Chronic cough in asthma is associated with increased airway inflammation, more comorbidities, and worse clinical outcomes.

Background: Cough is often the most prominent and intractable symptom reported by patients with asthma, but few studies have explored the characteristics of patients with asthma and with chronic cough (CC) in a real-world setting. Methods: In a prospective cohort study, patients ages ≥ 18 years with stable asthma were consecutively recruited at the West China Hospital, Sichuan University. The patients were classified as having asthma with CC (the CC group) or asthma with non-CC (the non-CC group) after 3 months of optimized asthma therapy according to standard guidelines. Multidimensional assessment was performed at baseline, followed by a 12-month follow-up to assess asthma exacerbations. Results: Of 323 patients with asthma, 127 patients were assigned to the CC group and 196 patients were assigned to the non-CC group. The participants with CC were older and had more airflow obstruction; worse asthma control and quality of life; increased airway inflammation; upper respiratory tract infection as a trigger; and more comorbidities, such as psychological dysfunction, rhinitis, chronic obstructive pulmonary disease, and bronchiectasis. They reported greater work productivity loss and daily activity impairment, and increased moderate-to-severe exacerbations. Conclusion: The participants with asthma and with CC had a significant disease burden, with increased exacerbations, health-care utilization, and impaired work productivity and daily activity. These observations indicated potential clinical implications in patients with asthma and with CC, and call for more attention to this aspect of asthma.

STAT1 participates in the induction of substance P expression in airway epithelial cells by respiratory syncytial virus.

PURPOSE: The regulation effect and mechanism of respiratory syncytial virus (RSV) infection on the expression of tachykinin substance P (SP) in airway epithelial cells was investigated. METHODS: The regulation of SP expression by RSV was investigated in the BEAS-2B airway epithelial cell line. RT-qPCR, immunofluorescence, and ELISA assay were used to examine the expression of the SP encoding gene TAC1, the intracellular SP protein expression, and the extracellular SP secretion. RESULTS: The mRNA expression of TAC1 and the intracellular SP protein level in BEAS-2B cells were significantly enhanced by RSV infection with multiplicity of infection (MOI) values of both 1 and 0.1 at 48 hours post infection. Heat-inactivated and UV-inactivated RSV, but not live RSV, significantly induced SP secretion in both control BEAS-2B cells and CX3CR1 receptor knockout cells without affecting the TAC1 gene expression or cell viability. RSV G protein (2-10 µg/ml) and fractalkine (10-50 ng/ml), both CX3CR1 receptor ligands, did not affect SP secretion in BEAS-2B cells. Inhibition of STAT1 phosphorylation by fludarabine (1 µM) markedly reduced the RSV-induced TAC1 gene expression and antagonized the inhibition of RSV replication by interferon-α in BEAS-2B cells. CONCLUSIONS: STAT1 participates in RSV infection-induced SP expression in airway epithelial cells.

NLRP3 knockout in mice provided protection against Serratia marcescens-induced acute pneumonia by decreasing PD-L1 and PD-1 expression in macrophages.

Antibiotic-resistant Serratia marcescens (Sm) is known to cause bloodstream infections, pneumonia, etc. The nod-like receptor family, pyrin domain-containing 3 (NLRP3), has been implicated in various lung infections. Yet, its role in Sm-induced pneumonia was not well understood. In our study, we discovered that deletion of Nlrp3 in mice significantly improved Sm-induced survival rates, reduced bacterial loads in the lungs, bronchoalveolar lavage fluid (BALF), and bloodstream, and mitigated the severity of acute lung injury (ALI) compared to wild-type (WT) mice. Mechanistically, we observed that 24 h post-Sm infection, NLRP3 inflammasome activation occurred, leading to gasdermin D NH2-terminal (GSDMD-NT)-induced pyroptosis in macrophages and IL-1ß secretion. The NLRP3 or NLRP3 inflammasome influenced the expression PD-L1 and PD-1, as well as the count of PD-L1 or PD-1-expressing macrophages, alveolar macrophages, interstitial macrophages, PD-L1-expressing neutrophils, and the count of macrophage receptors with collagenous structure (MARCO)-expressing macrophages, particularly MARCO+ alveolar macrophages. The frequency of MARCO+ alveolar macrophages, PD-1 expression, particularly PD-1+ interstitial macrophages were negatively or positively correlated with the Sm load, respectively. Additionally, IL-1ß levels in BALF correlated with three features of acute lung injury: histologic score, protein concentration and neutrophil count in BALF. Consequently, our findings suggest that Nlrp3 deletion offers protection agaisnt acute Sm pneumonia in mice by inhibiting inflammasome activation and reducing Sm infection-induced PD-L1/PD-1 or MARCO expression, particularly in macrophages. This highlights potential therapeutic targets for Sm and other gram-negative bacteria-induced acute pneumonia.

