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Biomedical subjects

K F Chung

Publications and source records attributed to K F Chung.

At least 127 records · Page 7Linked to original sources
PubMed1999

Effect of inhaled budesonide on lung function and airway inflammation. Assessment by various inflammatory markers in mild asthma.

In a double-blind, cross-over study, we examined the effect of inhaled budesonide (800 microgram twice daily via Turbohaler) on lung function and various markers of airway inflammation including airway responsiveness to methacholine (PC20), exhaled nitric oxide (NO), eosinophils in induced sputum, bronchoalveolar lavage (BAL), and airway biopsies from 14 patients with mild asthma needing beta2- agonist therapy only. After inhaled steroids, there was a significant increase in FEV1 and PC20, and reduction in exhaled NO. Eosinophils in induced sputum and airway biopsy sections were also significantly decreased, although BAL eosinophil counts remained unchanged. At baseline, significant correlations were observed between exhaled NO and PC20 methacholine (r = 0.64, p < 0.05), exhaled NO and peak expiratory flow rate (PEFR) variability (r = 0. 65, p < 0.05), sputum eosinophils and FEV1 (r = -0.63, p = 0.05), and sputum eosinophils and log PC20 methacholine (r = -0.67, p < 0. 05). After treatment with inhaled steroids, there was a significant correlation between eosinophils in biopsy sections, and BAL, with log PC20 methacholine. It is likely that these parameters represent different aspects of the inflammatory process, which are all inhibited by inhaled steroids.

Administration, Inhalation↗
PubMed1999

Cysteinyl-leukotrienes partly mediate eotaxin-induced bronchial hyperresponsiveness and eosinophilia in IL-5 transgenic mice.

Eotaxin, a selective chemoattractant for eosinophils, induces lung eosinophilia and bronchial hyperresponsiveness (BHR) when administered intratracheally to interleukin-5 (IL-5) transgenic mice. We determined whether these effects of eotaxin were mediated through the production of cysteinyl-leukotrienes. IL-5 transgenic mice were administered eotaxin (5 micrograms) intratracheally after pretreatment with either diluent or a selective 5-lipoxygenase inhibitor SB210661 or a cysteinyl-leukotriene receptor antagonist, pranlukast. Twenty-four hours later, bronchial responsiveness to acetylcholine was measured and the degree of eosinophil influx was determined in bronchoalveolar lavage fluid (BALF) or in lung tissue. Both pranlukast and SB210661 significantly attenuated BHR induced by eotaxin with logPC(50), which is the concentration of acetylcholine needed to increase baseline insufflation pressure by 50%, from -0.43 +/- 0.16 to 0.39 +/- 0.10 and from -0.22 +/- 0.10 to 0.53 +/- 0.10, respectively (p < 0.05). There was also a significant attenuation of the eosinophil counts in BALF and in airways. BALF levels of leukotriene C(4) (LTC(4)) showed a significant increase after eotaxin from 23.9 +/- 6.7 to 165.0 +/- 35.0 pg/ml (p < 0.05) but were partially suppressed by both SB210661 (71.2 +/- 21.0) and pranlukast (62.7 +/- 11.5). Concentrations of LTB(4) were not significantly changed. We conclude that eotaxin-induced effects in the airways of IL-5 transgenic mice are partly mediated by the activation of 5-lipoxygenase enzyme leading to the generation of cysteinyl-leukotrienes.

Acetylcholine↗
PubMed1999

Neutrophilic inflammation in severe persistent asthma.

