune system in the pathogenesis of chronic cough
Journal Pre-proof Immune system in the pathogenesis of chronic cough Tamasauskiene Laura, Sitkauskiene Brigita
PII:
S0165-2478(19)30583-8
DOI:
https://doi.org/10.1016/j.imlet.2019.12.013
Reference:
IMLET 6413
To appear in:
Immunology Letters
Received Date:
12 November 2019
Revised Date:
17 December 2019
Accepted Date:
30 December 2019
Please cite this article as: Tamasauskiene L, Brigita S, Immune system in the pathogenesis of chronic cough, Immunology Letters (2019), doi: https://doi.org/10.1016/j.imlet.2019.12.013
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Immune system in the pathogenesis of chronic cough
Tamasauskiene Laura, Sitkauskiene Brigita Department of Immunology and Allergology, Lithuanian University of Health Sciences
Corresponding author:
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Laura Tamasauskiene, MD, PhD student Department of Immunology and Allergology, Lithuanian University of Health Sciences, Eiveniu
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Tel.: +37061569127, e-mail: [email protected]
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Cough reflex sensitivities differ among individuals. Interaction between immune system and nervous system is important in the pathogenesis of cough. Eosinophils alter parasympathetic and sensory nerve function by releasing mediators. Neutrophils sensitize peripheral airway nerves through generation of ROS and proteases. Substance P, bradykinin, prostaglandins and cytokines are also involved in cough pathogenesis.
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Highlights
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str. 2, LT-50009, Kaunas, Lithuania
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Abstract. Chronic cough is a common symptom of various chronic diseases. However, the vast majority of individuals with conditions that are commonly associated with cough, such as asthma and GERD, do not have chronic cough. This implies that cough reflex sensitivities differ among individuals. It is known that in the pathogenesis of cough, the nervous system plays a vital role. Recently more information about the role of the immune system and its interaction with the nervous system in the pathogenesis of cough has appeared in the literature. The aim of this article is to review the most recent data about the role of the immune system in the pathogenesis of chronic cough.
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Abbreviations GERD – gastroesophageal reflux disease COPD – chronic obstructive pulmonary disease IL – interleukin CCR – CC chemokine receptor cys-LTs – cysteinyl-leukotrienes BAL – bronchoalveolar lavage
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ACE – angiotensin-converting enzyme
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Key words: cough, immune system, eosinophil, neutrophil.
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TRP – transient receptor potential
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1. Introduction
Chronic cough is among the most common symptoms for which patients worldwide seek
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medical attention [1]. Chronic cough is defined in adults as cough lasting for more than 8 weeks [2, 3]. According to a systematic review and meta-analysis, of published data originating from numerous countries, the overall prevalence of chronic cough is about 9.6% [4]. Chronic cough is
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a common symptom of various chronic diseases such as bronchiectasis, asthma, gastroesophageal reflux disease (GERD) and chronic rhinitis [5-7]. Chronic inflammation caused by inflammatory cells and cytokines plays a significant role in the pathogenesis of these conditions [8-10]. Moreover, female sex, advanced age and smoking status are also important risk factors of chronic cough [5, 6]. Studies have shown that cough, especially chronic, adversely affects quality of life,
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and has a large socioeconomic impact by increasing physician visits and sick leave days [11-13]. The vast majority of individuals with conditions that are commonly associated with cough,
such as asthma and GERD, do not have chronic cough. This implies that cough reflex sensitivities differ among individuals. The recently introduced term “Cough Hypersensitivity Syndrome”, supports the concept that hypersensitivity of airway sensory nerves may underlie chronic cough [14, 15]. It is known that in the pathogenesis of cough, the nervous system plays a vital role. The neurological mechanism of cough originates from stimulation of unmyelinated C fibers and
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myelinated Aδ fibers [16]. Most C fibers respond to a range of irritant stimuli of inflammatory origin, while Aδ fibers respond to mechanical and acid stimuli [17]. Recently more information about the role of the immune system and its interaction with the nervous system in the pathogenesis of cough has appeared in the literature [14, 17-23]. Immune cells release or activate a variety of inflammatory mediators such as prostaglandins, leukotrienes, major basic protein and others which stimulate peripheral nerves and induce cough [18-20, 23-25]. The aim of this article is to review
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the most recent data about the role of the immune system in the pathogenesis of chronic cough.