Dual ß2-adrenoceptor agonists-PDE4 inhibitors for the treatment of asthma and COPD.

We designed and synthesized a novel class of dual pharmacology bronchodilators targeting both ß(2)-adrenoceptor and PDE4 by applying a multivalent approach. The most potent dual pharmacology molecule, compound 29, possessed good inhibitory activity on PDE4B2 (IC(50)=0.278 µM, which was more potent than phthalazinone, IC(50)=0.520 µM) and possessed excellent relaxant effects on tracheal rings precontracted by histamine (pEC(50)=9.3).

A descending pathway emanating from the periaqueductal gray mediates the development of cough-like hypersensitivity.

Chronic cough is a common refractory symptom of various respiratory diseases. However, the neural mechanisms that modulate the cough sensitivity and mediate chronic cough remain elusive. Here, we report that GABAergic neurons in the lateral/ventrolateral periaqueductal gray (l/vlPAG) suppress cough processing via a descending pathway. We found that l/vlPAG neurons are activated by coughing-like behaviors and that tussive agent-evoked coughing-like behaviors are impaired after activation of l/vlPAG neurons. In addition, we showed that l/vlPAG neurons form inhibitory synapses with the nucleus of the solitary tract (NTS) neurons. The synaptic strength of these inhibitory projections is weaker in cough hypersensitivity model mice than in naïve mice. Important, activation of l/vlPAG GABAergic neurons projecting to the NTS decreases coughing-like behaviors. In contrast, suppressing these neurons enhances cough sensitivity. These results support the notion that l/vlPAG GABAergic neurons play important roles in cough hypersensitivity and chronic cough through disinhibition of cough processing at the medullary level.

IL-24 Contributes to Neutrophilic Asthma in an IL-17A-Dependent Manner and Is Suppressed by IL-37.

PURPOSE: Neutrophilic asthma is associated with asthma exacerbation, steroid insensitivity, and severe asthma. Interleukin (IL)-24 is overexpressed in asthma and is involved in the pathogenesis of several allergic inflammatory diseases. However, the role and specific mechanism of IL-24 in neutrophilic asthma are unclear. We aimed to elucidate the roles of IL-24 and IL-37 in neutrophilic asthma, the relationships with IL-17A and the mechanisms regulating neutrophilic asthma progression. METHODS: Purified human neutrophils were isolated from healthy volunteers, and a cell coculture system was used to evaluate the function of IL-24 in epithelium-derived IL-17A-dependent neutrophil migration. IL-37 or a small interfering RNA (siRNA) targeting IL-24 was delivered intranasally to verify the effect in a murine model of house dust mite (HDM)/lipopolysaccharide (LPS)-induced neutrophilic asthma. RESULTS: IL-24 enhanced IL-17A production in bronchial epithelial cells via the STAT3 and ERK1/2 signaling pathways; this effect was reversed by exogenous IL-37. Anti-IL-17A monoclonal antibodies reduced neutrophil chemotaxis induced by IL-24-treated epithelial cells in vitro. Increased IL-24 and IL-17A expression in the airway epithelium was observed in HDM/LPS-induced neutrophilic asthma. IL-37 administration or IL-24 silencing attenuated neutrophilic asthma, reducing IL-17A levels and decreasing neutrophil airway infiltration, airway hyperresponsiveness, and goblet cell metaplasia. Silencing IL-24 inhibited T-helper 17 (Th17) immune responses, but not Th1 or Th2 immune responses, in the lungs of a neutrophilic asthma model. CONCLUSIONS: IL-24 aggravated neutrophilic airway inflammation by increasing epithelium-derived IL-17A production, which could be suppressed by IL-37. Targeting the IL-24/IL-17A signaling axis is a potential strategy, and IL-37 is a potential candidate agent for alleviating neutrophilic airway inflammation in asthma.