Airway inflammation in severe asthma is not well characterized but may involve neutrophils. We have compared induced sputum profiles in patients with asthma of varying severity and normal control subjects. We have also measured exhaled nitric oxide (NO) as a noninvasive marker of inflammation. Asthma severity was based on clinical features before treatment and the minimum medication required to maintain asthma control at the time of sputum induction, and classified as (1) mild: treated with inhaled beta(2)-agonist occasionally (n = 23; FEV(1), 91%; peak expiratory flow (PEF) variability, 10.5%), (2) moderate: requiring medium dose inhaled steroids to maintain control (n = 16; FEV(1), 88%; PEF variability, 9.1%), and (3) severe: despite using inhaled and oral steroids (n = 16; FEV(1), 61%; PEF variability, 36.2%). The asthmatic patients were nonsmokers with evidence of airway hyperresponsiveness or reversible airway obstruction, and free of respiratory tract infection for at least 6 wk. Sputum revealed significantly increased neutrophil numbers in severe asthma (53.0 [38.4- 73.5]%, p < 0.05) compared with mild asthma (35.4 [29.8-46.1]%) and normal control subjects (27.7 [20.6-42.2]%). Interleukin-8 (IL-8) and neutrophil myeloperoxidase (MPO) levels were increased in asthmatic patients, with the highest levels in severe asthma. Eosinophil numbers were increased in both mild and severe asthma, but interleukin-5 (IL-5) levels were highest in mild asthma, whereas eosinophil cationic protein (ECP) levels were highest in severe asthma. Exhaled NO levels were highest in asthmatic untreated with corticosteroids, but there was no significant difference between asthmatics using corticosteroids (Groups 2 and 3), regardless of clinical asthma severity. This confirms the role of eosinophils in asthma but suggests a potential role of neutrophils in more severe asthma.

Adult↗
PubMed1999

Contribution of bradykinin B(1) and B(2) receptors in allergen-induced bronchial hyperresponsiveness.

Bradykinin (BK) is a peptide mediator generated at sites of inflammation and its effects are mediated through constitutively expressed B(2) receptor or through induction of B(1) receptors. We examined the role of these receptors in bronchial hyperresponsiveness (BHR). Brown-Norway rats sensitized with ovalbumin (OA) and Al(OH)(3) intraperitoneally, were exposed 3 wk later to either saline or OA aerosol. B(1) receptor antagonist desArg(10)[Hoe140] (200 nmol/kg or 1 micromol/kg, intraperitoneally) or B(2) receptor antagonist Hoe140 (200 nmol/kg, intraperitoneally) was administered 30 min before allergen exposure. Hoe140 had no effect on OA-induced BHR to acetylcholine (ACh) and bronchoalveolar lavage fluid (BALF) cellular profiles, but inhibited bronchoconstriction to BK (p < 0.04). At both doses, desArg(10)[Hoe140] dose-dependently inhibited allergen-induced BHR to ACh (p < 0.01), but had no effect on bronchoconstriction to BK or baseline ACh responsiveness. The inflammatory cells in BALF were not affected apart from reduced lymphocyte numbers at the highest dose. B(1) receptor mRNA expression measured by Northern analysis was increased after allergen exposure in sensitized lungs, with a peak at 2 to 6 h after exposure, whereas B(2) receptor mRNA expression remained unchanged. Newly induced BK B(1) receptors may be involved in allergen-induced BHR to ACh, whereas constitutive B(2) receptors mediate BK-induced bronchoconstriction.

Acetylcholine↗
PubMed1999

alpha4 integrin-dependent eotaxin induction of bronchial hyperresponsiveness and eosinophil migration in interleukin-5 transgenic mice.

We investigated the roles of eosinophil infiltration and activation induced by the eosinophil-selective chemokine eotaxin, and of the expression of eosinophil alpha4 and beta2 integrins in causing bronchial hyperresponsiveness (BHR) in interleukin (IL)-5 CBA/Ca transgenic mice. These mice did not show BHR, despite the presence of some eosinophils in the lungs. Intratracheal mouse recombinant eotaxin (3 micrograms) did not induce BHR in wild-type mice. In IL-5 transgenic mice, eotaxin (3 and 5 micrograms) increased responsiveness at 24 h and increased eosinophils in bronchoalveolar lavage (BAL) fluid by 9.4- and 14-fold by 24 h, respectively, together with augmentation of eosinophil peroxidase activity and eosinophil infiltration in the airway submucosa. Using flow cytometry, the expression of alpha4, CD11b, and CD18 was upregulated in BAL, but not in blood, eosinophils. A rat anti-alpha4 antibody inhibited eotaxin-induced BHR and eosinophil migration and activation, but an anti-CD11b antibody had no significant effects on BHR. A combination of both antibodies was more effective. IL-5 and eotaxin synergize in the induction of BHR and airway eosinophilia, effects that are dependent on the induction of eosinophil alpha4 integrin. Expression of BHR depends on the recruitment and activation of eosinophils.

