Elevated substance P levels in nasal lavage fluids from patients with chronic nonproductive cough and increased cough sensitivity to inhaled capsaicin

doi:10.1016/S0091-6749(03)01784-6

Journal of Allergy and Clinical Immunology

Volume 112, Issue 4, October 2003, Pages 695-701

https://doi.org/10.1016/S0091-6749(03)01784-6 Get rights and content

Abstract

Background

The exact mechanism of a chronic nonproductive cough is sometimes unclear when patients who are without symptoms or signs indicating the major causes of chronic cough remain undiagnosed.

Objective

We hypothesized that some neurochemical alterations in the sensory nerves in the cough reflex may occur in the upper airway of chronic nonproductive cough patients.

Methods

We took nasal lavage fluid (NLF) specimens from 38 patients with a chronic nonproductive cough as the sole presenting symptom. All 38 had normal chest radiography, spirometry, and bronchial responsiveness. We likewise took NLF specimens from 14 healthy control subjects. We used a capsaicin cough provocation test to determine cough sensitivity and considered the value of C₅ (the lowest capsaicin concentration inducing 5 consecutive coughs) as an index of cough sensitivity. We measured levels of substance P of NLF specimens by using ELISA. In addition, we evaluated the clinical response of each patient after subsequent therapeutic trials with an antihistamine and decongestant for 2 weeks.

Results

By using capsaicin cough sensitivity as the basis for grouping the study subjects, we divided the patients into 2 groups: an increased cough sensitivity group (ICS, C₅ <32 μmol/L) and a normal cough sensitivity (NCS) group. Patients with ICS showed an elevated SP concentration in NLF (median value, 408 pg/mL) compared with that of the NCS group (237 pg/mL) and the control subjects (138 pg/mL) (P < .01). The median value of the percentage of remnant cough after therapeutic trial compared with the cough status before treatment was significantly higher in the ICS subgroup (70%) than that of NCS (25%) (P < .05).

Conclusions

Elevated substance P contents in NLF specimens were associated with ICS in patients with chronic nonproductive cough, suggesting a neurochemical abnormality in the upper airway.

Section snippets

Subjects

Patients with a chronic nonproductive cough lasting more than 1 month as the sole presenting symptom were recruited from the outpatient department of our institution. All patients were nonsmokers, without any typical PND symptoms or signs, such as purulent sputum, rhinorrhea, sneezing, and nasal stuffiness, or any GER symptoms, including substernal pain and acid regurgitation. Each patient underwent a simple chest radiograph, Waters (occipitomental) view radiography, allergen skin prick testing

Clinical characteristics and distribution of cough sensitivity of patients and control subjects

We analyzed the distribution of the C₅ and the CC64 values obtained from the patients and control subjects and found a close negative correlation between them (r = −0.662, P < .0001, Fig 2). In this analysis, 6 normal control subjects and 6 patients with chronic cough were excluded because their C₅ values could not be determined exactly, as fewer than 4 coughs were induced during the capsaicin challenge test. The C₅ values for all the control subjects were >32 μmol/L, so we divided the patients

Discussion

The results of this study demonstrated that local SP content of the upper airway was elevated in some patients with chronic nonproductive cough showing ICS without bronchial hyperresponsiveness. This indicates that a neurochemical alteration of the upper airway may be related to the mechanism of ICS and may ultimately develop into a chronic cough.

Although ICS has been regarded as a distinctive feature in some patients with chronic cough, the exact mechanism has not been well defined. In our