Cough Inhibition Activity of Schisandra chinensis in Guinea Pigs.

Chronic cough is very common in respiratory clinics, and no effective drugs are available. Schisandra chinensis (Turcz.) Baill. (S. chinensis), an important traditional Chinese medicine, has been extensively prescribed for patients with a persistent cough. Preliminary research indicated that 95% ethanol extracts (EE) of S. chinensis showed remarkable antitussive activity in guinea pigs exposed to cigarette smoke (CS). To find out the antitussive ingredients of S. chinensis, EE was divided into four fractions according to the polarity: petroleum ether extract (PEE), ethyl acetate extract (ECE), n-butyl alcohol extract, and residue extract. The antitussive, antioxidant, and anti-inflammatory effects of the four fractions were evaluated in a guinea pig model of cough hypersensitivity induced by CS exposure. Eighteen main constituents of the two effective fractions, PEE and ECE, were identified using ultra-high-pressure liquid chromatography electronic spray ion time-of-flight mass spectrometry. The cough inhibition activities of compound 1, 3, 9, 10, 17 were evaluated on citric acid induced acute cough guinea pigs. The results showed that the antitussive activity of EE was almost all contained in PEE and ECE. The 16 major peaks in PEE were identified as 15 lignans (1-12 and 14-16) and 1 triterpene (compound 13), and 3 major peaks (1, 17, and 18) in ECE were also identified as lignans. Three doses of five compounds brought about a significant decrease in number of cough efforts (P < .01), and the cough inhibition rates were between 40.9% and 85.1%. Therefore, lignans are the antitussive ingredients of S. chinensis.

[A guinea pig model of parainfluenza virus type 3 infection-induced acute and postinfectious cough].

OBJECTIVE: To establish a guinea pig model of cough induced by human parainfluenza virus type 3 (PIV3) infection, and to investigate the change of the cough reflex sensitivity (CRS). METHODS: Sixty male SPF guinea pigs were divided into 6 groups (n=10, each), namely, a normal control group, an asthma group and 4 groups of PIV3 inoculation which included post-infection day (PID) 6, 12, 28, and 42. Infected animals were inoculated by intranasal instillation of PIV3 suspension. Control animals were inoculated by uninfected cell culture medium. Asthma animals were sensitized and challenged by ovalbumin. The Buxco system was used to assess cough reflex sensitivity (CRS) elicited by capsaicin and airway hyper-reaction (AHR). Airway inflammation was studied by bronchoalveolar lavage (BAL) cytology and lung histopathology. RESULTS: The CRS of PID 6, 12, 28 and 42 groups was 7.50 (5.25), 7.30 (7.25), 8.40 (9.75) and 8.20 (5.50) Cough counts (CCnt). Compared with 2.50 (3.00) CCnt of the vehicle group, the CRS to capsaicin increased significantly in all the animals with PIV3 inoculation (P value were 0.024, 0.03, 0.011 and 0.008) and peaked in PID 42. There was no significant difference (P=0.18) between 3.90 (1.75) CCnt of the asthma animals and the normal control. Animals of PID 6 showed significantly greater AHR to 2 highest concentrations of methacholine than the normal controls. BAL total cell counts of both the PIV3-inoculated and the asthma animals were significantly higher than those of the normal control, with the number of lymphocytes increased significantly within first 2 weeks after PIV3 inoculation. The lung pathology of PIV3-inoculated animals showed airway inflammation without pneumonia in acute infectious phase. CONCLUSIONS: An animal model of cough induced by PIV3 was created. The CRS of infected guinea pigs increased significantly in both acute and subacute phases of cough. Elevation of CRS may be characteristic of cough caused by virus.

