Eosinophilic tracheobronchitis and airway cough hypersensitivity in chronic non-productive cough

BACKGROUND: We have shown that some patients presenting with chronic bronchodilator-resistant non-productive cough have global atopic tendency and airway cough hypersensitivity without non-specific bronchial hyperresponsiveness, abbreviated as atopic cough. The cough is successfully treated with histamine H1-antagonists and/or glucocorticoids. OBJECTIVE: This prospective study was conducted to elucidate the histological feature of atopic cough. METHODS: Tracheal and bronchial mucosa obtained by transbronchoscopic biopsy and bronchoalveolar lavage (BAL) cell component were studied with special emphasis on eosinophils in eight non-smokers diagnosed with atopic cough, all of whom had increased sensitivity of cough response to inhaled capsaicin, normal lung function and bronchial responsiveness to methacholine and normal chest roentgenogram. Their cough completely resolved on histamine H1-antagonists and/or glucocorticoids. Transbronchoscopic tracheal and bronchial biopsy and BAL were also performed in healthy non-smokers as a control. RESULTS: A small number of eosinophils was detected in subepithelium of trachea in six of seven patients and in subepithelium of bronchi in seven of eight cough patients. The numbers of eosinophils in subepithelium of trachea and bronchi were significantly increased in the patients compared with control subjects. There was no BAL eosinophilia in any patients. CONCLUSION: It is concluded that eosinophilic tracheobronchitis and cough hypersensitivity are pathological and physiological characteristics of atopic cough.     

Effects of suplatast tosilate, a new type of anti-allergic agent, on airway cough hypersensitivity induced by airway allergy in guinea-pigs

BACKGROUND: Cough receptor hypersensitivity is a fundamental feature of some conditions presenting with chronic non-productive cough. Suplatast tosilate, an anti-allergic agent, is a T helper (Th)2 cytokine inhibitor that inhibits the synthesis of interleukin (IL)-4, IL-5, immunoglobulin (Ig)E production, and local eosinophil accumulation. OBJECTIVE: The purpose of this study was to investigate the effect of suplatast on antigen-induced airway cough hypersensitivity and eosinophil infiltration into the airway. METHODS: Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an antigen challenge in conscious guinea-pigs and then bronchoalveolar lavage was performed. We investigated the effect of single (before antigen challenge or capsaicin provocation) or repetitive treatment with intraperitoneal suplatast at a dose of 10 or 30 mg/kg on antigen-induced cough hypersensitivity. RESULTS: Twenty-four hours after antigen challenge, guinea-pigs developed an increase in cough receptor sensitivity to inhaled capsaicin and eosinophil infiltration in the airways. After a 2-week treatment with suplatast, but not after only a single treatment before antigen challenge or capsaicin provocation, the antigen-induced early phase bronchoconstriction, cough hypersensitivity, and airway eosinophilia were inhibited in a dose-dependent manner. CONCLUSION: These results indicate that suplatast inhibits airway cough hypersensitivity underlying allergic eosinophilic inflammation.     

Cough sensitivity and extrathoracic airway responsiveness to inhaled capsaicin in chronic cough patients

Enhanced cough response has been frequently observed in chronic cough. Recently, extrathoracic airway constriction to inhaled histamine was demonstrated in some chronic cough patients. However, relation between extrathoracic airway hyperresponsiveness (EAHR) and cough sensitivity determined by capsaicin inhalation is unclear in each etiological entity of chronic cough. Seventy-seven patients, with dry cough persisting for 3 or more weeks, normal spirometry and chest radiography, and 15 controls, underwent methacholine bronchial provocation test and capsaicin cough provocation test. Elicited cough number and flow-volume curve was examined after inhalation of capsaicin to evaluate cough sensitivity and EAHR. Thirty-three patients, with postnasal drip, showed normal extrathoracic airway responsiveness, and 27 of them showed normal cough sensitivity to capsaicin. Cough sensitivity was enhanced in 14 patients with cough variant asthma (CVA) who showed bronchial hyperresponsiveness; EAHR to inhaled capsaicin was present in 12 of them. The remaining 30 patients were tentatively diagnosed as idiopathic chronic cough (ICC). Eleven ICC patients showed enhanced cough sensitivity and EAHR to inhaled capsaicin while 19 patients showed normal values. These results indicate that cough sensitivity is closely related with extrathoracic airway responsiveness during capsaicin provocation in some chronic cough patients. EAHR and enhanced cough sensitivity to inhaled capsaicin may be a part of mechanism developing chronic cough.     

