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Clinical Investigations

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Plasma Substance P Levels in Patients with Persistent Cough

Otsuka K.a · Niimi A.a · Matsumoto H.a · Ito I.a · Yamaguchi M.a · Matsuoka H.a · Jinnai M.a · Oguma T.a · Takeda T.a · Nakaji H.a · Chin K.b · Sasaki K.c · Aoyama N.c · Mishima M.a

Author affiliations

Departments of aRespiratory Medicine and bRespiratory Care and Sleep Control Medicine, Kyoto University, Kyoto, and cKyowa Medex Co., Ltd., KM Assay Center, Nagaizumi-cho, Japan

Corresponding Author

Dr. Akio Niimi

Department of Respiratory Medicine

Graduate School of Medicine, Kyoto University

54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan)

Tel. +81 75 751 3830, E-Mail niimi@kuhp.kyoto-u.ac.jp

Related Articles for ""

Respiration 2011;82:431–438

Abstract

Background: Substance P (SP) is involved in the pathogenesis of cough in animal models. However, few studies in humans have been reported and the roles of SP in clinical cough remain obscure. Objectives: To clarify the relevance of plasma levels of SP in patients with persistent cough. Methods: We studied 82 patients with cough persisting for at least 3 weeks and 15 healthy controls. Patients were classified as having asthmatic cough (cough-variant asthma and cough-predominant asthma; n = 61) or nonasthmatic cough (n = 21; postinfectious cough, n = 6; gastroesophageal reflux disease, n = 5; idiopathic cough, n = 5, and others, n = 5). Correlations were evaluated between plasma SP levels as measured with ELISA and methacholine airway hyperresponsiveness (airway sensitivity and airway reactivity), capsaicin cough sensitivity, sputum eosinophil and neutrophil counts, and pulmonary function. Results: Plasma SP levels were significantly elevated in patients with both asthmatic and nonasthmatic cough compared with controls [31.1 pg/ml (range 18.0–52.2) and 30.0 pg/ml (range 15.1–50.3) vs. 15.4 pg/ml (range 11.3–23.7); p = 0.003 and p = 0.038, respectively] but did not differ between the two patient groups (p = 0.90). Plasma SP levels correlated with airway sensitivity (threshold dose of methacholine) in the patients with asthmatic cough (r = –0.37, p = 0.005) but not with airway reactivity, cough sensitivity, FEV1 values, or sputum eosinophil and neutrophil counts in either group. Conclusions: Increased levels of SP in plasma are associated with persistent cough in humans and might be related to airway sensitivity in asthmatic cough.

© 2011 S. Karger AG, Basel


Introduction

Substance P (SP) is one of several neuropeptides that are widely distributed in sensory peripheral nerves [1] and in the central nervous system [2]. Ample evidence supports a role for SP in the mechanism of cough in animal models [3,4,5]. Although its activity in cough induction is controversial [3,6], SP elicits a sensitizing effect on the cough reflex [4,5], while conflicting results also exist [7].

A few studies have examined the relationship between SP and cough in humans. Patients with attenuated cough sensitivity associated with advanced Parkinson’s disease and aspiration pneumonia have reduced SP levels in sputum [8,9]. SP-immunoreactive nerve densities of the bronchial epithelium are increased in patients with cough-variant asthma (CVA) compared with those of patients with classic asthma and healthy controls [10]. Levels of SP are also increased in nasal lavage fluid [11] and sputum [12] from patients with nonasthmatic cough. Furthermore, elevated numbers of calcitonin gene-related peptide (CGRP)-immunoreactive nerves in the bronchial epithelium of patients with idiopathic persistent cough correlate with cough sensitivity to inhaled capsaicin, whereas levels of SP are not elevated or correlated with cough sensitivity [13]. Yoshihara et al. [14] have shown that plasma SP levels are elevated in patients with paroxysmal cough due to pertussis. However, further information about plasma SP levels in persistent cough of other etiologies has not been reported.

Cough is attributed to various causes [15,16,17,18]. Persistent cough due to asthmatic and nonasthmatic causes might involve different mechanisms since asthmatic cough is elicited by bronchoconstriction whereas nonasthmatic cough might be primarily ascribed to increased cough sensitivity. Although cough and bronchoconstriction often occur simultaneously, they are regarded as separate reflexes [19]. Bronchoconstrictors including methacholine provoke cough without altering the cough reflex [20].

Other than cough, evidence shows that SP functions in bronchoconstriction and airway hyperresponsiveness (AHR) [21,22]. Therefore, SP might be differently involved in the mechanisms of both asthmatic and nonasthmatic cough. Indeed, SP contents in the nasal lavage fluid of patients with nonasthmatic cough are associated with increased cough sensitivity [11], whereas in asthma sputum levels of SP correlate with airflow obstruction [23].

Here, we compared plasma SP levels in patients with combined subacute cough (duration of 3–8 weeks) and chronic cough (>8 weeks) as defined by a guideline [15] with those of healthy controls. We also examined the relationship between plasma SP levels and various clinical and functional indices to determine the roles of SP in patients with asthmatic and nonasthmatic cough.

Subjects and Methods

Participants

We studied 82 consecutive patients who were referred to the outpatient asthma and cough clinic of Kyoto University Hospital between October 2007 and August 2009 because of cough that had persisted for at least 3 weeks. None of the patients had abnormal chest radiographic findings or had been prescribed angiotensin-converting enzyme inhibitors, oral or inhaled corticosteroids, leukotriene receptor antagonists, or other antiallergic drugs. None had been taking drugs that may interfere with circulating SP levels, such as antihistamines, angiotensin-converting enzyme inhibitors, or centrally acting drugs such as dopamine receptor agonists. All patients were either never-smokers or former smokers who had smoked less than 10 pack-years and had quit smoking more than 1 year prior to the study.