[Diagnostic values of the clinical characteristics of chronic cough].

OBJECTIVE: To evaluate whether the clinical characteristics of chronic cough were helpful in determining its specific causes. METHODS: Patients with chronic cough were evaluated by a validated systematic diagnostic protocol. The patients with identified single cause were divided into 4 groups accordingly: cough-variant asthma (CVA), upper airway cough syndrome (UACS) or post-nasal drip syndrome (PNDS), eosinophilic bronchitis (EB), gastroesophageal reflux related cough (GERC), and the characteristics of the timing, character, onset and associated manifestations of chronic cough in different causes were compared. RESULTS: A total of 196 patients met the inclusion criteria, including 55 with EB, 45 with UACS, 50 with CVA and 46 with GERC. No significant difference was found in age, gender and course among EB, UACS, CVA and GERC. The incidence of nocturnal cough in CVA was 26.0% (13/44), significantly higher than in EB (9.1% (5/55), chi2 = 5.272, P<0.05), UACS (2.2% (1/45), chi2 = 10.657, P<0.01) and GERC (0% (0/46), chi2 = 13.833, P<0.01). The specificity of nocturnal cough for CVA was 95.9%. The sensitivity and specificity of cough associated with meals in GERC was 52.2% (24/46) and 83.3%, and regurgitation associated symptom in GERC were 69.6% (32/46) and 80.0%, which were significantly higher than other groups. The incidence of postnasal drip, rhinitis associated symptom and case history of nasal diseases in UACS were 66.7% (30/45), 88.9% (40/45) and 82.2% (37/45), and the specificity of them were 89.4%, 65.6% and 63.6% respectively. CONCLUSION: The timing character and some associated symptoms of chronic cough are useful in predicting a single cause.

The duration of cough in patients with H1N1 influenza.

BACKGROUND: Cough is one of common symptoms of influenza, the cough duration and prevalence of postinfectious cough (PIC) after viral upper respiratory tract infection has not been well described. OBJECTIVES: We aim to investigate the duration of cough and prevalence of PIC and its relation with acute symptoms, airway inflammation and cough sensitivity in patients with H1N1 influenza. METHODS: Patients with acute symptoms of H1N1 influenza were enrolled and followed up until cough relived. Spirometry, induced sputum test, capsaicin challenge test were conducted in patients with PIC. Cough sensitivity was presented as logarithm of provocative concentration inducing five or more coughs (logC5). RESULTS: A total of 141 cases with H1N1 influenza were enrolled. In patients with H1N1 influenza, 97.2% of them complained cough. The duration of cough was as following: <1 week (73.0%); 1-2 weeks (7.8%); 2-3 weeks (7.8%); ≥3 weeks (8.5%). Twelve (8.5%) patients had cough lasting more than 3 weeks (PIC), 4 (2.8%) patients developed chronic cough (>8 weeks). Acute symptoms, spirometry, bronchial responsiveness and sputum differential cell count were similar between patients with PIC and those without PIC, however, there was a higher prevalence of previous PIC (58.3% vs 14.7%, P < 0.05) and elevated cough sensitivity (lgC5: 1.18 ± 0.58 vs 2.73 ± 0.33, P < 0.01) in patients with PIC as compared with the patients without PIC. CONCLUSIONS: Acute cough is common in patients with H1N1 PIC, only a few of patients develop chronic cough. Acute symptoms cannot predict PIC which is related with previous PIC and increased cough sensitivity.

[Etiology and a diagnostic protocol for patients with chronic cough].