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The aim of this study was to explore the effects of spray cryotherapy (SCT) on cough receptors and airway microenvironment in a canine model of chronic bronchitis. We examined the expression of transient receptor potential vanilloid 1/4 (TRPV1/4) and the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) at the gene and protein levels before and after SCT. In addition, we explored whether TRPV1/4 could regulate inflammatory factors via mediator adenosine triphosphate (ATP). The levels of ATP and cytokines in alveolar lavage fluid and cell supernatant were measured using ELISA. SCT effectively downregulated the expression of TRPV1/4 and SP/CGRP in canine airway tissues with chronic bronchitis and reduced the levels of inflammatory mediators and cytokines that affect cough receptor sensitivity, achieving cough relief. TRPV1/4 - ATP - inflammatory cytokines axis has been demonstrated at the cellular level, which in turn modulate the milieu of the airways and promote the formation of a cough feedback loop. Our study has fully revealed the specific mechanism of SCT in treating cough in a canine model of chronic bronchitis, providing a solid theoretical basis for future clinical treatment.
Neurokinin 1 and 2 receptors are involved in PGE<inf>2</inf>- and citric acid-induced cough and ventilatory responses
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For example, plasma or sputum SP levels were markedly elevated in patients with both asthmatic and nonasthmatic cough (Otsuka et al., 2011; Patterson et al., 2007). Moreover, SP levels in nasal lavage fluids were enhanced in patients with chronic nonproductive cough and oversensitized cough response to inhalion of CAP (Cho et al., 2003). SP aerosols given to healthy subjects or to patients with asthma did not cause cough, but evoked a sensation of tightness in the asthmatic chest, indicating that some peripheral sensory nerves were being stimulated (Joos et al., 1987).
Exposure to aerosolized citric acid (CA, 150 mM) and prostaglandin E₂ (PGE₂, 0.43 mM) for 10 min in guinea pigs reportedly produces the distinct cough patterns (Type I vs. II) and ventilatory responses (long-lasting hyperventilation vs. brief tachypnea) even though triggering the same cough numbers. Type I and II coughs are primarily mediated by activation of TRPV1 and EP3 receptors (a PGE₂ receptor) of vagal C-fibers respectively. Substance P (SP) and neurokinin A (NKA) released by vagal pulmonary sensory fibers peripherally are capable of affecting CA-induced cough and ventilation via preferentially activating neurokinin 1 and 2 receptors (NK₁R and NK₂R) respectively. This study aimed to define the impacts of CA- and PGE₂-exposure on pulmonary SP and NKA levels and the roles of NK₁R and NK₂R in modulating CA- and PGE₂-evoked cough and ventilatory responses. In unanesthetized guinea pigs, we determined: (1) pulmonary SP and NKA contents induced by the CA- or PGE₂-exposure; (2) effects of CP-99994 and SR-48968 (a NK₁R and a NK₂R antagonist respectively) given by intraperitoneal injection (IP) or aerosol inhalation (IH) on the CA- and PGE₂-evoked cough and ventilatory responses; and (3) immunocytochemical expressions of NK₁R/NK₂R in vagal C-neurons labeled by TRPV1 or EP3 receptors. We found that CA- and PGE₂-exposure evoked Type I and II cough respectively associated with different degrees of increases in pulmonary SP and NKA. Applications of CP-99994 and SR-48968 via IP and IH efficiently suppressed the cough responses to CA with less impact on the cough response to PGE₂. These antagonists inhibited or blocked the ventilatory response to CA and caused hypoventilation in response to PGE₂. Moreover, NK₁R and NK₂R were always co-expressed in vagal C-neurons labeled by TRPV1 or EP3 receptors. These results suggest that SP and NKA endogenously released by CA- and PGE₂-exposure play important roles in generating the cough and ventilatory responses to CA and PGE₂, at least in part, via activation of NK₁R and NK₂R expressed in vagal C-neurons (pulmonary C-neurons).
The research of the possible mechanism and the treatment for capsaicin-induced cough
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In addition, TRPV1 can mediate airway neurogenic inflammation caused by SP, CGRP, NKA (released by sensory nerve terminals), which may also play an important role in the enhancement of cough sensitivity [12,36,37]. Cho et al. observed in nasal fluids that were rinsed from chronic cough patients, that the SP levels were significantly higher in the increased cough sensitivity group than in the normal cough sensitivity group [38]. The consequences of airway neurogenic inflammation include an increase in vascular permeability, excess mucus production, plasma exosmosis and edema in the mucosa.
Unexplained chronic cough (UCC) affects millions of patients worldwide. New therapeutic approaches to this condition are urgently needed, since current treatment options provide only symptomatic relief. Cough reflex hypersensitivity has been shown to play an important role in the pathogenesis of UCC. The transient receptor potential vanilloid type 1 (TRPV1) is present on peripheral terminals of airway sensory nerves and modulation of its activity represents a potential target for the pharmacological treatment of UCC. The aim of this study was to explore the efficacy and the possible mechanism of SB705498, a TRPV1 antagonist, for cough in a capsaicin-induced cough animal model (i.e. guinea pigs). Induction of cough by capsaicin was successfully implemented in the guinea pigs, and the animals that met the inclusion criteria were randomly divided into four treatment groups: (1) Saline inhalation group (NSInh group, N = 10, negative control group), (2) Codeine phosphate intraperitoneal injection group (CPInp group, N = 10, positive control group), (3) SB705498 inhalation group (SBInh group, N = 10), (4) SB705498 intragastric administration group (SBIng group, N = 10). After treatment with above compounds, the capsaicin-induced cough experiment was performed again. The cough numbers and the cough incubation periods were recorded to evaluate the antitussive effect of SB705498. Enzyme-linked immunosorbent assay (ELISA) testing and Immunohistochemistry (IHC) staining for substance P (SP), calcitonin gene related peptide (CGRP) and neurokinin A (NKA) expression in lung and brain tissues were performed as an indication of neurogenic inflammation. Hematoxylin-Eosin (H&E) staining was used to observe the pathology morphology of lung and brain tissues. When the CPInp, SBInh and SBIng groups were compared to the NSInh group, the cough numbers were significantly reduced (p < .001), while the cough incubation periods were significantly prolonged (P < .001). In addition, the expression of SP, CGRP and NKA in lung and brain tissue was reduced (P < .05). None of the animals in the four groups exhibited lung and brain parenchymal inflammation. The results from this study showed that SB705498 had a significant antitussive effect, could reduce the neurogenic inflammation by reducing the expression of SP, CGRP and NKA in a capsaicin-induced cough model of guinea pigs. The results further indicated that TRPV1 played an important role in UCC and SB705498 might be a promising therapeutic agent for UCC.