Histamine type 1 receptor deficiency reduces airway inflammation in a murine asthma model

BACKGROUND: Histamine plays an important role in immediate and late immune responses. The histamine type 1 (H1) receptor is expressed on several immune cell populations, but its role in a murine model of asthma remains unclear. The present study evaluated the role of histamine H1 receptors in airway allergic inflammation by comparing the development of bronchial asthma in histamine H1 receptor gene knockout (H1RKO) and wild-type mice. METHODS: H1RKO and wild-type mice were sensitized by intraperitoneal injection of ovalbumin (OVA) or saline, and then challenged with aerosolized OVA or saline. Ventilatory timing in response to inhaled methacholine was measured, and samples of blood, bronchoalveolar lavage, and lung tissues were taken 24 h after the last OVA challenge. RESULTS: OVA-treatedwild-type mice showed significantly increased airway eosinophilic infiltration, and airway response to methacholine compared to OVA-treated H1RKO mice. The serum level of immunoglobulin E and levels of interleukin (IL)-4, IL-5, IL-13, and TGF-beta1 in bronchoalveolar lavage fluid were lower in OVA-treated H1RKO mice than in OVA-treated wild-type mice, but there was no significant difference in interferon-gamma expression. Overall, deletion of histamine H1 receptors reduced allergic responses in a murine model of bronchial asthma. CONCLUSION: Histamine plays an important role via H1 receptors in the development of T helper type 2 responses to enhance airway inflammation.     

Utility of Cough Provocation Tests in Chronic Cough and Respiratory Diseases: A Comprehensive Review and Introduction of New Reference Ranges for the Capsaicin Test

Cough provocation tests (CPTs) are an objective measurement of the sensitivity of the cough reflex arc. However, they are not established in clinical practice because a large variability of response in healthy subjects limits their diagnostic value. There is a paucity of studies that have investigated CPT reference ranges in healthy subjects. This systematic review describes the variability of the responses to CPTs in healthy subjects and factors that influence it. A new analysis of 134 healthy subjects was conducted to create reference ranges for single-breath capsaicin CPT by calculating the interquartile ranges for the provocative concentration of capsaicin to induce 2 and 5 coughs. Female subjects had a more sensitive cough reflex than male counterparts. The ability of CPTs to distinguish various respiratory diseases from healthy subjects was also reviewed. Cough sensitivity was consistently heightened in the following groups: unselected patients with chronic, refractory, or recurrent cough, unexplained chronic cough, gastro-esophageal reflux-associated cough, cough-variant asthma, lower airway symptoms induced by chemical irritants, and fibrotic interstitial lung diseases. In the following groups, hypersensitivity of the cough reflex was present in those individuals whose symptom profile was predominated by cough: asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, and sarcoidosis. In the following conditions, patients usually cough in order to expectorate mucus from their airways, not because of a hypersensitive cough reflex arc: productive cough, asthma, upper airway cough syndrome, COPD, bronchiectasis, cystic fibrosis, and chronic respiratory infections. CPTs have the potential to identify patients with chronic respiratory symptoms due to cough reflex hypersensitivity, thereby providing a targeted approach for therapy.     