OBJECTIVE: The spectrum and frequency of causes and the diagnostic protocol for chronic cough were explored. METHODS: A total of 194 patients with at least 3 weeks of chronic cough and normal chest radiographs were recruited from the outpatient clinic of Guangzhou Institute of Respiratory Diseases between July 2003 to June 2004. The causes were investigated using a well-established protocol. The diagnostic protocol included history inquiring and physical examination, pulmonary function tests, induced sputum cell differentials, 24 h esophageal pH monitoring, CT of the paranasal sinuses or chest, fiberoptic rhinoscopy or bronchoscopy. The final diagnosis was made based on clinical manifestation, examination findings and a positive response to therapy. RESULTS: The cause of chronic cough was defined in 95.4% of the patients, with a single cause found in 153 patients (82.7%), and multiple causes in 32 patients (17.3%). The five most important causes of cough were: eosinophilic bronchitis (n = 51, 22.4%), rhinitis and/or paranasal sinusitis (PNDs, n = 39, 17.1%), cough-variant asthma (n = 31, 13.6%), atopic cough (n = 28, 12.3%), and gastroesophageal reflux (n = 27, 11.8%). CONCLUSIONS: The spectrum and frequency of causes of chronic cough in our study is different from the previous reports in western countries. Eosinophilic bronchitis and atopic cough are important causes of chronic cough. A modified diagnostic protocol was established accordingly.

Initial empirical treatment based on clinical feature of chronic cough.

BACKGROUND: An empirical therapy based on the clinical characteristics of cough had not been reported. We evaluated this strategy of empirical therapy on chronic cough. METHODS: Patients with chronic cough were initially diagnosed with corticosteroid-responsive cough (CRC), postnasal drip syndrome (PNDS) and gastroesophageal reflux-related cough (GERC) based on their medical history and clinical presentation, and received a sequential three-step empirical therapy. A successful response was required for final diagnosis. RESULTS: A total of 96 patients were recruited with a median duration of cough for 4 months (range, 2-100). The primary diagnosis based on history and clinical presentation was CRC in 53 patients (55.2%), PNDS in 36 (37.5%) and GERC in 7 (7.3%). Cough improved in 60 patients (62.5%) at the first step with mean time of 6.2 ± 3.3 days. Three-step empirical therapy was beneficial in 78 of 96 (81.2%) patients at last. The final spectrum and frequency of causes of cough based on therapeutic response were as follows: CRC (46.7%), PNDS (27.5%) and GERC (10.8%). Eighteen cases (18.8%) were not responsive to empirical treatment, seven of whom were identified as other causes by diagnostic tests. CONCLUSIONS: The empirical therapy aimed at primary diagnosis on the basis of history and clinical characteristics is a more targeted approach, and leads to improvement of chronic cough more quickly in most patients. CRC is the most common cause of chronic cough.

A Critical Review of the Quality of Cough Clinical Practice Guidelines.

BACKGROUND: Clinical practice guidelines (CPGs) have been developed to provide health-care practitioners with the best possible evidence, but the quality of these CPGs varies greatly. OBJECTIVE: The goal of this study was to systematically evaluate the quality of cough CPGs and identify gaps limiting evidence-based practice. METHODS: Systematic searches were conducted to identify cough CPGs in guideline databases, developers' Websites, and Medline. Four reviewers independently evaluated eligible guidelines by using the Appraisal of Guidelines for Research and Evaluation II assessment tool. Agreement among reviewers was measured by using the intraclass correlation coefficient. The number of recommendations, strength of recommendation, and levels of evidence were determined. RESULTS: Fifteen cough CPGs were identified. An overall high degree of agreement among reviewers was observed (intraclass correlation coefficient, 0.82 [95% CI, 0.79-0.85]). The quality ranged from good to acceptable in the scope and purpose (mean, 72%; range, 54%-93%) and clarity and presentation (mean, 68%; range, 50%-90%) domains but not in stakeholder involvement (mean, 36%; range, 18%-90%), rigor of development (mean, 36%; range, 9%-93%), applicability (mean, 23%; range, 9%-83%), and editorial independence domains (mean, 24%; range, 0-96%). Seven guidelines (46.7%) were considered "strongly recommended" or "recommended with modifications" for clinical practice. More than 70% of recommendations were based on nonrandomized studies (Level C, 30.4%) and expert opinion (Level D, 41.3%). CONCLUSIONS: The quality of cough CPGs is variable, and recommendations are largely based on low-quality evidence. There is significant room for improvement to develop high-quality guidelines, which urgently warrants first-class research to minimize the vital gaps in the evidence for formulation of cough CPGs.