Causes of cough were determined according to Japanese cough guidelines [16]. In brief, patients with AHR to methacholine or reversible airflow obstruction and improvement of coughing with β2-agonists were considered as having chronic cough due to asthma. Patients with cough as the sole or predominant symptom (CVA or cough-predominant asthma) were included and were categorized as having asthmatic cough. The others were categorized as having nonasthmatic cough caused by the following [16]: sinobronchial syndrome (chronic sinusitis complicated by neutrophilic airway inflammation of the lower airways) [17,24] diagnosed based on positive sinus images, and symptoms related to chronic sinusitis improved with macrolides; gastroesophageal reflux disease (GERD) based on response to treatment with proton pump inhibitors; postinfectious cough based on a history of upper respiratory tract infection followed by cough that spontaneously subsided; atopic cough based on findings suggesting an atopic predisposition or induced sputum eosinophilia as well as a response to antihistamines [16,25]; cough due to pertussis based on the typical clinical course of pertussis and a positive antipertussis toxin antibody reaction, and idiopathic cough for which extensive examinations and intensive therapeutic trials were negative or failed to reveal any conclusive findings. The numbers of patients who underwent more specialized and detailed examinations or assessment were as follows: 9 for thoracic CT, 4 for sinus CT, 3 for esophageal endoscopy, 3 for bronchoscopy, and 3 for ENT consultations. To compare the plasma SP levels among different causes of subacute and chronic cough, patients with cough due to multiple causes were not included in the cohort who had asthma and GERD (n = 4), postinfectious cough and GERD (n = 2), asthma and sinobronchial syndrome (n = 2), or sinobronchial syndrome and GERD (n = 1).

We also studied 15 healthy controls recruited from our hospital staff who had no history of respiratory disease. We excluded individuals with atopic dermatitis from this study because its presence positively affects the plasma SP levels [26]. The Ethics Committee of Kyoto University approved the research protocol (approval No. E-300) and written informed consent was obtained from all participants.

Measurement of Plasma Levels of SP

Blood was sampled at presentation in all subjects. Samples were immediately centrifuged and plasma was mixed with an equal volume of a stabilizer (Kyowa Medex Co., Ltd., Nagaizumi-cho, Japan) that inhibits neutral endopeptidase [27]. The samples were frozen at –20°C. Investigators who were blinded to the clinical conditions of the patients measured plasma SP levels using a competitive ELISA method [27,28]. The sensitivity of this assay is 4.1 pg/ml. The specificity of the assay for SP measurement is 100%, and the assay does not significantly cross-react with neurokinin A or neurokinin B.

Sputum Induction and Processing

Sputum was induced and processed as described by Pin et al. [29] with slight modifications [30]. In brief, after pretreatment with salbutamol, sputum was induced by inhalation of hypertonic saline (3%) solution for 15 min from an ultrasonic nebulizer. Adequate plugs of sputum were treated with 0.1% dithiothreitol (Sputasol; Oxoid Ltd., Hampshire, UK) followed by Dulbecco’s phosphate-buffered saline (PBS). Eosinophil and neutrophil percentages were determined by counting at least 400 nonsquamous cells on centrifuged preparations visualized by May-Grünwald-Giemsa staining.

Our primary purpose in evaluating sputum cells was to investigate the association of cellular inflammation of the airways with plasma levels of SP. Sputum cell differentials were also used for the diagnosis of disease, e.g. atopic cough.

Pulmonary Function Test

We measured forced vital capacity (FVC), FEV1, and forced mid-expiratory flow (FEF25–75%) using a Chestac-65V (Chest MI Corp., Tokyo, Japan) as described [31].

Methacholine Challenge Test

We determined AHR by measuring respiratory resistance (Rrs; cm H2O/l/s) (Astograph™; Chest, Tokyo, Japan) under continuous methacholine inhalation as described [32,33]. The index of airway sensitivity was Dmin, i.e. the cumulative dose of inhaled methacholine at the inflection point where Rrs started to continuously increase. One unit of Dmin is equivalent to a dose of 1 mg/ml of methacholine inhalation for 1 min. When the Rrs did not increase despite methacholine inhalation at the highest concentration, Dmin was assigned a value of 50 units, which was the total cumulative dose of methacholine. The slope of the respiratory dose-response curve was used as the measure of airway reactivity [33]. Fifty-nine patients with asthmatic cough and all 21 patients with nonasthmatic cough underwent the test.

Capsaicin Cough Sensitivity Test

Cough sensitivity was tested by continuous inhalation of capsaicin as described [34], with a slight modification of capsaicin concentrations [24]. Ten doubling concentrations of capsaicin solution (0.61–312 µM) were inhaled until ≥5 coughs were induced. Each concentration of capsaicin was inhaled for 15 s during tidal breathing every 60 s. The concentration of capsaicin causing ≥5 coughs is referred to as C5 [24,34]. Fifty-nine patients with asthmatic cough and all 21 patients with nonasthmatic cough underwent the test.

Statistical Analysis

Data are expressed as median values (25th to 75th percentiles) except when noted otherwise and were analyzed using JMP 6.0 (SAS, Cary, N.C., USA). Comparisons of 2 and 3 groups were achieved using Mann-Whitney and Kruskal-Wallis tests, respectively, and the latter were analyzed post hoc using the Steel-Dwass test [35,36,37]. Categorical data were compared using the χ2 test. Correlations between data were analyzed using Spearman’s rank correlation test. p < 0.05 was considered statistically significant.