Antitussive activity of the Schisandra chinensis fruit polysaccharide (SCFP-1) in guinea pigs models
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CHS is characterized by cough reflux hypersensitivity, which can be evaluated by cough challenge test with protussive agents such as capsaicin or ally isothiocyanate (Morice, 2011). The pathogenesis of CHS is related with the activation of transient receptor potential vaniloid 1 (TRPV1), transient receptor potential ankyrin 1 (TRPA1) in airway (Groneberg et al., 2004; Birrell et al., 2009; Andrè et al., 2009), airway inflammation (Jatakanon et al.,1999; Cho et al., 2003), immune dysfunction (Birring et al., 2003; Mund et al., 2005; Grace et al., 2012), submucosa injury mediated by oxidative stress (Koskela and Purokivi, 2013; Rahman and MacNee, 2000) and mucus hypersecretion (Niimi et al., 2005; Thai et al., 2008; Jackson, 2001) etc. Currently available drugs are ineffective for patients with CHS.
Schisandra chinensis (Turcz.) Baill. (S. chinensis), locally known as “Wuweizi”, has been used in the treatment of chronic cough as prescription medications of Traditional Chinese Medicine for thousands of years. However, the components of antitussive activity of S. chinensis and the mechanism are poorly understood.
This study aims to investigate the antitussive activity of polysaccharides extracted from S. chinensis.
S. chinensis fruit polysaccharide-1 (SCFP-1) was extracted by 95% ethanol and distilled water successively, and then the water extraction was isolated with chromatographic columns. The preliminary characterization of SCFP-1 was analyzed by gel permeation chromatography (GPC), gas chromatography–mass spectrometry (GC–MS) and some other recognized chemical methods. Antitussive potential of SCFP-1 was estimated at dose of 250, 500, and 1000 mg/kg respectively by peroral administration in a guinea pigs model with cough hypersensitivity induced by cigarette smoke (Chronic cough model) or acute cough guinea model induced by citric acid (Acute cough model). Also, the time-dependent antitussive effect of SCFP-1 were evaluated with acute cough model, and compared with codeine.
The molecular of SCFP-1 was 3.18×10⁴ Da, mainly being composed of glucose and arabinose (66.5% and 29.4%, respectively). Peroral administration of SCFP-1 at 250, 500, and 1000 mg/kg showed remarkable suppressive effects respectively on cough in both of chronic cough model and acute cough model. Meanwhile, inflammatory cell in BALF and some typical characteristics of nonspecific airway inflammation in animals exposed to CS was significantly attenuated after pretreatment with SCFP-1. The cough suppression of SCFP-1 (500 mg/kg) stablly lasted during the whole 5 h of time-dependent experiment, while no positive effect was observed after 300 min of oral administration of codeine.
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Neuropeptide levels in nasal secretions from patients with and without chronic cough
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A previous study measured SP in nasal lavage fluid in subjects with dry cough and used capsaicin sensitivity to divide subjects into increased cough sensitivity and normal cough sensitivity.7 Subjects with higher cough sensitivity had higher mean SP levels.7 Our study further supports a role for neuropeptides in patients with chronic cough by demonstrating that elevated neuropeptide levels are not simply a reflection of increased posterior nasal drainage, but rather appear to be specific to cough.
The pathophysiology of upper airway cough syndrome is not well understood.
To investigate the levels of neuropeptides found in nasal mucus of subjects with and without the complaint of chronic cough.
Preformed nasal mucus from 26 subjects complaining of postnasal drip with chronic cough and 17 without self-reported chronic cough was collected at the time of presentation. The nasal secretions were assayed for 3 neuropeptides—substance P (SP), calcitonin gene-related peptide (CGRP), and Neurokinin A (NKA)—that have been previously linked to chronic cough.
Coughing subjects with postnasal drip have significantly higher levels of CGRP and SP than noncoughing subjects with postnasal drip (69.0 ng vs 4.6 ng, P < .001 and 4.5 ng vs 3.4 ng, P = .004). The differences in NKA levels in nasal secretions between coughing and noncoughing subjects did not reach statistical significance (16.3 ng vs 3.4 ng, P = .067).
Both CGRP and SP levels are elevated in preformed nasal secretions of coughing subjects when compared with noncoughing subjects. Additional studies are needed to clarify whether CGRP and SP levels in preformed nasal secretions may assist in diagnosis or predicting treatment response in patients presenting with chronic cough.
Immunoassay-based measurement of clinical biomarkers for monitoring changes in nasal cavity
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Many drugs for treatment of allergies, migraine headaches, inflammation, and other indications are administered into the nasal cavity providing access to the immune and central nervous systems. One of the concerns for using this route of administration is potential damage to the nasal epithelium and mucosal regions. We assembled a panel of clinical biomarkers that can be used to monitor changes in the nasal epithelium, mucosa, and olfactory regions in preparation for clinical trials involving drugs administered via intranasal route. These biomarkers included albumin, elastase, IL-6, IL-8, lactoferrin, myeloperoxidase and nerve growth factor.
Immunoassays were developed and used to measure changes in these biomarkers in nasal lavage samples collected twice daily from 30 assumed-healthy volunteers over a 2-day period. Various statistical methods including analysis of variance (ANOVA), paired t-test and Pearson's product–moment correlation were used to evaluate the data.
Although the basal levels of these biomarkers were varied among subjects, the data show that the concentrations of albumin, elastase and IL-8 were significantly higher in samples collected in the morning compared to samples collected later during the day. Pre-washing nasal cavity prior to collecting nasal lavage samples did alter the measurement of elastase and albumin, but did not influence the levels of the other biomarkers.
These data show that this panel of biomarkers can be used to monitor changes in the nasal cavity including those affected by diurnal fluctuations. These results also provide useful baseline values and sources of variability for each biomarker that could be used to help design clinical trials.