Antitussive activity of the Schisandra chinensis fruit polysaccharide (SCFP-1) in guinea pigs models.

ETHNOPHARMACOLOGICAL RELEVANCE: 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. AIM OF THE STUDY: This study aims to investigate the antitussive activity of polysaccharides extracted from S. chinensis. MATERIALS AND METHODS: 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 1000mg/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. RESULTS: The molecular of SCFP-1 was 3.18×104Da, mainly being composed of glucose and arabinose (66.5% and 29.4%, respectively). Peroral administration of SCFP-1 at 250, 500, and 1000mg/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. CONCLUSIONS: SCFP-1 is one of the antitussive components of S. chinensis.

[The clinical features and the diagnosis of gastro-esophageal reflux induced cough].

OBJECTIVE: Gastro-esophageal reflux (GER) is an important etiological factor inducing chronic cough. This study aims to identify the clinical features for the diagnosis of GER induced cough (GERC). METHODS: A modified Irwin's diagnostic protocol and continuous 24-hour esophageal pH monitoring were performed in 50 patients with chronic cough. Twenty patients were diagnosed as having GERC. The clinical features were compared with those of non-GER (NGER) induced cough. RESULTS: One hundred and ninety-two patients met the chronic cough criteria and were fully evaluated. The x +/- s of age was (40.6 +/- 12.1) years (range, 10 - 69 years) and 101 were males and 91 were females, with a cough history of 25 months (range, 2 - 487 months). GER accounted for 10.4% (n = 20) of the causes and was the fourth common cause of chronic cough. The mean +/- SD of age was (37.7 +/- 13.9) years (range, 10 - 60 years) in the GERC group, with a cough history of 61 months (range, 3 - 360 months). Cough associated with having meals (occurring while eating or anytime during the subsequent 2 h) was present in 13 out of the 20 patients in GERC, significantly higher than that in NGER (2 out of 23 patients) (chi2= 14.29, P < 0.01). The specificity, the positive predictive value and the sensitivity of cough associated with meals for GERC were 91.3%, 86.7% and 65.0%, respectively. Regurgitation associated symptom was present in 11 out of the 20 patients in the GERC group, not significantly different from that in the NGER group (8 out of 23 patients). Continuous 24 hour ambulatory esophageal pH measurement showed that reflux events were more common in upright [8.9 (range, 1.9 - 71.9)%] than in supine position [1.4 (range, 0 - 41.2)%] as well as at post-meal [20.2 (range, 2.1 - 84.2)%] than during meal period [1.95 (range, 0 - 51.6)%] (P < 0.01 and P < 0.05). CONCLUSION: Cough associated with having meals is of diagnostic value for GERC. The reflux events are more frequent when patients are awake, with upright position and after meals.

[The role of airway neurogenic inflammation in gastro-esophageal reflux induced cough].