Nature of airway inflammation and remodeling in chronic cough

BACKGROUND: Chronic cough may be a result of asthma and non-asthma causes, but it is unclear whether there are specific inflammatory or remodeling changes. OBJECTIVE: We determined airway mucosal changes in patients presenting with asthmatic cough and cough associated with non-asthmatic causes. METHODS: Patients with chronic cough of non-asthmatic (n=33; postnasal drip/rhinitis in 6, gastroesophageal reflux in 5, bronchiectasis in 3, and idiopathic in 19) and asthmatic (n=14) causes and 15 healthy controls underwent fiberoptic bronchoscopy. Morphometry of bronchial biopsies and capsaicin cough sensitivity were assessed. RESULTS: Compared with controls, submucosal eosinophils and neutrophils were increased in patients with asthmatic cough (P<.005) and submucosal mast cells in patients with non-asthmatic cough (P=.01). Sub-basement membrane thickness, goblet cell area, vascularity, and vessel size were also increased in both groups. Smooth muscle area was higher only in patients with non-asthmatic cough (P=.0007 vs control and P=.019 vs asthmatic cough). None of the pathologic changes were related to the duration of coughing. Cough sensitivity was heightened in patients with non-asthmatic cough compared with controls and patients with asthmatic cough. The degree of goblet cell hyperplasia and epithelial shedding positively correlated with cough sensitivity in patients with non-asthmatic cough (r=0.43; P=.01; and r=0.40; P=.02, respectively). CONCLUSION: Features of airway wall remodeling are prominent in the airways with non-asthmatic as well as asthmatic cough. These are linked to chronic cough rather than to asthma. Mast cell hyperplasia rather than eosinophilia is distinctive for non-asthmatic cough.     

CD4+CD25+ T cell depletion impairs tolerance induction in a murine model of asthma

Background Regulatory T cells (Tregs) are key players in controlling the development of airway inflammation. However, their role in the mechanisms leading to tolerance in established allergic asthma is unclear. Objective To examine the role of Tregs in tolerance induction in a murine model of asthma. Methods Ovalbumin (OVA) sensitized asthmatic mice were depleted or not of CD25⁺ T cells by anti‐CD25 PC61 monoclonal antibody (mAb) before intranasal treatment (INT) with OVA, then challenged with OVA aerosol. To further evaluate the respective regulatory activity of CD4⁺CD25⁺ and CD4⁺CD25^? T cells, both T cell subsets were transferred from tolerized or non‐tolerized animals to asthmatic recipients. Bronchoalveolar lavage fluid (BALF), T cell proliferation and cytokine secretion were examined. Results Intranasal treatment with OVA led to increased levels of IL‐10, TGF‐β and IL‐17 in lung homogenates, inhibition of eosinophil recruitment into the BALF and antigen specific T cell hyporesponsiveness. CD4⁺CD25⁺Foxp3⁺ T cells were markedly upregulated in lungs and suppressed in vitro and in vivo OVA‐specific T cell responses. Depletion of CD25⁺ cells before OVA INT severely hampered tolerance induction as indicated by a strong recruitment of eosinophils into BALF and a vigorous T cell response to OVA upon challenge. However, the transfer of CD4⁺CD25^? T cells not only suppressed antigen specific T cell responsiveness but also significantly reduced eosinophil recruitment as opposed to CD4⁺CD25⁺ T cells. As compared with control mice, a significantly higher proportion of CD4⁺CD25^? T cells from OVA treated mice expressed mTGF‐β. Conclusion Both CD4⁺CD25⁺ and CD4⁺CD25^? T cells appear to be essential to tolerance induction. The relationship between both subsets and the mechanisms of their regulatory activity will have to be further analyzed.     

Characterization of increased cough sensitivity after antigen challenge in guinea pigs