2. Methods
Original articles published during the period 2007-2018 were searched in Pubmed database
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using key words: cough, chronic cough, eosinophil, neutrophil, interleukin, immune system,
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pathogenesis.
3.1 Role of eosinophils in cough
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3. Discussion
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Eosinophils are important in the pathogenesis of allergic asthma and non-asthmatic eosinophilic bronchitis, [26] and cough is a common symptom of these diseases [26]. Kansal et al. investigated the correlation of induced sputum eosinophil levels with clinical parameters in mild
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and moderate persistent asthma in children aged 7–18 years [27]. Results revealed that sputum eosinophil percentage was significantly higher in moderate persistent asthma than that in mild persistent asthma. Reduction in sputum eosinophil percentage after three months of inhaled budesonide therapy in both mild and moderate persistent asthmatics was achieved. This eosinophil reduction had a significant positive correlation with decreased number of nights with cough [27].
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A study performed by Yu et al. showed that children with cough variant asthma had sputum eosinophil counts higher than 3% [28]. However, another study which analysed the link between the score on the Leicester Cough Questionnaire (LCQ) and sputum eosinophils in adults with severe asthma revealed no correlation between these variables [29]. However, chronic cough and sputum production were more prevalent in chronic obstructive pulmonary disease (COPD) patients with higher blood eosinophilia [30].
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A study which investigated patients with non-asthmatic eosinophilic bronchitis and chronic cough revealed that the sputum eosinophil level was significantly increased in these patients compared with healthy individuals and was positively associated with eotaxin and interleukin (IL) 4 level in sputum [31]. Wang et al. also found increased levels of IL-4 and IL-5 in peripheral blood mononuclear cells in children with cough variant asthma compared with healthy individuals [32]. These cytokines can be important in cough pathogenesis by activating eosinophils. It is known that eotaxin and IL-5 induce chemotaxis and migration of eosinophils to certain tissues via interaction
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with CC chemokine receptor (CCR) 3 which is expressed on eosinophils [31]. IL-4 also contributes to the activation and recruitment of eosinophils [31].
A possible link between chronic cough and eosinophils was suggested by the results of a
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study performed by Macedo et al. [24]. Patients were divided into two groups: chronic explained cough (associated with asthma, GERD, postnasal drip, etc.) and chronic idiopathic cough.
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Bronchial biopsies were performed in these patients. Results revealed that the number of eosinophils in tissue was significantly associated with goblet cell hyperplasia, basement membrane
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thickening, lymphocyte infiltration and neutrophil infiltration [24]. A greater degree of basement membrane thickening was observed in patients with chronic idiopathic cough compared with those
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with chronic explained cough.
In chronic airway diseases such as asthma, during acute viral infection, or with exposure to air pollutants, eosinophils are recruited to the airway nerves and interact with airway nerves,
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possibly through expression of chemotactic substances and adhesion molecules by the nerves [33]. Eosinophils can alter both parasympathetic and sensory nerve function [33-35]. These cells release major basic protein, which is an antagonist of M2 muscarinic receptors on parasympathetic nerves [33, 34]. Eosinophils also increase sensory nerve responsiveness by lowering neuronal activation threshold, stimulating nerve growth, and altering neuropeptide expression [35]. Experimental
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studies show that eosinophil granule-derived cationic proteins stimulate vagal C-fiber afferents in the lungs [36, 37]. The vagus nerve transmits sensory information from the lungs to the brainstem. C- fibers are known to be very important in pathogenesis of cough [16, 17]. Moreover, eosinophils produce cysteinyl-leukotrienes (cys-LTs) which are among the chemical mediators that play a major pathophysiological role in asthma. There is indirect evidence that cys-LTs can be important in the pathogenesis of cough. For example, treatment with leukotriene receptor antagonists can attenuate cough severity and capsaicin cough sensitivity [38].