OBJECTIVE: To investigate the role of airway neurogenic inflammation in the pathogenesis of gastro-esophageal reflux induced cough (GERC). METHODS: Sputum was induced by hypertonic saline aerosol inhalation in 20 patients with GERC (GERC group), 10 healthy subjects (normal control group) and 8 patients with chronic cough due to other causes but complicated with gastro-esophageal reflux diseases (GERD, GERD group). Airway mucosal biopsy was performed in 6 patients with GERC and 4 patients with GERD using flexible fiberoptic bronchoscopy. The expression of substance P (SP), neurokinin 1 receptor and neurokinin A (NKA) in sputum cells and airway mucosa were detected by immunohistochemistry, and was assessed semi-quantitatively. SP, NKA, and NKB in the supernatant of induced sputum were measured with enzyme linked immunosorbent assay. Calcitonin gene-related peptide (CGRP) was measured with radioimmunoassay. RESULTS: The concentration of SP in the supernatant of induced sputum was significantly higher in GERC group [(266 +/- 207) ng/L] than those in normal control group [(143 +/- 36) ng/L, P < 0.05] and GERD group [(130 +/- 11) ng/L, P < 0.05], and the sputum supernatant concentration of CGRP in GERC group [(180 +/- 83) ng/L] was significantly higher than those in normal control group [(105 +/- 64) ng/L, P < 0.01] and GERD group [(89 +/- 16) ng/L, P < 0.01]. The expression of SP, NK-1 receptor and NKA in induced sputum cells in GERC group were significantly higher than those in normal control group (P < 0.01, < 0.05, < 0.05) and GERD group (all P < 0.05); Expressions of SP in airway mucosa was significantly higher in GERC group than in GERD group (P < 0.01). After treatment, the concentration of CGRP in the supernatant of sputum in GERC patients was significantly lower than that before treatment (P < 0.05); the expression of SP, NK-1 and NKA in the induced sputum cells were significantly lower than that before treatment (P < 0.01, P < 0.01 or P < 0.05). CONCLUSION: There is airway neurogenic inflammation in GERC patients, which maybe closely related to the development of GERC.

[The development and safety of cough provocation test by capsaicin inhalation].

OBJECTIVE: To assess the application and the safety of capsaicin cough provocation test by dosimeter method. METHODS: Capsaicin inhalation cough challenge test by dosimeter method was performed on 60 healthy volunteers (group A), 11 subjects with upper respiratory infection (group B), 10 patients with gastroesophageal reflux cough (group C) and 10 patients with asthma (group D). Each subject inhaled doubling concentrations of capsaicin (1.95, 3.90, 7.80, 15.6, 31.2, 62.5, 125, 250, 500, 1,000 micromol/L) by a breath-activated dosimeter until the concentration inducing five or more coughs (C(5)) was reached. The lg C(5) was calculated as the cough reflex sensitivity. General lung ventilation and impedance with impulse oscillometry were measured before and after the cough provocation test. RESULTS: There was no serious side effect of the test in all subjects; two subjects complained of slight nausea; one of heartburn, and three of hoarseness. Before the provocation the values of FEV(1) in group A, B, C and D were (3.6 +/- 0.5) L, (3.7 +/- 0.7) L, (2.7 +/- 0.8) L and (2.1 +/- 0.8) L, compared with (3.6 +/- 0.5) L, (3.7 +/- 0.8) L, (2.6 +/- 0.7) L and (2.1 +/- 0.8) L after the test, the differences being not significant (all P > 0.05). Compared with the measurements after provocation, Zrs was (2.6 +/- 0.8) mm Hg.L(-1).s(-1) vs (2.7 +/- 0.8) mm Hg.L(-1).s(-1) in group A, (2.5 +/- 0.5) mm Hg.L(-1).s(-1) vs (2.6 +/- 0.3) mm Hg.L(-1).s(-1) in group B, (2.7 +/- 0.7) mm Hg.L(-1).s(-1) vs (2.7 +/- 0.7) mm Hg.L(-1).s(-1) in group C, (3.3 +/- 1.5) mm Hg.L(-1).s(-1) vs (3.7 +/- 2.0) mm Hg.L(-1).s(-1) in group D, the differences showed no significance (all P > 0.05 respectively). The lg C(5) value was 2.45 +/- 0.46 in group A, 2.51 +/- 0.20 in group B, 1.52 +/- 0.70 in group C, 2.34 +/- 0.56 in group D. Compared with group A, B and D, the lg C(5) value in group C was significantly different (all P < 0.01 respectively). The lg C(5) value showed no significant difference among group A, group B and group D (all P > 0.05). CONCLUSION: Capsaicin inhalation cough provocation test by dosimeter method is a safe and specific tool for measuring cough reflex sensitivity.

[Characteristics of airway inflammatory cells and mediators in eosinophilic bronchitis patients].