Increased sensitivity of cough reflex is a fundamental feature of bronchodilator resistant non-productive cough associated with eosinophilic tracheobronchitis. Our hypothesis is that cough sensitivity is increased by airway allergic reaction characterized by airway eosinophilic inflammation. The aim of this study was to elucidate the hypothesis and clarify the characteristics of the increased cough sensitivity. Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an aerosolized antigen or saline in actively sensitized or non-sensitized (naive) conscious guinea pigs and then bronchoalveolar lavage was performed. The cough response was also measured 1 day before and 1, 2, 3, 5 and 7 days after an aerosolized antigen challenge in sensitized or naive animals. In addition, effect of procaterol (0.1 mg/kg), atropine (1 or 10 mg/kg), phosphoramidon (2.5 mg/kg) given intraperitoneally 30 min before the capsaicin challenge or capsaicin desensitization on the cough response was examined. Furthermore, the thromboxane A2 (TXA2) receptor antagonist S-1452 in a dose of 0.01 or 0.1 mg/kg or vehicle (saline) was given intraperitoneally at 24 and 1 h before the measurement of cough response. Number of coughs caused by capsaicin was extremely increased 24 h after an antigen challenge in sensitized guinea pigs compared with a saline or an antigen challenge in naive animals or a saline challenge in sensitized animals. The increased cough response disappeared at 3-7 days after the antigen challenge. Eosinophils in bronchoalveolar lavage fluid obtained after the measurement of capsaicin-induced coughs, which was performed 24 h after the antigen challenge, were significantly increased in sensitized guinea pigs. The eosinophil count was significantly correlated to the number of capsaicin-induced coughs. Procaterol or atropine did not alter the antigen-induced increase of cough sensitivity, whereas atropine did reduce the cough response in naive animals. Phosphoramidon increased the number of capsaicin-induced coughs in naive guinea pigs but not in sensitized and antigen-challenged animals. Capsaicin desensitization decreased the cough response in both antigen-challenged sensitized guinea pigs and naive animals. S-1452 reduced the antigen-induced increase of cough response in sensitized guinea pigs, but not in naive animals. Airway allergy accompanied with airway eosinophilia induces transient increase in cough sensitivity, which is not mediated by bronchoconstriction. The increased cough sensitivity may result in part from inactivation of neutral endopeptidase and TXA2, one of the inflammatory mediators.     

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

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 mumol/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.     

Lesions in the suprachiasmatic nuclei suppress inflammatory mediators in sensitized rats

BACKGROUND: Although bronchial asthma is well known as an inflammatory disease that shows obvious circadian rhythms of airway narrowing, it remains to be elucidated whether the suprachiasmatic nucleus (SCN), a major circadian pacemaker, regulates inflammatory mediators relevant to asthma. Thus, we investigated the effects of electrolytic lesioning of the SCN on the antigen-induced immediate allergic response and the late allergic response (LAR) in male Brown Norway rats, i.e. in a model of allergic inflammation. METHODS: The immediate allergic response, assessed by the histamine levels in plasma and bronchoalveolar lavage fluid (BALF), and the LAR, assessed by the eosinophilic infiltration into BALF and the lamina propria mucosae of the left main bronchus, were examined in three groups of 18 rats each, including (1) an unoperated control group, (2) a sham SCN-lesioned group, and (3) an SCN-lesioned group. RESULTS: Both the plasma histamine levels and the number of eosinophils in bronchial tissues in the SCN-lesioned group were significantly lower than those in the other groups. The concentration of histamine and the number of eosinophils in the right BALF showed a similar pattern; however, no significant differences were found. Both plasma adrenaline and noradrenaline levels were highest during the LAR, whereas the corticosterone level was lowest in the SCN-lesioned group; again, no significant differences were obtained. CONCLUSIONS: These findings indicate that the SCN has a significant effect on the inflammatory mediators relevant to bronchial asthma.     

CD4+ T cells from mice with intestinal immediate-type hypersensitivity induce airway hyperreactivity