Results

Characteristics of the Three Groups

Table 1 shows the characteristics of the 61 patients with asthmatic cough, 21 patients with nonasthmatic cough, and 15 controls. Only the ratios of sputum eosinophils significantly differed among the three groups.

Table 1

Characteristics of the three subject groups

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Cough in the nonasthmatic cough group was due to postinfection (n = 6), GERD (5), atopic cough (2), pertussis (2), and sinobronchial syndrome (1) but was idiopathic in 5 patients.

Outcomes in Patients with Asthmatic and Nonasthmatic Cough

Table 2 shows the outcomes of the two patient groups. Two of the patients with asthmatic cough were ineligible for AHR analysis since the inflection point where Rrs increased could not be determined because severe coughing was elicited. Patients with asthmatic cough were significantly more sensitive to methacholine as determined by Dmin than those with nonasthmatic cough. C5 was marginally lower in patients with nonasthmatic cough than in those with asthmatic cough.

Table 2

Characteristics of the two patient groups

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Comparison of Plasma SP Levels among the Three Groups

Plasma SP levels were significantly higher in patients with asthmatic and nonasthmatic cough compared to healthy controls [31.1 pg/ml (range 18.0–52.2) and 30.0 pg/ml (range 15.1–50.3) vs. 15.4 pg/ml (range 11.3–23.7)] but did not significantly differ between the two patient groups (fig. 1).

Fig. 1

Comparison of plasma SP levels among groups. Plasma SP levels are elevated in patients with asthmatic and nonasthmatic cough compared with controls, while the two patient groups do not significantly differ.

http://www.karger.com/WebMaterial/ShowPic/224966

Relationships between Plasma SP Levels and Clinical Indices

Plasma SP levels significantly correlated with airway sensitivity determined by Dmin only in patients with asthmatic cough (table 3; fig. 2). Plasma SP levels did not correlate with cough duration, airway reactivity, capsaicin cough sensitivity, spirometric indices, or sputum neutrophil and eosinophil counts in either patient group (table 3).

Table 3

Correlations between plasma SP levels and clinical indices in the two patient groups

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Fig. 2

Correlation between plasma SP levels and airway sensitivity. Plasma SP levels negatively correlate with Dmin in asthmatic cough but not in nonasthmatic cough. Logarithmic data are presented for Dmin.

http://www.karger.com/WebMaterial/ShowPic/224965

Discussion

We measured plasma levels of SP in patients with subacute and chronic cough of various origins and healthy subjects. We discovered that plasma SP levels are elevated in patients with cough of asthmatic and nonasthmatic origins. We also found that plasma SP levels correlate with airway sensitivity in patients with asthmatic cough. These results indicate that SP is involved in both asthmatic and nonasthmatic cough, and its role in the mechanisms of these types of cough might differ.

SP synthesized in the cell body of C-fibers is transported along axons towards the peripheral and central terminals, where it is stored in large granular vesicles. C-fiber activation evokes SP release into the airway dependent on the axon reflex in guinea pigs. Airway SP causes bronchospasm, vasodilation, edema, and mucus secretion, which secondarily evokes the activation of rapidly adapting receptors (RARs) in the airway, resulting in an enhanced cough reflex [5,6]. The sensitizing effect of SP on RARs has also been demonstrated in the central nervous system, especially in the nucleus tractus solitarius, which also results in an enhanced cough reflex [38,39]. While airway SP levels or expression in patients with persistent cough are conflicting [10,11,12,13,40,41], we found elevated plasma SP levels in patients with persistent asthmatic and nonasthmatic cough.

We found that SP may be associated with airway sensitivity in asthmatic cough. Airway sensitivity and airway reactivity are two major components of AHR and might have different underlying mechanisms [33,42]. Both airway sensitivity and reactivity are associated with SP. Umeno et al. [22] reported that intravenous SP increases airway sensitivity to histamine in guinea pigs and Cheung et al. [21] showed that inhaled SP enhances maximal airway narrowing to methacholine in patients with asthma. Airway sensitivity may be determined by the strength of the stimulus that triggers the airways to constrict, e.g. epithelial damage, neural control, and inflammatory cell numbers, while airway reactivity may be caused by the responsiveness of airways to applied stimuli such as smooth muscle contractility, viscous and elastic loads, and airway swelling [42]. Our results suggest that SP plays a role in the pathophysiology of asthmatic cough by affecting airway sensitivity.

Although levels of plasma SP were higher in patients with nonasthmatic cough than in healthy controls, we found no correlation between plasma SP levels and various indices including capsaicin cough sensitivity. This is in conflict with the findings of Cho et al. [11], who showed that SP levels in nasal lavage fluid correlate with capsaicin cough sensitivity in patients with nonasthmatic cough. This discrepancy might be attributed to the different sample sources or the smaller sample size in our study. Indeed, although Cho et al. [11] found a correlation between SP in nasal lavage fluid and cough sensitivity in all 38 of their patients with nonasthmatic cough, no correlation was evident when the patients were separated into 2 equal, separately analyzed groups (n = 19 for each) with increased and normal cough sensitivity.

The two phenotypes of asthma might involve different pathophysiological mechanisms: CVA or cough-predominant asthma and classic asthma that predominantly presents with wheezing. De Diego et al. [43] reported that although classic asthma and CVA have similar profiles of airway inflammatory markers their relationships with AHR and cough sensitivity differ. Lee et al. [10] found increased SP-immunoreactive nerve densities in patients with CVA but not in those with classic asthma. SP is associated with neurogenic inflammation and subsequent airflow obstruction in asthma [23,44]. We found no correlation between plasma SP levels and spirometric indices, which contradicts the findings of Tomaki et al. [23], who found a negative correlation between sputum SP levels and FEV1/FVC in patients with classic asthma. This discrepancy might be attributed to the different sample sources and less prominent airflow obstruction in our patients (FEV1/FVC of 80.3% by average) compared with those of Tomaki et al. [23] (71.3%).