Animals↗
PubMed1999

Expression of monocyte chemotactic protein (MCP)-1, MCP-2, and MCP-3 by human airway smooth-muscle cells. Modulation by corticosteroids and T-helper 2 cytokines.

We have demonstrated that, in addition to their contractile function, human airway smooth-muscle cells (HASMC) are able to express and to secrete chemokines of the monocyte chemotactic protein (MCP)/ eotaxin subfamily. This group of chemokines is believed to play a fundamental role in the development of allergic airway diseases such as asthma. The expression levels of MCP (MCP-1, -2, and -3) messenger RNA (mRNA) were compared with those of regulated on activation, normal T cells expressed and secreted (RANTES) mRNA in HASMC in culture. HASMC express MCP and RANTES mRNA after stimulation with interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma. MCP mRNA was maximal at 8 h, whereas RANTES mRNA expression was delayed to 24 h after stimulation. Further, significant differences were observed in the induction patterns of MCP and RANTES mRNA expression after stimulation with the individual cytokines. Dexamethasone (DEX) significantly inhibited cytokine-induced accumulation of MCP and RANTES mRNA, in contrast to IL-4, IL-10, and IL-13, which had no inhibitory effect on cytokine-induced chemokine expression. The cytokine-induced MCP mRNA expression in HASMC was associated with MCP release, which was inhibited by DEX and post-translationally by IL-4. HASMC can actively participate in the pathogenesis of asthma by the expression and release of chemokines, which are likely to play a critical role in the generation and regulation of the inflammatory response characteristic of allergic airway diseases.

Bronchi↗
PubMed1999

Prostaglandins mediate bradykinin-induced reduction of exhaled nitric oxide in asthma.

Bradykinin (BK) is a mediator of inflammation in asthma with potent bronchoconstrictor actions. Endogenous release of nitric oxide may inhibit BK-induced bronchoconstriction. This study investigated whether bradykinin inhalation could modulate exhaled NO levels in normal and asthmatic subjects, and whether the bradykinin-induced effects were mediated through the production of cyclo-oxygenase products in patients with asthma, by studying the effect of the cyclo-oxygenase inhibitor, L-acetylsalicylic acid (L-ASA). Exhaled NO concentration and forced expiratory volume in one second (FEV1) were measured by chemiluminescence following inhalation of increasing concentrations of BK. In asthmatics (n=11), BK induced a dose-dependent decrease in exhaled NO concentration from 21.3+/-1.6 to 6.+/-0.5 parts per billion (ppb) (p<0.01) at the highest concentration, associated with a significant fall in FEV1. In normal subjects (n=10), the exhaled NO concentration fell from 7.2+/-0.13 to 4.3+/-0.51 ppb (p<0.001) 15 min, after a single inhalation of BK, but without a significant change in FEV1. In asthmatic subjects, pretreatment with inhaled L-ASA (90 x mg x mL(-1), 4 mL) did not alter exhaled NO levels, but prevented a BK-induced fall in exhaled NO concentration, as indicated by a significant increase in exhaled NO levels at the provocative concentration of BK causing a 20% fall in FEV1, (5.7 +/- 0.94 ppb after placebo and 12.0 +/- 1.8 ppb after L-ASA; p<0.05). L-ASA significantly reduced bronchial responsiveness to BK 3.9-fold (p<0.01). Inhaled bradykinin induced bronchoconstriction and a reduction in exhaled nitric oxide levels in asthmatic subjects, an effect that is partly mediated by cyclo-oxygenase products.

Administration, Inhalation↗
PubMed1999

Long-term benzodiazepine users--characteristics, views and effectiveness of benzodiazepine reduction information leaflet.