BACKGROUND: A subset of food-allergic patients does not only respond clinically with symptoms in the gastro-intestinal tract but also with asthmatic reactions. OBJECTIVE: The aim of this study was to analyse whether CD4+ T cells from mice with intestinal immediate-hypersensitivity reactions to food allergen are involved in the development of experimental asthma. METHODS: BALB/c mice were intraperitoneally sensitized to ovalbumin (OVA), followed by repeated intra-gastric (i.g.) OVA challenges. Control animals were either sham-sensitized or sham-challenged with phosphate-buffered saline (PBS). Duodenum, jejunum, ileum and colon were histologically examined. CD4+ T cells from mesenteric lymph nodes were transferred from various donor groups into recipient mice that received either OVA or PBS aerosol challenges. Recipients were analysed by measurements of lung function using head-out body-plethysmography and examination of broncho-alveolar lavage and lung histology. RESULTS: The highest levels of OVA-specific IgE antibody levels were detected in OVA-sensitized and OVA-challenged mice. Throughout the lower intestinal tract, a marked infiltration with eosinophils was observed, and goblet cell numbers as well as goblet cell area were significantly increased. The villus/crypt ratio was decreased compared with controls. The transfer of CD4+ T cells from mesenteric lymph nodes of OVA-sensitized and OVA-challenged mice triggered airway hyperreactivity and eosinophilic airway inflammation in recipients aerosol challenged with OVA, but not with PBS. CONCLUSION: We conclude that CD4+ T cells from mesenteric lymph nodes of mice with allergen-induced immediate-type hypersensitivity reactions in the gut are able to transfer the phenotype of experimental asthma.     

Complementary roles of capsaicin cough sensitivity test and induced sputum test to methacholine bronchial provocation test in predicting response to inhaled corticosteroids in patients with chronic nonproductive cough.

BACKGROUND: The capsaicin cough sensitivity test (CCST), methacholine bronchial provocation test (MBPT), and induced sputum test (IST) are widely used in the clinical evaluation of chronic nonproductive cough. However, little is known about their roles in predicting response to inhaled corticosteroids (ICSs) in patients with chronic nonproductive cough. OBJECTIVE: To test the hypothesis that the CCST and IST play complementary roles to the MBPT for predicting the response to ICS treatment in patients with chronic nonproductive cough. METHODS: A total of 43 patients with chronic nonproductive cough who showed isolated capsaicin cough hypersensitivity (CCST group) and 55 patients with chronic nonproductive cough who had methacholine airway hyperresponsiveness (MBPT group) were enrolled. These patients underwent the IST followed by treatment with ICSs for 4 weeks. Measurement of symptom improvement was recorded by the visual analog scale. RESULTS: The response rates to ICS treatment in the CCST and MBPT groups were similar (74.5% vs 86.0%; P = .21). Only the neutrophil count in the IST group was significantly different in responders and nonresponders after the ICS treatments (P = .005 for the CCST group and P = .006 for the MBPT group). Interestingly, the absence of sputum neutrophilia used as a criterion for subgroup analysis increased response rates in the patients with either methacholine airway hyperresponsiveness or capsaicin cough hypersensitivity. CONCLUSIONS: In the present study, we demonstrate that CCST and IST play complementary roles to MBPT. By combining the results of these tests, we are able to identify more patients with chronic nonproductive cough and treat patients more successfully with ICSs by improving the response rate to ICS treatment.     

Desloratadine inhibits allergen-induced airway inflammation and bronchial hyperresponsiveness and alters T-cell responses in murine models of asthma

BACKGROUND: Histamine elicits many features of immediate hypersensitivity reactions. Recent evidence indicates that H1 receptors modulate immune responses to antigens. Desloratadine (DL), a new, long-acting, H1 receptor antagonist, has both a potent antihistaminic function and anti-inflammatory properties. OBJECTIVE: We sought to evaluate the effect of DL on allergic-airway responses in mice after inhalation of the naturally occurring aeroallergen Aspergillus fumigatus (Af ) and to examine the effects of DL on specific immune responses to a defined protein antigen with the use of an ovalbumin (OVA) model of asthma. METHODS: Mice were subjected either to repeated, intranasal application of Af extract or to intraperitoneal immunization with OVA, followed by inhalation challenge. DL or a control fluid was given daily throughout the sensitization process. Immunoglobulin E (IgE) levels, bronchoalveolar lavage-fluid cytokines and cytology, lung histology, and physiologic responses to methacholine were assessed in the allergen-treated mice. Anti-OVA IgE responses and OVA-driven T-cell cytokine production were examined. RESULTS: Treatment with DL did not impair IgE production but did inhibit bronchial inflammation and bronchial hyperresponsiveness in both Af- and OVA-treated mice. This inhibition required that DL be administered concurrently with allergen sensitization, indicating that the attenuation of bronchial hyperresponsiveness and inflammation was not caused by anticholinergic receptor effects. OVA-responsive T cells from DL-treated mice exhibited depressed production of IL-4, IL-5, and IL-13 and normal amounts of interferon-gamma. The amounts of IL-5 and IL-13 were also diminished in the bronchoalveolar lavage fluid. CONCLUSION: DL, given at the time of exposure to the allergen, inhibits T(H)2 responses, the induction of allergic pulmonary inflammation, and bronchial hyperresponsiveness. These results suggest that DL or similar agents given during times of antigen exposure might alter disease progression in patients with respiratory allergy.     