Airway inflammation stimulates receptors of unmyelinated C-fibers of the vagus nerve, thus causing the release of tachykinins such as SP from the C-fibers [11,45,46]. A correlation between sputum SP levels and sputum eosinophil count has been reported in asthma [23]. Since patients with CVA show evidence of airway inflammation with increased eosinophils [47] and since nonasthmatic cough might be associated with increased neutrophils [48], we evaluated the correlation between plasma SP levels and sputum counts of eosinophils and neutrophils in each patient group. However, we found no correlation between plasma SP levels and these sputum cells in either patient group. Circulating levels of SP might not be related to cellular inflammation of the airways in patients with persistent cough.

Our study has some limitations. Firstly, we could not determine whether SP levels in plasma reflect those in the airways. Moreover, although SP is widely distributed in the central and peripheral nervous system, there is increasing evidence that it may be synthesized and released from inflammatory cells such as eosinophils, monocytes and macrophages, lymphocytes, and dendritic cells [49,50,51,52]. Therefore, elevated levels of SP in plasma may reflect overexpression of SP in inflammatory cells as well as those in sensory nerves. Secondly, atopic dermatitis might have influenced the levels of SP in plasma [53]. Atopic dermatitis was present in 8 patients with asthmatic cough but in none of the patients with nonasthmatic cough. However, we found no difference in plasma SP levels between patients with and without atopic dermatitis (p = 0.51). Thirdly, the sample size of patients with nonasthmatic cough was small, and the etiology of their cough was diverse. We found no difference in plasma SP levels among the 3 most common diagnostic subgroups of nonasthmatic cough [postinfectious cough (n = 6), GERD (n = 5), and idiopathic cough (n = 5); p = 0.196 by Kruskal-Wallis test]. Future larger studies might clarify the roles of SP, especially in nonasthmatic cough. Fourthly, while the success rate of sputum induction in our previous series of 407 patients with classic asthma was 73.0% [54], the success rate in the present study was lower (57/97, 59%). This may be because cough due to CVA or nonasthmatic origins such as GERD is more dry or nonproductive in nature compared with the cough of classic asthma [55], and ‘healthy’ controls do not present with sputum by definition. Fifthly, patients diagnosed as not having GERD might actually have had GERD, because the diagnosis of GERD solely depended on the response to specific therapy not involving the gold standard for the diagnosis. The same is true for more uncommon causes of cough such as obstructive sleep apnea and tracheal collapse.

Despite these limitations, the elevated plasma SP levels in patients with asthmatic and nonasthmatic cough are notable. SP in plasma is associated with persistent cough and it might be related to airway sensitivity in asthmatic cough.