OBJECTIVE: The authors looked at the clinical characteristics of long-term benzodiazepine users and how they viewed their use of benzodiazepine. We also examined the effectiveness of a self-help leaflet on reducing benzodiazepine use. METHOD: One hundred and nine long-term benzodiazepine users (daily use for more than 1 year) were assessed. Their perceived beneficial and undesirable effects of benzodiazepine and intention to reduce benzodiazepine use were studied and their history of benzodiazepine use was obtained. Psychiatric diagnosis and medical history were reviewed. A self-help leaflet was provided to 56 users whose anxiety symptoms were assessed to have been under control. We re-examined these 56 users 3 months later on their use of benzodiazepine and anxiety levels. RESULTS: The 109 long-term benzodiazepine users used a therapeutic dose of benzodiazepine (median: 10 mg diazepam equivalent) regularly for a median of 9 years (range: 1-40). Most of the users found benzodiazepine helpful and only 11% of them reported undesirable side effects. Half of the 109 subjects refused to reduce the dosage. Most of the subjects still experienced significant anxiety despite the use of benzodiazepine. Fourteen of the 56 subjects provided with a self-help leaflet were able to reduce a median of 2.5 mg of diazepam equivalent when re-examined after 3 months. CONCLUSION: The results are compared with previous studies in Western societies and are discussed in the light of clinical management of patients with anxiety disorders.

Anti-Anxiety Agents↗
PubMed1998

Peripheral airways obstruction on high-resolution computed tomography in chronic severe asthma.

Long-standing chronic severe asthma may be associated with structural changes of both proximal and distal airways. To assess these changes, high-resolution computed tomography (CT) using an Imatron Ultrafast CT scanner with 3 mm thick sections at 10 min intervals was performed at full inspiration. A limited set of CT sections was also obtained on full expiration. Twenty-four chronic severe asthmatic patients (age, 47.0 +/- 2.4 years; FEV1, 56.5% +/- 4.1% of predicted) were studied. The scans were assessed independently by two radiologists. While concomitant dilatation and thickening of intrapulmonary airways were observed in 12 patients, air trapping as assessed by areas of increased lucency on expiratory scans was noted in 20. The mean expiratory-to-inspiratory cross-sectional area (Exp/Ins) was 75.9% +/- 2.0%, compared with 44.6% +/- 1.0% in historical non-asthmatic subjects. FEV1 (% predicted) correlated with Exp/Ins and with CT features of air trapping (both rs = 0.60; P < 0.001) but not with airway dilatation or thickening. Our data indicate the presence of peripheral airways obstruction in chronic severe asthma, which may be one of the underlying reasons for increased severity of asthma.

Airway Obstruction↗
PubMed1998

The complementary role of glucocorticosteroids and long-acting beta-adrenergic agonists.

In summary, beta 2-adrenergic agonists and corticosteroids can interact to produce beneficial effects on airway function. The regular use of short-acting, beta 2-adrenergic agonists as relief therapy is safe and effective; however, some degree of caution may be required with the use of very high doses. Long-acting beta 2-adrenergic agonists provide further benefits in terms of asthma control in patients already established on inhaled corticosteroid therapy. The mechanism by which this interaction occurs remains to be elucidated, but may involve a protective effect of corticosteroids on dysfunctional beta-adrenergic receptor expression and function. In asthma, there may be a degree of uncoupling of the airway receptors, probably caused by cytokines such as IL-1 beta. However, this has not been established yet. Furthermore, beta-adrenergic receptor-mediated effects may be more quickly downregulated with beta-receptor stimulation, leading to a reduction in anti-inflammatory effects. The regular use of corticosteroids leads to an inhibition of cytokine production and prevents beta-adrenergic receptor downregulation, allowing beta 2-adrenergic agonists to be more effective. Further research, which may lead to a greater understanding of these mechanisms, may also lead to the development of more effective treatment regimens.

Adrenergic beta-Agonists↗
PubMed1998

Increase in exhaled nitric oxide levels in patients with difficult asthma and correlation with symptoms and disease severity despite treatment with oral and inhaled corticosteroids. Asthma and Allergy Group.