Effects of Bakumondo-to (Mai-Men-Dong-Tang) on cough sensitivity to capsaicin in asthmatic patients with cough hypersensitivity]

Some patients with bronchial asthma have increased cough sensitivity. In such patients coughing may be an inducer of wheeze. The aim of the present study was to investigate the effect of Bakumondo-to on the cough sensitivity and respiratory tract inflammation in asthmatic patients with increased cough sensitivity. In addition influences of intensity of respiratory tract inflammation, gender, type of asthma, and disease period on the effect of Bakumondo-to on the cough sensitivity were examined. Twenty-one bronchial asthmatics whose cough thresholds to capsaicin were less than 3.9 microM were examined. METHODS: Cough thresholds to capsaicin (concentration of inhaled capsaicin solution causing 5 or more coughs) was measured before and after 2 months or more treatment with Bakumondo-to (9 g/day, TJ-29). Number of eosinophils in peripheral blood, sputum eosinophil ratio, and ECP level in the serum were also measured before and after treatment. RESULTS: Bakumondo-to significantly increased the cough threshold. Although respiratory tract inflammation was not significantly improved, number of eosinophils in peripheral blood, sputum eosinophil ratio and ECP level in the serum were remarkably decreased more than the half. And Bakumondo-to was more effective in asthmatic subjects with severe airway inflammation. Furthermore, a greater effect of it was observed in women. A greater effect was also observed in patients having a disease duration of less than 1 year. CONCLUSION: Our results suggest that Bakumondo-to may be an effective therapeutic preparation for coughing in asthmatic patients with cough hypersensitivity.     

Capsaicin and histamine antagonist-sensitive mechanisms in the immediate allergic reaction of pig airways

The airway vascular and bronchial responses were studied in pigs sensitized with Ascaris suum. Ascaris, histamine (H) and capsaicin aerosol all induced a clear-cut increase in blood flow in the nasal, laryngeal and bronchial circulation with a decrease in vascular resistance of 20-40%. When delivered to the lung both ascaris and histamine, but not capsaicin, caused pulmonary airflow obstruction with increase in resistance and a fall in dynamic compliance of 40-70%. After pretreatment of pigs with a combination of the H1- and H2-receptor antagonists terfenadine and cimetidine, the vascular and bronchial responses were strongly reduced to both histamine (by greater than 77%) and ascaris (by greater than 58%), but not to capsaicin aerosol. The bronchoconstriction to histamine was found to be mediated by H1-receptors only, while both H1- and H2-antagonists were necessary to block the vasodilatory response, with H2-receptors being more important in the bronchial circulation and H1-receptors being more important in the laryngeal and nasal circulation. Furthermore, when pigs were pretreated with capsaicin systemically 2 days before the experiment, the vasodilation was decreased upon capsaicin (by 80%), ascaris (by greater than 40%) and histamine (by greater than 50%) aerosol challenge. When histamine was administered intravenously the desensitizing effect of capsaicin pretreatment was much less pronounced. The effect of capsaicin desensitization on the pulmonary obstruction upon ascaris and histamine challenge was limited to a 60% reduction of the fall in dynamic compliance and a delayed peak in resistance upon ascaris challenge. We conclude that histamine is one of the main vasodilatory mediators released upon allergen challenge at three different levels of the pig airways. A considerable part of the histamine effect is indirect and probably due to activation of capsaicin-sensitive sensory nerves.     