References

  1. Groneberg DA, Harrison S, Dinh QT, Geppetti P, Fischer A: Tachykinins in the respiratory tract. Curr Drug Targets 2006;7:1005–1010.
  2. Bonham AC, Sekizawa SI, Joad JP: Plasticity of central mechanisms for cough. Pulm Pharmacol Ther 2004;17:453–457; discussion 469–470.
  3. Kohrogi H, Graf PD, Sekizawa K, Borson DB, Nadel JA: Neutral endopeptidase inhibitors potentiate substance P- and capsaicin-induced cough in awake guinea pigs. J Clin Invest 1988;82:2063–2068.
  4. Fox AJ: Modulation of cough and airway sensory fibres. Pulm Pharmacol 1996;9:335–342.
  5. Moreaux B, Nemmar A, Vincke G, Halloy D, Beerens D, Advenier C, Gustin P: Role of substance P and tachykinin receptor antagonists in citric acid-induced cough in pigs. Eur J Pharmacol 2000;408:305–312.
  6. Takahama K, Fuchikami J, Isohama Y, Kai H, Miyata T: Neurokinin A, but not neurokinin B and substance P, induces codeine-resistant coughs in awake guinea-pigs. Regul Pept 1993;46:236–237.
  7. El-Hashim AZ, Amine SA: The role of substance P and bradykinin in the cough reflex and bronchoconstriction in guinea-pigs. Eur J Pharmacol 2005;513:125–133.
  8. Ebihara S, Saito H, Kanda A, Nakajoh M, Takahashi H, Arai H, Sasaki H: Impaired efficacy of cough in patients with Parkinson disease. Chest 2003;124:1009–1015.
  9. Nakagawa T, Ohrui T, Sekizawa K, Sasaki H: Sputum substance P in aspiration pneumonia. Lancet 1995;345:1447.
  10. Lee SY, Kim MK, Shin C, Shim JJ, Kim HK, Kang KH, Yoo SH, In KH: Substance P-immunoreactive nerves in endobronchial biopsies in cough-variant asthma and classic asthma. Respiration 2003;70:49–53.
  11. Cho YS, Park SY, Lee CK, Yoo B, Moon HB: Elevated substance P levels in nasal lavage fluids from patients with chronic nonproductive cough and increased cough sensitivity to inhaled capsaicin. J Allergy Clin Immunol 2003;112:695–701.
  12. Pizzichini MM, Pizzichini E, Parameswaran K, Clelland L, Efthimiadis A, Dolovich J, Hargreave FE: Nonasthmatic chronic cough: no effect of treatment with an inhaled corticosteroid in patients without sputum eosinophilia. Can Respir J 1999;6:323–330.
  13. O’Connell F, Springall DR, Moradoghli-Haftvani A, Krausz T, Price D, Fuller RW, Polak JM, Pride NB: Abnormal intraepithelial airway nerves in persistent unexplained cough? Am J Respir Crit Care Med 1995;152:2068–2075.
  14. Yoshihara S, Kanno N, Ando T, Fukuda N, Abe T, Ichimura T, Yanaihara N: Involvement of substance P in the paroxysmal cough of pertussis. Regul Pept 1993;46:238–240.
  15. Pratter MR, Brightling CE, Boulet LP, Irwin RS: An empiric integrative approach to the management of cough: ACCP evidence-based clinical practice guidelines. Chest 2006:129:222S–231S.
  16. Kohno S, Ishida T, Uchida Y, Kishimoto H, Sasaki H, Shioya T, Tokuyama K, Niimi A, Nishi K, Fujimura M, et al: The Japanese Respiratory Society guidelines for management of cough. Respirology 2006;11(suppl 4):S135–S186.
  17. Niimi A: Geography and cough aetiology. Pulm Pharmacol Ther 2007;20:383–387.
  18. Wei W, Yu L, Lu H, Wang L, Shi C, Ma W, Huang Y, Qiu Z: Comparison of cause distribution between elderly and non-elderly patients with chronic cough. Respiration 2009;77:259–264.
  19. Karlsson JA, Sant’Ambrogio G, Widdicombe J: Afferent neural pathways in cough and reflex bronchoconstriction. J Appl Physiol 1988;65:1007–1023.
  20. Ohkura N, Fujimura M, Hara J, Ohsawa M, Kamei J, Nakao S: Bronchoconstriction-triggered cough in conscious guinea pigs. Exp Lung Res 2009;35:296–306.
  21. Cheung D, van der Veen H, den Hartigh J, Dijkman JH, Sterk PJ: Effects of inhaled substance P on airway responsiveness to methacholine in asthmatic subjects in vivo. J Appl Physiol 1994;77:1325–1332.
  22. Umeno E, Hirose T, Nishima S: Pretreatment with aerosolized capsaicin potentiates histamine-induced bronchoconstriction in guinea pigs. Am Rev Respir Dis 1992;146:159–162.
  23. Tomaki M, Ichinose M, Miura M, Hirayama Y, Yamauchi H, Nakajima N, Shirato K: Elevated substance P content in induced sputum from patients with asthma and patients with chronic bronchitis. Am J Respir Crit Care Med 1995;151:613–617.
  24. Matsumoto H, Niimi A, Tabuena RP; Takemura M, Ueda T, Yamaguchi M, Matsuoka H, Jinnai M, Chin K, Mishima M: Airway wall thickening in patients with cough variant asthma and nonasthmatic chronic cough. Chest 2007;131:1042–1049.
  25. Fujimura M, Ogawa H, Yasui M, Matsuda T: Eosinophilic tracheobronchitis and airway cough hypersensitivity in chronic non-productive cough. Clin Exp Allergy 2000;30:41–47.
  26. Toyoda M, Nakamura M, Makino T, Hino T, Kagoura M, Morohashi M: Nerve growth factor and substance P are useful plasma markers of disease activity in atopic dermatitis. Br J Dermatol 2002:147:71–79.
  27. Hosokawa C, Takeuchi S, Furue M: Severity scores, itch scores and plasma substance P levels in atopic dermatitis treated with standard topical therapy with oral olopatadine hydrochloride. J Dermatol 2009:36:185–190.