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Mincheva et al. showed that this treatment relieved only cough due to upper airway cough syndrome or gastroesophageal reflux but not asthma [39]. These data suggest that cys-LTs can also be involved in the pathogenesis of cough.
3.2 Role of neutrophils in cough Neutrophils play an important role in chronic diseases causing cough such as COPD and GERD [40-42]. A study performed by Sumner et al. revealed that cough frequency was related to
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the percentage of sputum neutrophils [43]. Snijders et al. showed that seemingly healthy children with unexplained chronic cough had an increased percentage of neutrophils in bronchoalveolar lavage (BAL) fluid compared with the control group [44]. Moreover, Ferreira et al. found that
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BAL neutrophils were higher in atopic and nonatopic children with chronic cough compared with a control group [45]. The mechanism by which neutrophils may induce cough remains unclear.
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However, we can hypothesize that these cells cause inflammation through generation of reactive oxygen species and release proteases such as neutrophil elastase and cathepsins [8, 40, 42].
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Neutrophilic inflammation can sensitize peripheral airway nerves and induce the cough reflex [42, 43, 46, 47]. Neutrophils are activated by neutrophil-associated cytokines such as interleukin-8 and
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tumor necrosis factor-alpha [8, 41, 42]. Increased levels of these inflammatory mediators were found in the sputum of non-asthmatic chronic cough patients [41].
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3.3 Role of lymphocytes in cough
According to scientific literature, lymphocytes are also involved in cough mechanisms, especially in idiopathic cough. Birring et al. investigated patients with idiopathic cough and found a mild chronic lymphocytic inflammation in airway (predominately in female population) [48]. BAL lymphocytes count was higher in patients with idiopathic cough compared with healthy
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individuals. Authors suggested that the increased lymphocytes in the airway can be associated with autoimmune process [48]. Another study performed by Mund et al. confirmed these findings. They found increased level of CD4+ lymphocytes in the airways of females with idiopathic dry cough. [49]. We can raise the hypothesis that CD4+ lymphocytes mediated response can be associated with cough in chronic inflammatory airway diseases such as allergic asthma or eosinophilic bronchitis. The main pathogenetic background of these disease is T lymphocytes helper 2 (Th2)
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mediated inflammation. Cytokines which are secreted by Th2 (eg., interleukin (IL) - 5) activate eosinophils which role in cough is described previously. Studies of patients having non-asthmatic eosinophilic bronchitis, a common cause of chronic cough, revealed that IL-17 which is mainly produced by Th17 levels in sputum were higher compared with healthy subjects [50]. Moreover, higher IL-17 levels were observed in patients with eosinophilic and non-eosinophilic asthma compared with healthy subjects [50]. This study showed that sputum IL-17 level correlated with sputum neutrophils [50]. We can hypothesize that IL-17
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enhances neutrophilic inflammation which is important in cough pathogenesis.