Blockade of macrophage migration inhibitory factor (MIF) prevents the antigen-induced response in a murine model of allergic airway inflammation

Objective and Design: The role of macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, was tested using a mouse asthma model. Materials: One hundred and four male BALB/c mice were used in this study. Treatment: Mice were actively sensitized with an intraperitoneal injection of ovalbumin (OVA) and challenged with repeated nebulization of 1 w/v% OVA. Polyclonal anti-MIF antibody was intraperitoneally injected at 10 mg/kg during the antigen challenge period. Methods: Bronchoalveolar lavage (BAL) was performed 8 h after the last challenge. Airway hyperresponsiveness to inhaled methacholine was measured 24 h after the last challenge. Results: Antigen challenge to immunized mice induced increase in inflammatory cells and concentration of Th2 cytokines in BAL fluid (BALF), and caused the development of airway hyperresponsiveness. Anti-MIF antibody significantly decreased the numbers of inflammatory cells including macrophages, eosinophils, lymphocytes and neutrophils in BALF from OVA-challenged mice. Prednisolone decreased the numbers of eosinophils, lymphocytes and neutrophils but not macrophages. Anti-MIF antibody reduced airway hyperresponsiveness. Anti-MIF antibody affected neither the cytokine levels in BALF nor the IgE levels in serum. Conclusion: MIF was involved in the antigen-induced inflammatory cell accumulation in the lung and airway hyperresponsiveness without affecting immune responses. Received 17 November 2005; returned for revision 14 June 2006; accepted by M. Katori 25 July 2006     

Eosinophilic inflammation, remodeling of lower airway, bronchial responsiveness and cough reflex sensitivity in non-asthmatic subjects with nasal allergy

BACKGROUND: It has been reported that nasal allergy influences the lower airway inflammation and functions. We elucidated whether nasal allergy would contribute to lower airway inflammation and functions. METHODS: 266 subjects aged 21-39 years were interviewed with special emphasis on history of asthma and nasal allergies (perennial allergic rhinitis (PAR) and seasonal allergic rhinitis (Japanese cedar pollinosis; PO)). Symptomatic subject was defined when nasal symptoms were present during a 3-week study period. Pulmonary function, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC20), capsaicin cough threshold defined as capsaicin concentration eliciting 5 or more coughs (C5) and eosinophil percentage in hypertonic saline-induced sputum were measured. RESULTS: Based on the interview, 232 subjects without asthma were divided into symptomatic (n = 25) and asymptomatic (n = 22) PAR, PO on-season (n = 15) and off-season (n = 36), and non-nasal allergy subjects (control) (n = 134). Sputum eosinophils were significantly greater in symptomatic PAR than another four groups (p < 0.01). FEV1/FVC ratio was significantly lower in PAR than control (p < 0.05). Maximum mean expiratory flow was lower in PAR than control (asymptomatic: p < 0.05, symptomatic: p = 0.06). C5 was not different among groups. PAR tended to have a lower PC20 compared to control (symptomatic: p = 0.078; asymptomatic: p = 0.086). CONCLUSIONS: These results suggest that eosinophilic inflammation occurred in symptomatic period of PAR may contribute to development of lower airway remodeling and bronchial hyperresponsiveness. Reversely, PO may not be associated with lower airway eosinophilic inflammation or abnormal bronchial functions. Nasal allergy dose not influence the cough reflex sensitivity.     