  28. Fehder WP, Campbell DE, Tourtellotte WW, Michaels L, Cutilli JR, Uvaydova M, Douglas SD: Development and evaluation of chromatographic procedure for partial purification of substance P with quantitation by enzyme immunoassay. Clin Diagn Lab Immunol 1998;5:303–307.
  29. Pin I, Gibson PG, Kolendowicz R, Girgis-Gabardo A, Denburg JA, Hargreave FE, Dolovich J: Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax 1992;47:25–29.
  30. Takemura M, Niimi A, Minakuchi M, Matsumoto H, Ueda T, Chin K, Mishima M: Bronchial dilatation in asthma: relation to clinical and sputum indices. Chest 2004;125:1352–1358.
  31. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J, ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J 2005;26:319–338.
  32. Takishima T, Hida W, Sasaki H, Suzuki S, Sasaki T: Direct-writing recorder of the dose-response curves of the airway to methacholine: clinical application. Chest 1981;80:600–606.
  33. Niimi A, Matsumoto H, Takemura M, Ueda T, Chin K, Mishima M: Relationship of airway wall thickness to airway sensitivity and airway reactivity in asthma. Am J Respir Crit Care Med 2003;168:983–988.
  34. Niimi A, Matsumoto H, Ueda T, Takemura M, Suzuki K, Tanaka E, Chin K, Mishima M, Amitani R: Impaired cough reflex in patients with recurrent pneumonia. Thorax 2003;58:152–153.
  35. Steel RG: A rank sum test for comparing all pairs of treatments. Technometrics 1960;2:197–207.
    External Resources
  36. Dwass M: Some k-sample rank-order tests; in Olkin et al. (eds): Contributions to Probability and Statistics. Palo Alto, Stanford University Press, 1960, pp 198–202.
  37. Neuhauser M, Bretz F: Nonparametric all-pairs multiple comparisons. Biom J 2001;43:571–580.
    External Resources
  38. Joad JP, Munch PA, Bric JM, Evans SJ, Pinkerton KE, Chen CY, Bonham AC: Passive smoke effects on cough and airways in young guinea pigs: role of brainstem substance P. Am J Respir Crit Care Med 2004;169:499–504.
  39. Sekizawa S, Joad JP, Bonham AC: Substance P presynaptically depresses the transmission of sensory input to bronchopulmonary neurons in the guinea pig nucleus tractus solitarii. J Physiol 2003;552:547–559.
  40. Patterson RN, Johnston BT, Ardill JE, Heaney LG, McGarvey LP: Increased tachykinin levels in induced sputum from asthmatic and cough patients with acid reflux. Thorax 2007;62:491–495.
  41. Chang AB, Gibson PG, Ardill J, McGarvey LP: Calcitonin gene-related peptide relates to cough sensitivity in children with chronic cough. Eur Respir J 2007;30:66–72.
  42. Sterk PJ, Bel EH: Bronchial hyperresponsiveness: the need for a distinction between hypersensitivity and excessive airway narrowing. Eur Respir J 1989;2:267–274.
  43. De Diego A, Martínez E, Perpiñá M, Nieto L, Compte L, Macián V, Senent L: Airway inflammation and cough sensitivity in cough-variant asthma. Allergy 2005;60:1407–1411.
  44. Boomsma JD, Said SI: The role of neuropeptides in asthma. Chest 1992;101(6 suppl):389S–392S.
    External Resources
  45. Bonham AC, Kott KS, Ravi K, Kappagoda CT, Joad JP: Substance P contributes to rapidly adapting receptor responses to pulmonary venous congestion in rabbits. J Physiol 1996;493:229–238.
  46. Widdicombe JG: Neurophysiology of the cough reflex. Eur Respir J 1995;8:1193–1202.
  47. Niimi A, Amitani R, Suzuki K, Tanaka E, Murayama T, Kuze F: Eosinophilic inflammation in cough variant asthma. Eur Respir J 1998;11:1064–1069.
  48. Jatakanon A, Lalloo UG, Lim S, Chung KF, Barnes PJ: Increased neutrophils and cytokines, TNF-alpha and IL-8, in induced sputum of non-asthmatic patients with chronic dry cough. Thorax 1999;54:234–237.
  49. Aliakbari J, Sreedharan SP, Turck CW, Goetzl EJ: Selective localization of vasoactive intestinal peptide and substance P in human eosinophils. Biochem Biophys Res Commun 1987;148:1440–1445.
  50. Germonpre PR, Bullock GR, Lambrecht BN, Van De Velde V, Luyten WH, Joos GF, Pauwels RA: Presence of substance P and neurokinin 1 receptors in human sputum macrophages and U-937 cells. Eur Respir J 1999;14:776–782.
  51. Lai JP, Douglas SD, Ho WZ: Human lymphocytes express substance P and its receptor. J Neuroimmunol 1998;86:80–86.
  52. Lambrecht BN, Germonpre PR, Everaert EG, Carro-Muino I, De Veerman M, de Felipe C, Hunt SP, Thielemans K, Joos GF, Pauwels RA: Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation. Eur J Immunol 1999;29:3815–3825.
  53. Toyoda M, Nakamura M, Makino T, Hino T, Kagoura M, Morohashi M: Nerve growth factor and substance P are useful plasma markers of disease activity in atopic dermatitis. Br J Dermatol 2002;147:71–79.
  54. Matsuoka H, Niimi A, Matsumoto H, Ueda T, Takemura M, Yamaguchi M, Jinnai M, Chang L, Otsuka K, Oguma T, Takeda T, Chin K, Mishima M: Patients’ characteristics associated with unsuccessful sputum induction in asthma. J Allergy Clin Immunol 2008;121:774–776.
  55. Jinnai M, Niimi A, Ueda T, Matsuoka H, Takemura M, Yamaguchi M, Otsuka K, Oguma T, Takeda T, Ito I, Matsumoto H, Mishima M: Induced sputum concentrations of mucin in patients with asthma and chronic cough. Chest 2010;137:1122–1129.