3.4 Role of other immune components in cough
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The nervous system plays a vital role in cough pathogenesis. Small amino acidic molecules (neuropeptides) can affect inflammatory responses which can be important in the cough reflex,
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especially in chronic respiratory disorders [51, 52]. Substance P is a neuropeptide that is widely distributed in sensory peripheral nerves and in the central nervous system [53]. Substance P
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activates neurokinin-1 receptor [54]. Animal studies have demonstrated that substance P can be involved in cough pathogenesis [55, 56]. For example, Moreaux et al. showed a release of
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substance P in pigs after cough induction by citric acid [55]. Kohrogi et al. revealed that substance P stimulated cough in very low concentrations in guinea pigs [56]. A study by Qiu et al. demonstrated that patients with GERD and cough had significantly higher substance P and mast
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cell tryptase levels in sputum compared with healthy individuals and patients with GERD without cough [57]. Otsuka at al. showed that plasma substance P levels were significantly higher in patients with asthmatic and non-asthmatic cough compared to healthy controls but did not significantly differ between the two patient groups [58]. There is evidence that substance P inhibits apoptosis, increases migration and prolongs the survival of eosinophils [59]. These studies suggest
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that one pathway through which substance P may play a role in cough pathogenesis is by the activation of eosinophils. Substance P together with bradykinin may be involved in the pathogenesis of cough
induced by angiotensin-converting enzyme (ACE) inhibitors [60]. Substance P and bradykinin are degraded by ACE and accumulate in the upper respiratory tract or lung when the enzyme is inhibited [60]. It has been shown that exposure of guinea-pigs to bradykinin results in a significant enhancement of the cough response [61]. Bradykinin can stimulate prostaglandins which can be
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important in cough pathogenesis by activating sensory ganglia and vagal sensory nerves through transient receptor potential (TRP) channels [60, 62, 63]. Furthermore, animal studies have shown that prostaglandin E2 exacerbates bronchoconstriction-triggered cough through EP1 and EP3 receptors [62, 64]. The investigation of immune system in pathogenesis of cough is important for development of new treatment options. Relieving cough in patients with chronic cough, especially, idiopathic, often is a challenge. A few years ago, Harle et al. found that the drug blocking substance P through
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inhibition of neurokinin-1 receptor significantly reduced awake cough frequency in patients with lung cancer [65]. This year Smith et al. published data about the efficacy of Neurokinin-1 receptor antagonist Orvepitant for the treatment of chronic refractory cough. The results revealed that
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Orvepitant statistically and clinically significant improved objective daytime cough frequency and quality of life [66].
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The role of the immune system in the pathogenesis of cough is summarized in figure 1 and
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the main results of clinical studies of patients with cough are provided in table 1.
4. Conclusions
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In summary, there is significant evidence that the immune system may play an important role in the pathogenesis of chronic cough, a frequent symptom of chronic inflammatory diseases. Immune cells including eosinophils and neutrophils are most strongly implicated in cough
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development. Cytokines released or induced by these cells cause chronic inflammation which may sensitize peripheral airway nerves and induce cough. Further investigation of the mechanism(s) of chronic cough will hopefully promote the development of new therapeutic agents.
Acknowledgment
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The authors thank Prof. Peter Dicpinigaitis for critical review of this manuscript.
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Figure legend
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Figure 1. Summary of immune mechanisms in relation to cough pathogenesis [8, 17-27,
29-38, 40, 44, 45, 47, 50-54, 58, 59, 61-64]
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Table 1. Summary of the main results of studies of cough patients reviewed in this article [27, 28, 30, 31, 42-45, 50, 57, 58]
Zhang et al.
Neutrophil
Sumner et al. Snijders et al. Ferreira et al.
Substance P
Qiu et al.
Otsuka at al. Zhan et al.
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IL-17
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Zysman et al.
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Yu et al.
Main results Eosinophil reduction in asthma positively correlated with decreased number of nights with cough Children with cough variant asthma had sputum eosinophil count higher than 3% Chronic cough was more prevalent in COPD patients with higher blood eosinophilia Sputum eosinophil level was significantly increased in patients with non-asthmatic eosinophilic bronchitis having cough compared with healthy individuals Cough frequency was related to percentage of sputum neutrophils Children with unexplained chronic cough had an increased percentage of neutrophils BAL compared with the control group BAL neutrophils were higher in children with chronic cough compared with control group Patients with GERD and cough had significantly higher substance P level in sputum compared with healthy individuals and patients with GERD without cough Plasma substance P levels were significantly higher in patients with asthmatic and non-asthmatic cough compared to healthy controls IL-17 level in sputum was higher in patients having non-asthmatic eosinophilic bronchitis compared with healthy subjects
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Reference Kansal et al.