BACKGROUND: Patients with difficult asthma suffer chronic moderate to severe persistent asthma symptoms despite high doses of inhaled and oral corticosteroid therapy. These patients suffer a high level of treatment and disease related morbidity but little is known about the degree of airway inflammation in these patients. METHODS: Fifty two patients were examined to assess levels of exhaled nitric oxide (NO) as a surrogate marker of inflammatory activity in this condition. From this group, 26 patients were defined with severe symptoms and current physiological evidence of reversible airway obstruction requiring high dose inhaled (> or = 2000 micrograms beclomethasone dipropionate (BDP) equivalent) or oral steroid therapy to maintain disease control. RESULTS: Exhaled NO levels were higher in subjects with difficult asthma (mean 13.9 ppb, 95% CI 9.3 to 18.5) than in normal controls (7.4 ppb, 95% CI 6.9 to 7.8; p < 0.002), but lower than levels in steroid naive mild asthmatics (36.9 ppb, 95% CI 34.6 to 39.3; p < 0.001). Prednisolone treated patients had higher exhaled NO levels than patients only requiring inhaled corticosteroids (17.5 ppb, 95% CI 11.1 to 24.0 versus 7.2 ppb, 95% CI 4.6 to 9.8; p = 0.016), suggesting greater disease severity in this group. Non-compliance with prednisolone treatment was observed in 20% of patients but this did not explain the difference between the treatment groups. Exhaled NO levels were closely correlated with symptom frequency (p = 0.03) and with rescue beta agonist use (p < 0.002), but they did not correlate with lung function. CONCLUSIONS: Exhaled NO may serve as a useful complement to lung function and symptomatology in the assessment of patients with chronic severe asthma, and in the control and rationalisation of steroid therapy in these patients.

Administration, Inhalation↗
PubMed1998

Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma.

BACKGROUND: Eosinophils in induced sputum and exhaled nitric oxide (NO) are currently used as non-invasive markers in the assessment of airway inflammation in asthma. As both sputum eosinophils (%) and exhaled NO are raised in asthmatic subjects not receiving inhaled steroids and decreased following corticosteroid therapy, a relationship between them is plausible. METHODS: Exhaled NO was measured by chemiluminescence analyser, sputum induction by 3.5% saline inhalation, and bronchial responsiveness was measured as PC20FEV1 methacholine in 35 stable asthmatic patients using beta 2 agonist alone and the correlation between these non-invasive markers of airway inflammation was studied. RESULTS: There were significant correlations between exhaled NO and PC20 (r = -0.64), exhaled NO and sputum eosinophils (%) (r = 0.48), and also between sputum eosinophils (%) and PC20 (r = -0.40). CONCLUSION: The correlation between exhaled NO and PC20 suggests that exhaled NO or the mechanisms leading to its increase may contribute to airway hyperresponsiveness in asthma. Furthermore, the relationship between sputum eosinophils (%), exhaled NO, and PC20 highlight the potential use of eosinophils (%) in induced sputum and exhaled NO to monitor the severity of asthma.

Adult↗
PubMed1998

Effect of inhaled L-arginine on exhaled nitric oxide in normal and asthmatic subjects.

BACKGROUND: Nitric oxide (NO) plays an important part in the regulation of many physiological functions and may also be involved in several pulmonary diseases. Endogenous NO is synthesised by different isoforms of NO synthase (NOS) from L-arginine. METHODS: The effect of inhaled L-arginine 0.75 g (six normal and six asthmatic subjects), 1.5 g (six normal and six asthmatic subjects), and 3 g (seven normal and six asthmatic subjects) has been studied in a double blind placebo controlled, randomised, parallel group design study. In addition, the effect of a single dose (3 g) of inhaled L-alanine has been assessed in five normal and five asthmatic subjects. RESULTS: L-arginine increased exhaled NO in a dose-dependent fashion with a maximum at 60 minutes. The cumulative effect of L-arginine (3 g) on NO in asthmatic subjects, expressed as the area under the curve in arbitrary units (au) and compared with the effect of placebo (0.9% NaCl), was significantly higher (mean 0.11 au; 95% confidence interval (CI) 0.03 to 0.19) than in normal subjects (0.012 au; 95% CI 0.002 to 0.022). There was a negative correlation (r = -0.72) between the increase in exhaled NO and the fall in forced expiratory volume in one second (FEV1) (0.034 au, 95% CI 0.030 to 0.038) after 3 g L-arginine in asthmatic subjects. Inhalation of 3 g of L-alanine produced a similar reduction in FEV1 (0.033 au, 95% CI 0.007 to 0.059) but no significantly different changes in exhaled NO (0.017 au, 95% CI 0.001 to 0.039) compared with placebo (0.020 au, 95% CI 0.001 to 0.042). CONCLUSIONS: An increase in the amount of substrate for NOS increases the formation of endogenous NO. L-arginine may have therapeutic potential in diseases in which there is defective production of NO, but in asthma it may amplify the inflammatory response in the airways.