Author Contacts

Dr. Akio Niimi

Department of Respiratory Medicine

Graduate School of Medicine, Kyoto University

54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan)

Tel. +81 75 751 3830, E-Mail niimi@kuhp.kyoto-u.ac.jp


Article / Publication Details

First-Page Preview
Abstract of Clinical Investigations

Received: August 11, 2010
Accepted: June 28, 2011
Published online: August 12, 2011
Issue release date: October 2011

Number of Print Pages: 8
Number of Figures: 2
Number of Tables: 3

ISSN: 0025-7931 (Print)
eISSN: 1423-0356 (Online)

For additional information: https://www.karger.com/RES


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References

  1. Groneberg DA, Harrison S, Dinh QT, Geppetti P, Fischer A: Tachykinins in the respiratory tract. Curr Drug Targets 2006;7:1005–1010.
  2. Bonham AC, Sekizawa SI, Joad JP: Plasticity of central mechanisms for cough. Pulm Pharmacol Ther 2004;17:453–457; discussion 469–470.
  3. Kohrogi H, Graf PD, Sekizawa K, Borson DB, Nadel JA: Neutral endopeptidase inhibitors potentiate substance P- and capsaicin-induced cough in awake guinea pigs. J Clin Invest 1988;82:2063–2068.
  4. Fox AJ: Modulation of cough and airway sensory fibres. Pulm Pharmacol 1996;9:335–342.
  5. Moreaux B, Nemmar A, Vincke G, Halloy D, Beerens D, Advenier C, Gustin P: Role of substance P and tachykinin receptor antagonists in citric acid-induced cough in pigs. Eur J Pharmacol 2000;408:305–312.
  6. Takahama K, Fuchikami J, Isohama Y, Kai H, Miyata T: Neurokinin A, but not neurokinin B and substance P, induces codeine-resistant coughs in awake guinea-pigs. Regul Pept 1993;46:236–237.
  7. El-Hashim AZ, Amine SA: The role of substance P and bradykinin in the cough reflex and bronchoconstriction in guinea-pigs. Eur J Pharmacol 2005;513:125–133.
  8. Ebihara S, Saito H, Kanda A, Nakajoh M, Takahashi H, Arai H, Sasaki H: Impaired efficacy of cough in patients with Parkinson disease. Chest 2003;124:1009–1015.
  9. Nakagawa T, Ohrui T, Sekizawa K, Sasaki H: Sputum substance P in aspiration pneumonia. Lancet 1995;345:1447.
  10. Lee SY, Kim MK, Shin C, Shim JJ, Kim HK, Kang KH, Yoo SH, In KH: Substance P-immunoreactive nerves in endobronchial biopsies in cough-variant asthma and classic asthma. Respiration 2003;70:49–53.
  11. Cho YS, Park SY, Lee CK, Yoo B, Moon HB: Elevated substance P levels in nasal lavage fluids from patients with chronic nonproductive cough and increased cough sensitivity to inhaled capsaicin. J Allergy Clin Immunol 2003;112:695–701.
  12. Pizzichini MM, Pizzichini E, Parameswaran K, Clelland L, Efthimiadis A, Dolovich J, Hargreave FE: Nonasthmatic chronic cough: no effect of treatment with an inhaled corticosteroid in patients without sputum eosinophilia. Can Respir J 1999;6:323–330.
  13. O’Connell F, Springall DR, Moradoghli-Haftvani A, Krausz T, Price D, Fuller RW, Polak JM, Pride NB: Abnormal intraepithelial airway nerves in persistent unexplained cough? Am J Respir Crit Care Med 1995;152:2068–2075.
  14. Yoshihara S, Kanno N, Ando T, Fukuda N, Abe T, Ichimura T, Yanaihara N: Involvement of substance P in the paroxysmal cough of pertussis. Regul Pept 1993;46:238–240.
  15. Pratter MR, Brightling CE, Boulet LP, Irwin RS: An empiric integrative approach to the management of cough: ACCP evidence-based clinical practice guidelines. Chest 2006:129:222S–231S.
  16. Kohno S, Ishida T, Uchida Y, Kishimoto H, Sasaki H, Shioya T, Tokuyama K, Niimi A, Nishi K, Fujimura M, et al: The Japanese Respiratory Society guidelines for management of cough. Respirology 2006;11(suppl 4):S135–S186.
  17. Niimi A: Geography and cough aetiology. Pulm Pharmacol Ther 2007;20:383–387.
  18. Wei W, Yu L, Lu H, Wang L, Shi C, Ma W, Huang Y, Qiu Z: Comparison of cause distribution between elderly and non-elderly patients with chronic cough. Respiration 2009;77:259–264.
  19. Karlsson JA, Sant’Ambrogio G, Widdicombe J: Afferent neural pathways in cough and reflex bronchoconstriction. J Appl Physiol 1988;65:1007–1023.
  20. Ohkura N, Fujimura M, Hara J, Ohsawa M, Kamei J, Nakao S: Bronchoconstriction-triggered cough in conscious guinea pigs. Exp Lung Res 2009;35:296–306.
  21. Cheung D, van der Veen H, den Hartigh J, Dijkman JH, Sterk PJ: Effects of inhaled substance P on airway responsiveness to methacholine in asthmatic subjects in vivo. J Appl Physiol 1994;77:1325–1332.
  22. Umeno E, Hirose T, Nishima S: Pretreatment with aerosolized capsaicin potentiates histamine-induced bronchoconstriction in guinea pigs. Am Rev Respir Dis 1992;146:159–162.
  23. Tomaki M, Ichinose M, Miura M, Hirayama Y, Yamauchi H, Nakajima N, Shirato K: Elevated substance P content in induced sputum from patients with asthma and patients with chronic bronchitis. Am J Respir Crit Care Med 1995;151:613–617.
  24. Matsumoto H, Niimi A, Tabuena RP; Takemura M, Ueda T, Yamaguchi M, Matsuoka H, Jinnai M, Chin K, Mishima M: Airway wall thickening in patients with cough variant asthma and nonasthmatic chronic cough. Chest 2007;131:1042–1049.
  25. Fujimura M, Ogawa H, Yasui M, Matsuda T: Eosinophilic tracheobronchitis and airway cough hypersensitivity in chronic non-productive cough. Clin Exp Allergy 2000;30:41–47.
  26. Toyoda M, Nakamura M, Makino T, Hino T, Kagoura M, Morohashi M: Nerve growth factor and substance P are useful plasma markers of disease activity in atopic dermatitis. Br J Dermatol 2002:147:71–79.