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Marker Eosinophil
PII:
S0165-2478(19)30583-8
DOI:
https://doi.org/10.1016/j.imlet.2019.12.013
Reference:
IMLET 6413
To appear in:
Immunology Letters
Received Date:
12 November 2019
Revised Date:
17 December 2019
Accepted Date:
30 December 2019
Please cite this article as: Tamasauskiene L, Brigita S, Immune system in the pathogenesis of chronic cough, Immunology Letters (2019), doi: https://doi.org/10.1016/j.imlet.2019.12.013
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
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Immune system in the pathogenesis of chronic cough
Tamasauskiene Laura, Sitkauskiene Brigita Department of Immunology and Allergology, Lithuanian University of Health Sciences
Corresponding author:
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Laura Tamasauskiene, MD, PhD student Department of Immunology and Allergology, Lithuanian University of Health Sciences, Eiveniu
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Tel.: +37061569127, e-mail: [email protected]
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Cough reflex sensitivities differ among individuals. Interaction between immune system and nervous system is important in the pathogenesis of cough. Eosinophils alter parasympathetic and sensory nerve function by releasing mediators. Neutrophils sensitize peripheral airway nerves through generation of ROS and proteases. Substance P, bradykinin, prostaglandins and cytokines are also involved in cough pathogenesis.
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Highlights
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str. 2, LT-50009, Kaunas, Lithuania
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Abstract. Chronic cough is a common symptom of various chronic diseases. However, the vast majority of individuals with conditions that are commonly associated with cough, such as asthma and GERD, do not have chronic cough. This implies that cough reflex sensitivities differ among individuals. It is known that in the pathogenesis of cough, the nervous system plays a vital role. Recently more information about the role of the immune system and its interaction with the nervous system in the pathogenesis of cough has appeared in the literature. The aim of this article is to review the most recent data about the role of the immune system in the pathogenesis of chronic cough.
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Abbreviations GERD – gastroesophageal reflux disease COPD – chronic obstructive pulmonary disease IL – interleukin CCR – CC chemokine receptor cys-LTs – cysteinyl-leukotrienes BAL – bronchoalveolar lavage
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ACE – angiotensin-converting enzyme
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Key words: cough, immune system, eosinophil, neutrophil.
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TRP – transient receptor potential
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1. Introduction
Chronic cough is among the most common symptoms for which patients worldwide seek
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medical attention [1]. Chronic cough is defined in adults as cough lasting for more than 8 weeks [2, 3]. According to a systematic review and meta-analysis, of published data originating from numerous countries, the overall prevalence of chronic cough is about 9.6% [4]. Chronic cough is
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a common symptom of various chronic diseases such as bronchiectasis, asthma, gastroesophageal reflux disease (GERD) and chronic rhinitis [5-7]. Chronic inflammation caused by inflammatory cells and cytokines plays a significant role in the pathogenesis of these conditions [8-10]. Moreover, female sex, advanced age and smoking status are also important risk factors of chronic cough [5, 6]. Studies have shown that cough, especially chronic, adversely affects quality of life,
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and has a large socioeconomic impact by increasing physician visits and sick leave days [11-13]. The vast majority of individuals with conditions that are commonly associated with cough,
such as asthma and GERD, do not have chronic cough. This implies that cough reflex sensitivities differ among individuals. The recently introduced term “Cough Hypersensitivity Syndrome”, supports the concept that hypersensitivity of airway sensory nerves may underlie chronic cough [14, 15]. It is known that in the pathogenesis of cough, the nervous system plays a vital role. The neurological mechanism of cough originates from stimulation of unmyelinated C fibers and
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myelinated Aδ fibers [16]. Most C fibers respond to a range of irritant stimuli of inflammatory origin, while Aδ fibers respond to mechanical and acid stimuli [17]. Recently more information about the role of the immune system and its interaction with the nervous system in the pathogenesis of cough has appeared in the literature [14, 17-23]. Immune cells release or activate a variety of inflammatory mediators such as prostaglandins, leukotrienes, major basic protein and others which stimulate peripheral nerves and induce cough [18-20, 23-25]. The aim of this article is to review
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the most recent data about the role of the immune system in the pathogenesis of chronic cough.