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Asthma, Rhinitis, Other Respiratory DiseasesElevated substance P levels in nasal lavage fluids from patients with chronic nonproductive cough and increased cough sensitivity to inhaled capsaicin

Abstract

Background

Objective

Methods

Results

Conclusions

Section snippets

Subjects

Clinical characteristics and distribution of cough sensitivity of patients and control subjects

Discussion

Lancet

Chest

Lancet

Respir Med

An algorithmic approach to chronic cough

Ann Intern Med.

Chronic cough: the spectrum and frequency of causes, key component of diagnostic evaluation and outcomes of specific therapy

Am Rev Respir Dis

Eosinophilic bronchitis is an important cause of chronic cough

Am J Respir Crit Care Med

Abnormal intraepithelial airway nerves in persistent unexplained cough

Am J Respir Crit Care Med

Airway inflammation as an assessment of chronic nonproductive cough

Chest

Airway inflammation in non-asthmatic subjects with chronic cough

Am J Respir Crit Care Med

Increased neutrophils and cytokines, TNF-a and IL-8, in induced sputum of non-asthmatic patients with chronic dry cough

Thorax

Airway inflammation, airway responsiveness and cough before and after inhaled budesonide in patients with eosinophilic bronchitis

Eur Respir J

Sensitivity of the cough reflex in patients with chronic cough

Eur Respir J

Capsaicin cough sensitivity decreases with successful treatment of chronic cough

Am J Respir Crit Care Med

Effect of loratadine, an H1 antihistamine on induced cough in non-asthmatic patients with chronic cough

Thorax

Increased cough reflex associated with angiotensin converting enzyme inhibitor cough

Br Med J

Tussive effect of capsaicin in patients with gastroeosphageal reflux without cough

Am J Respir Crit Care Med

Asthma, Rhinitis, Other Respiratory Diseases
Elevated substance P levels in nasal lavage fluids from patients with chronic nonproductive cough and increased cough sensitivity to inhaled capsaicin