  27. Hosokawa C, Takeuchi S, Furue M: Severity scores, itch scores and plasma substance P levels in atopic dermatitis treated with standard topical therapy with oral olopatadine hydrochloride. J Dermatol 2009:36:185–190.
  28. Fehder WP, Campbell DE, Tourtellotte WW, Michaels L, Cutilli JR, Uvaydova M, Douglas SD: Development and evaluation of chromatographic procedure for partial purification of substance P with quantitation by enzyme immunoassay. Clin Diagn Lab Immunol 1998;5:303–307.
  29. Pin I, Gibson PG, Kolendowicz R, Girgis-Gabardo A, Denburg JA, Hargreave FE, Dolovich J: Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax 1992;47:25–29.
  30. Takemura M, Niimi A, Minakuchi M, Matsumoto H, Ueda T, Chin K, Mishima M: Bronchial dilatation in asthma: relation to clinical and sputum indices. Chest 2004;125:1352–1358.
  31. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J, ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J 2005;26:319–338.
  32. Takishima T, Hida W, Sasaki H, Suzuki S, Sasaki T: Direct-writing recorder of the dose-response curves of the airway to methacholine: clinical application. Chest 1981;80:600–606.
  33. Niimi A, Matsumoto H, Takemura M, Ueda T, Chin K, Mishima M: Relationship of airway wall thickness to airway sensitivity and airway reactivity in asthma. Am J Respir Crit Care Med 2003;168:983–988.
  34. Niimi A, Matsumoto H, Ueda T, Takemura M, Suzuki K, Tanaka E, Chin K, Mishima M, Amitani R: Impaired cough reflex in patients with recurrent pneumonia. Thorax 2003;58:152–153.
  35. Steel RG: A rank sum test for comparing all pairs of treatments. Technometrics 1960;2:197–207.
    External Resources
  36. Dwass M: Some k-sample rank-order tests; in Olkin et al. (eds): Contributions to Probability and Statistics. Palo Alto, Stanford University Press, 1960, pp 198–202.
  37. Neuhauser M, Bretz F: Nonparametric all-pairs multiple comparisons. Biom J 2001;43:571–580.
    External Resources
  38. Joad JP, Munch PA, Bric JM, Evans SJ, Pinkerton KE, Chen CY, Bonham AC: Passive smoke effects on cough and airways in young guinea pigs: role of brainstem substance P. Am J Respir Crit Care Med 2004;169:499–504.
  39. Sekizawa S, Joad JP, Bonham AC: Substance P presynaptically depresses the transmission of sensory input to bronchopulmonary neurons in the guinea pig nucleus tractus solitarii. J Physiol 2003;552:547–559.
  40. Patterson RN, Johnston BT, Ardill JE, Heaney LG, McGarvey LP: Increased tachykinin levels in induced sputum from asthmatic and cough patients with acid reflux. Thorax 2007;62:491–495.
  41. Chang AB, Gibson PG, Ardill J, McGarvey LP: Calcitonin gene-related peptide relates to cough sensitivity in children with chronic cough. Eur Respir J 2007;30:66–72.
  42. Sterk PJ, Bel EH: Bronchial hyperresponsiveness: the need for a distinction between hypersensitivity and excessive airway narrowing. Eur Respir J 1989;2:267–274.
  43. De Diego A, Martínez E, Perpiñá M, Nieto L, Compte L, Macián V, Senent L: Airway inflammation and cough sensitivity in cough-variant asthma. Allergy 2005;60:1407–1411.
  44. Boomsma JD, Said SI: The role of neuropeptides in asthma. Chest 1992;101(6 suppl):389S–392S.
    External Resources
  45. Bonham AC, Kott KS, Ravi K, Kappagoda CT, Joad JP: Substance P contributes to rapidly adapting receptor responses to pulmonary venous congestion in rabbits. J Physiol 1996;493:229–238.
  46. Widdicombe JG: Neurophysiology of the cough reflex. Eur Respir J 1995;8:1193–1202.
  47. Niimi A, Amitani R, Suzuki K, Tanaka E, Murayama T, Kuze F: Eosinophilic inflammation in cough variant asthma. Eur Respir J 1998;11:1064–1069.
  48. Jatakanon A, Lalloo UG, Lim S, Chung KF, Barnes PJ: Increased neutrophils and cytokines, TNF-alpha and IL-8, in induced sputum of non-asthmatic patients with chronic dry cough. Thorax 1999;54:234–237.
  49. Aliakbari J, Sreedharan SP, Turck CW, Goetzl EJ: Selective localization of vasoactive intestinal peptide and substance P in human eosinophils. Biochem Biophys Res Commun 1987;148:1440–1445.
  50. Germonpre PR, Bullock GR, Lambrecht BN, Van De Velde V, Luyten WH, Joos GF, Pauwels RA: Presence of substance P and neurokinin 1 receptors in human sputum macrophages and U-937 cells. Eur Respir J 1999;14:776–782.
  51. Lai JP, Douglas SD, Ho WZ: Human lymphocytes express substance P and its receptor. J Neuroimmunol 1998;86:80–86.
  52. Lambrecht BN, Germonpre PR, Everaert EG, Carro-Muino I, De Veerman M, de Felipe C, Hunt SP, Thielemans K, Joos GF, Pauwels RA: Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation. Eur J Immunol 1999;29:3815–3825.
  53. Toyoda M, Nakamura M, Makino T, Hino T, Kagoura M, Morohashi M: Nerve growth factor and substance P are useful plasma markers of disease activity in atopic dermatitis. Br J Dermatol 2002;147:71–79.
  54. Matsuoka H, Niimi A, Matsumoto H, Ueda T, Takemura M, Yamaguchi M, Jinnai M, Chang L, Otsuka K, Oguma T, Takeda T, Chin K, Mishima M: Patients’ characteristics associated with unsuccessful sputum induction in asthma. J Allergy Clin Immunol 2008;121:774–776.
  55. Jinnai M, Niimi A, Ueda T, Matsuoka H, Takemura M, Yamaguchi M, Otsuka K, Oguma T, Takeda T, Ito I, Matsumoto H, Mishima M: Induced sputum concentrations of mucin in patients with asthma and chronic cough. Chest 2010;137:1122–1129.
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