2. Methods
Original articles published during the period 2007-2018 were searched in Pubmed database
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using key words: cough, chronic cough, eosinophil, neutrophil, interleukin, immune system,
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pathogenesis.
3.1 Role of eosinophils in cough
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3. Discussion
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Eosinophils are important in the pathogenesis of allergic asthma and non-asthmatic eosinophilic bronchitis, [26] and cough is a common symptom of these diseases [26]. Kansal et al. investigated the correlation of induced sputum eosinophil levels with clinical parameters in mild
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and moderate persistent asthma in children aged 7–18 years [27]. Results revealed that sputum eosinophil percentage was significantly higher in moderate persistent asthma than that in mild persistent asthma. Reduction in sputum eosinophil percentage after three months of inhaled budesonide therapy in both mild and moderate persistent asthmatics was achieved. This eosinophil reduction had a significant positive correlation with decreased number of nights with cough [27].
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A study performed by Yu et al. showed that children with cough variant asthma had sputum eosinophil counts higher than 3% [28]. However, another study which analysed the link between the score on the Leicester Cough Questionnaire (LCQ) and sputum eosinophils in adults with severe asthma revealed no correlation between these variables [29]. However, chronic cough and sputum production were more prevalent in chronic obstructive pulmonary disease (COPD) patients with higher blood eosinophilia [30].
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A study which investigated patients with non-asthmatic eosinophilic bronchitis and chronic cough revealed that the sputum eosinophil level was significantly increased in these patients compared with healthy individuals and was positively associated with eotaxin and interleukin (IL) 4 level in sputum [31]. Wang et al. also found increased levels of IL-4 and IL-5 in peripheral blood mononuclear cells in children with cough variant asthma compared with healthy individuals [32]. These cytokines can be important in cough pathogenesis by activating eosinophils. It is known that eotaxin and IL-5 induce chemotaxis and migration of eosinophils to certain tissues via interaction
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with CC chemokine receptor (CCR) 3 which is expressed on eosinophils [31]. IL-4 also contributes to the activation and recruitment of eosinophils [31].
A possible link between chronic cough and eosinophils was suggested by the results of a
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study performed by Macedo et al. [24]. Patients were divided into two groups: chronic explained cough (associated with asthma, GERD, postnasal drip, etc.) and chronic idiopathic cough.
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Bronchial biopsies were performed in these patients. Results revealed that the number of eosinophils in tissue was significantly associated with goblet cell hyperplasia, basement membrane
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thickening, lymphocyte infiltration and neutrophil infiltration [24]. A greater degree of basement membrane thickening was observed in patients with chronic idiopathic cough compared with those
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with chronic explained cough.
In chronic airway diseases such as asthma, during acute viral infection, or with exposure to air pollutants, eosinophils are recruited to the airway nerves and interact with airway nerves,
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possibly through expression of chemotactic substances and adhesion molecules by the nerves [33]. Eosinophils can alter both parasympathetic and sensory nerve function [33-35]. These cells release major basic protein, which is an antagonist of M2 muscarinic receptors on parasympathetic nerves [33, 34]. Eosinophils also increase sensory nerve responsiveness by lowering neuronal activation threshold, stimulating nerve growth, and altering neuropeptide expression [35]. Experimental
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studies show that eosinophil granule-derived cationic proteins stimulate vagal C-fiber afferents in the lungs [36, 37]. The vagus nerve transmits sensory information from the lungs to the brainstem. C- fibers are known to be very important in pathogenesis of cough [16, 17]. Moreover, eosinophils produce cysteinyl-leukotrienes (cys-LTs) which are among the chemical mediators that play a major pathophysiological role in asthma. There is indirect evidence that cys-LTs can be important in the pathogenesis of cough. For example, treatment with leukotriene receptor antagonists can attenuate cough severity and capsaicin cough sensitivity [38].