Administration, Inhalation↗
PubMed1998

Effect of inhaled endotoxin on induced sputum in normal, atopic, and atopic asthmatic subjects.

BACKGROUND: Inhalation of lipopolysaccharide (LPS) causes an inflammatory response in the lungs. To explore this response, inflammatory indices were measured in induced sputum from atopic asthmatic patients and compared with atopic and non-atopic subjects after inhalation of LPS. METHODS: The effects of inhaled LPS (60 micrograms) or placebo (0.9% saline) were examined in a randomised, double blind, crossover trial in 11 non-atopic normal subjects, seven atopic, non-asthmatic individuals, and eight atopic, asthmatic patients. Sputum was induced by inhalation of 3.5% saline before the test inhalation and again at six hours and 24 hours. Spirometry (forced expiratory volume in one second (FEV1), forced vital capacity (FVC)), heart rate, blood pressure, and temperature were recorded before challenge and at intervals until eight hours, and at 24 hours after challenge. RESULTS: There was no change in cardiovascular parameters or spirometry with either exposure in any group. In the asthmatic patients only, inhalation of LPS caused a rise in temperature, with a peak of 0.6 degree C at seven hours, which was significantly higher than following placebo inhalation (p < 0.05). In normal subjects, LPS caused a significant rise in absolute neutrophil counts at 24 hours compared with placebo (median 1.1 x 10(6) cells/ml after LPS; median 0.2 x 10(6) cells/ml after placebo, p < 0.01), but no change in differential counts. In asthmatic patients, LPS caused a significant rise in differential neutrophil counts at six hours compared with placebo (median 88% after LPS; median 56% after placebo, p < 0.05), but no change in absolute cell counts at any time point. There was no change in neutrophil counts in the atopic subjects. There was a significant rise in sputum interleukin 8 (IL-8) concentrations in normal subjects at six hours compared with placebo (mean placebo 1.1 ng/ml; LPS 3.0 ng/ml, p < 0.05) and in asthmatics at 24 hours (mean placebo 2.0 ng/ml, LPS 6.9 ng/ml, p < 0.05). There were no changes in sputum concentrations of tumour necrosis factor alpha or granulocyte macrophage colony stimulating factor at any time. CONCLUSIONS: Inhalation of LPS causes a neutrophilic inflammation with increases in IL-8 in both normal and asthmatic subjects.

Administration, Inhalation↗
PubMed1998

Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-1alpha, granulocyte-macrophage colony-stimulating factor, and interferon-gamma release from alveolar macrophages in asthma.

We determined the effect of inhaled corticosteroid, budesonide, on the release of the anti-inflammatory cytokine, interleukin-10 (IL-10), and of pro-inflammatory cytokines, macrophage inflammatory protein-1alpha (MIP-1alpha), interferon-gamma (IFN-gamma), and granulocyte-macrophage colony-stimulating factor (GM-CSF), from blood monocytes and alveolar macrophages of mild asthmatic subjects in a double-blind, cross-over, placebo-controlled study. Budesonide reduced bronchial hyperresponsiveness and improved baseline FEV1. Alveolar macrophages were obtained by bronchoalveolar lavage performed at the end of each treatment phase. IL-10 from blood monocytes was not altered, but both IL-10 mRNA and protein expression from alveolar macrophages stimulated by lipopolysaccharide and IL-1beta were increased after corticosteroid therapy. By contrast, alveolar macrophages released significantly less MIP-1alpha, IFN-gamma, and GM-CSF after steroid treatment. In comparison to alveolar macrophages from normal nonasthmatic volunteers, those from asthmatic patients released more MIP-1alpha, IFN-gamma, and GM-CSF but lower amounts of IL-10 particularly at baseline and after IL-1beta stimulation. The ability of steroids to inhibit pro-inflammatory cytokines but to enhance the anti-inflammatory cytokine such as IL-10 may contribute to their beneficial actions in asthma. Asthma is characterized by alveolar macrophages exhibiting both an enhanced capacity to release pro-inflammatory cytokines and a reduced capacity to produce IL-10.

Administration, Inhalation↗