Quality of life and capsaicin sensitivity in patients with sensory airway hyperreactivity

BACKGROUND: A group of patients with asthma-like symptoms and sensitivity to chemical irritants has shown an increased cough sensitivity to inhaled capsaicin compared to patients with asthma and to healthy controls. The condition is called sensory hyperreactivity (SHR), and the patients often feel that they are socially handicapped because of the risk of exposure to chemical irritants in daily life. METHODS: Twenty-six patients with asthma-like symptoms after exposure to nonspecific irritating stimuli, but without IgE-mediated allergy or demonstrable bronchial obstruction, were selected for a study of the response to a capsaicin test and measurement of quality of life by a general health profile (the Nottingham Health Profile [NHP]). We also investigated whether there was a correlation between quality of life and sensitivity to capsaicin. RESULTS: The patients demonstrated a dose-dependent response to the capsaicin provocation, with coughing and respiratory and other symptoms, that significantly differed from 12 healthy controls. The health profile showed that patients with SHR had a significantly reduced quality of life compared to reference values, and there was a significant correlation between the health profile and sensitivity to capsaicin. CONCLUSIONS: Patients with asthma-like symptoms verified by the capsaicin inhalation test for sensory hyperreactivity have a poor quality of life. The correlation between quality of life and sensitivity to capsaicin objectively demonstrates the validity of this general health profile study.     

Influence of viral infection on the development of nasal hypersensitivity

BACKGROUND: The underlying relationship between viral infections and allergic diseases of the upper respiratory tract has not been well clarified. METHODS: In order to clarify the relationship between viral infection and nasal hypersensitivity, mice were sensitized with ovalbumin (OVA) and then infected intranasally with respiratory syncytial virus (RSV), after which their nasal sensitivity to histamine or antigen was examined. RESULTS: Non-sensitized mice showed transient mild nasal hypersensitivity following nasal administration of histamine after intranasal RSV inoculation. In mice sensitized with OVA, RSV infection significantly exaggerated their nasal hypersensitivity to histamine and OVA. Treatment of these mice with a neurokinin (NK)-1/NK-2 receptor antagonist, but not with anti-IL-5 antibodies, reduced their hypersensitivity. The infiltration of nasal mucosa with eosinophils was temporarily associated with accelerated rate of RSV elimination in these animals. CONCLUSION: RSV infection induced transient nasal hypersensitivity. Several mechanisms, including impairment of nasal epithelial cells are thought to mediate this effect. In allergen-sensitized mice, RSV inoculation strongly enhanced nasal hypersensitivity.     

IL-12~+重组卡介苗降低哮喘小鼠气道炎症的作用及其机制研究

目的探讨IL-12+重组卡介苗(recombinant balillus calmette-guerin secreting IL-12,rBCG)新生期接种对实验性哮喘小鼠气道炎症和气道高反应(airway hyperresponsiveness,AHR)的作用及其可能机制。方法新生Balb/c小鼠分4组:对照组(control组),卵白蛋白(OVA)组,rBCG干预(rBCG/OVA)组,rBCG/OVA/IFN-gamma中和抗体(rBCG/OVA/anti-IFN-gamma Ab)组。除对照组外,其余3组均给予OVA致敏和激发。最后一次激发后测24 h内AHR,观察支气管肺泡灌洗液(bronchoalveolarlavage fluid,BALF)中细胞总数及分类,评估肺部炎症变化程度,采用酶联免疫吸附双抗体夹心法(ELISA)检测BALF中IFN-gamma、IL-10水平。结果 1)OVA组BALF中细胞总数、嗜酸性粒细胞、中性粒细胞、淋巴细胞绝对计数和炎症病理评分均明显高于对照组,rBCG/OVA组上述内容均显著低于OVA组。2)新生期rBCG接种能显著降低哮喘小鼠模型的气道高反应性。3)rBCG/OVA组支气管肺泡灌洗液中IFN-gamma、IL-10水平明显高于OVA组。4)rBCG/OVA组与接种rBCG同时并使用anti-IFN-gamma Ab的哮喘小鼠相比气道炎症和AHR无显著差异。结论新生期rBCG接种能抑制哮喘小鼠气道炎症和AHR,促进IFN-gamma和IL-10的产生,其抗哮喘效应可能与其促进IL-10分泌有关。