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Mincheva et al. showed that this treatment relieved only cough due to upper airway cough syndrome or gastroesophageal reflux but not asthma [39]. These data suggest that cys-LTs can also be involved in the pathogenesis of cough.
3.2 Role of neutrophils in cough Neutrophils play an important role in chronic diseases causing cough such as COPD and GERD [40-42]. A study performed by Sumner et al. revealed that cough frequency was related to
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the percentage of sputum neutrophils [43]. Snijders et al. showed that seemingly healthy children with unexplained chronic cough had an increased percentage of neutrophils in bronchoalveolar lavage (BAL) fluid compared with the control group [44]. Moreover, Ferreira et al. found that
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BAL neutrophils were higher in atopic and nonatopic children with chronic cough compared with a control group [45]. The mechanism by which neutrophils may induce cough remains unclear.
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However, we can hypothesize that these cells cause inflammation through generation of reactive oxygen species and release proteases such as neutrophil elastase and cathepsins [8, 40, 42].
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Neutrophilic inflammation can sensitize peripheral airway nerves and induce the cough reflex [42, 43, 46, 47]. Neutrophils are activated by neutrophil-associated cytokines such as interleukin-8 and
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tumor necrosis factor-alpha [8, 41, 42]. Increased levels of these inflammatory mediators were found in the sputum of non-asthmatic chronic cough patients [41].
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3.3 Role of lymphocytes in cough
According to scientific literature, lymphocytes are also involved in cough mechanisms, especially in idiopathic cough. Birring et al. investigated patients with idiopathic cough and found a mild chronic lymphocytic inflammation in airway (predominately in female population) [48]. BAL lymphocytes count was higher in patients with idiopathic cough compared with healthy
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individuals. Authors suggested that the increased lymphocytes in the airway can be associated with autoimmune process [48]. Another study performed by Mund et al. confirmed these findings. They found increased level of CD4+ lymphocytes in the airways of females with idiopathic dry cough. [49]. We can raise the hypothesis that CD4+ lymphocytes mediated response can be associated with cough in chronic inflammatory airway diseases such as allergic asthma or eosinophilic bronchitis. The main pathogenetic background of these disease is T lymphocytes helper 2 (Th2)
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mediated inflammation. Cytokines which are secreted by Th2 (eg., interleukin (IL) - 5) activate eosinophils which role in cough is described previously. Studies of patients having non-asthmatic eosinophilic bronchitis, a common cause of chronic cough, revealed that IL-17 which is mainly produced by Th17 levels in sputum were higher compared with healthy subjects [50]. Moreover, higher IL-17 levels were observed in patients with eosinophilic and non-eosinophilic asthma compared with healthy subjects [50]. This study showed that sputum IL-17 level correlated with sputum neutrophils [50]. We can hypothesize that IL-17
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enhances neutrophilic inflammation which is important in cough pathogenesis.