OBJECTIVE: To investigate the features of airway inflammation in patients with eosinophilic bronchitis (EB) by analyzing the inflammatory cells and mediators in induced sputum and bronchoalveolar lavage fluid (BALF). METHODS: Sputum induced by hypertonic saline aerosol inhalation was collected in 43 patients with EB (EB group), 20 patients with cough variant asthma (CVA, CVA group), 16 patients with bronchial asthma (asthma group) and 21 healthy controls (healthy group). Bronchoalveolar lavage was also performed in 11 patients with EB and 10 patients with CVA. Differential cell count was carried out in sputum and BALF. Levels of eosinophilic cationic protein (ECP), leukotriene C(4) (LTC(4)) and histamine in sputum and BALF were measured. RESULTS: The percentage of sputum eosinophils (EOS) showed significant difference among the four groups; healthy group 0.0020 +/- 0.0050, EB group 0.1130 +/- 0.1470, CVA group 0.1900 +/- 0.1800, asthma group 0.3860 +/- 0.2670 (P < 0.01). The difference between asthma group and CVA group, and the difference between CVA group and EB group were significant (P < 0.05). The percentage of EOS in BALF was (0.011 +/- 0.016) in EB group, (0.053 +/- 0.040) in CVA group, the difference being significant (P < 0.05). The concentration of sputum ECP was (0.62 +/- 0.66) mg/L in EB group, (1.27 +/- 1.74) mg/L in CVA group, (0.07 +/- 0.10) mg/L in healthy group, the difference among the three groups being significant (P < 0.01). The difference of LTC(4) level was also significant when CVA group (0.65 +/- 0.62) microg/L was compared with EB group (0.39 +/- 0.61) microg/L (P < 0.05) and healthy group (0.15 +/- 0.11) microg/L (P < 0.01). The difference of histamine level in the supernatant of BALF was significant between CVA group (3.4 +/- 1.4) microg/L and EB group (1.6 +/- 1.5) microg/L (P < 0.05). CONCLUSIONS: EOS infiltration is mainly localized to the central airway in EB, with lower airway levels of LTC(4) and histamine as compared to CVA. These inflammatory features may partly explain the absence of non-specific airway hyperresponsiveness in patients with EB.

Effects of Schisandra chinensis extracts on cough and pulmonary inflammation in a cough hypersensitivity guinea pig model induced by cigarette smoke exposure.

Schisandra chinensis (S. chinensis) is a traditional Chinese medicine commonly used in prescription medications for the treatment of chronic cough. However, the material basis of S. chinensis in relieving cough has not been completely elucidated yet. This study established a guinea pig model of cough hypersensitivity induced by 14 days of cigarette smoke (CS) exposure, to evaluate the antitussive, antioxidant, and anti-inflammatory effects of three S. chinensis extracts. And then the function of four lignans in reducing expression of TRPV1 and TRPA1 was examined using A549 cells induced by cigarette smoke extract (CSE). The results demonstrated that both ethanol extract (EE) and ethanol-water extract (EWE) of S. chinensis, but not water extract (WE), significantly reduced the cough frequency enhanced by 0.4M citric acid solution in these cough hypersensitivity guinea pigs. Meanwhile, pretreatment with EE and EWE both significantly attenuated the CS-induced increase in infiltration of pulmonary neutrophils and total inflammatory cells, as well as pulmonary MDA, TNF-α, and IL-8, while remarkably increased activities of pulmonary SOD and GSH. According to H&E and immunofluorescence staining assays, airway epithelium hyperplasia, smooth muscle thickening, inflammatory cells infiltration, as well as expression of TRPV1 and TRPA1, were significantly attenuated in animals pretreatment with 1g/kg EE. Moreover, four lignans of EE, including schizandrin, schisantherin A, deoxyschizandrin and γ-schisandrin, significantly inhibited CSE-induced expression of TRPV1, TRPA1 and NOS3, as well as NO release in A549 cells. In conclusion, S. chinensis reduces cough frequency and pulmonary inflammation in the CS-induced cough hypersensitivity guinea pigs. Lignans may be the active components.