3.4 Role of other immune components in cough
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The nervous system plays a vital role in cough pathogenesis. Small amino acidic molecules (neuropeptides) can affect inflammatory responses which can be important in the cough reflex,
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especially in chronic respiratory disorders [51, 52]. Substance P is a neuropeptide that is widely distributed in sensory peripheral nerves and in the central nervous system [53]. Substance P
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activates neurokinin-1 receptor [54]. Animal studies have demonstrated that substance P can be involved in cough pathogenesis [55, 56]. For example, Moreaux et al. showed a release of
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substance P in pigs after cough induction by citric acid [55]. Kohrogi et al. revealed that substance P stimulated cough in very low concentrations in guinea pigs [56]. A study by Qiu et al. demonstrated that patients with GERD and cough had significantly higher substance P and mast
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cell tryptase levels in sputum compared with healthy individuals and patients with GERD without cough [57]. Otsuka at al. showed that plasma substance P levels were significantly higher in patients with asthmatic and non-asthmatic cough compared to healthy controls but did not significantly differ between the two patient groups [58]. There is evidence that substance P inhibits apoptosis, increases migration and prolongs the survival of eosinophils [59]. These studies suggest
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that one pathway through which substance P may play a role in cough pathogenesis is by the activation of eosinophils. Substance P together with bradykinin may be involved in the pathogenesis of cough
induced by angiotensin-converting enzyme (ACE) inhibitors [60]. Substance P and bradykinin are degraded by ACE and accumulate in the upper respiratory tract or lung when the enzyme is inhibited [60]. It has been shown that exposure of guinea-pigs to bradykinin results in a significant enhancement of the cough response [61]. Bradykinin can stimulate prostaglandins which can be
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important in cough pathogenesis by activating sensory ganglia and vagal sensory nerves through transient receptor potential (TRP) channels [60, 62, 63]. Furthermore, animal studies have shown that prostaglandin E2 exacerbates bronchoconstriction-triggered cough through EP1 and EP3 receptors [62, 64]. The investigation of immune system in pathogenesis of cough is important for development of new treatment options. Relieving cough in patients with chronic cough, especially, idiopathic, often is a challenge. A few years ago, Harle et al. found that the drug blocking substance P through
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inhibition of neurokinin-1 receptor significantly reduced awake cough frequency in patients with lung cancer [65]. This year Smith et al. published data about the efficacy of Neurokinin-1 receptor antagonist Orvepitant for the treatment of chronic refractory cough. The results revealed that
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Orvepitant statistically and clinically significant improved objective daytime cough frequency and quality of life [66].
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The role of the immune system in the pathogenesis of cough is summarized in figure 1 and
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the main results of clinical studies of patients with cough are provided in table 1.
4. Conclusions
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In summary, there is significant evidence that the immune system may play an important role in the pathogenesis of chronic cough, a frequent symptom of chronic inflammatory diseases. Immune cells including eosinophils and neutrophils are most strongly implicated in cough
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development. Cytokines released or induced by these cells cause chronic inflammation which may sensitize peripheral airway nerves and induce cough. Further investigation of the mechanism(s) of chronic cough will hopefully promote the development of new therapeutic agents.
Acknowledgment
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The authors thank Prof. Peter Dicpinigaitis for critical review of this manuscript.
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Figure legend
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Figure 1. Summary of immune mechanisms in relation to cough pathogenesis [8, 17-27,
29-38, 40, 44, 45, 47, 50-54, 58, 59, 61-64]
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Table 1. Summary of the main results of studies of cough patients reviewed in this article [27, 28, 30, 31, 42-45, 50, 57, 58]
Zhang et al.
Neutrophil
Sumner et al. Snijders et al. Ferreira et al.
Substance P
Qiu et al.
Otsuka at al. Zhan et al.
Jo
ur na
lP
IL-17
of
Zysman et al.
ro
Yu et al.
Main results Eosinophil reduction in asthma positively correlated with decreased number of nights with cough Children with cough variant asthma had sputum eosinophil count higher than 3% Chronic cough was more prevalent in COPD patients with higher blood eosinophilia Sputum eosinophil level was significantly increased in patients with non-asthmatic eosinophilic bronchitis having cough compared with healthy individuals Cough frequency was related to percentage of sputum neutrophils Children with unexplained chronic cough had an increased percentage of neutrophils BAL compared with the control group BAL neutrophils were higher in children with chronic cough compared with control group Patients with GERD and cough had significantly higher substance P level in sputum compared with healthy individuals and patients with GERD without cough Plasma substance P levels were significantly higher in patients with asthmatic and non-asthmatic cough compared to healthy controls IL-17 level in sputum was higher in patients having non-asthmatic eosinophilic bronchitis compared with healthy subjects
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Reference Kansal et al.
re
Marker Eosinophil