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Biomedical subjects

K F Chung

Publications and source records attributed to K F Chung.

At least 37 records · Page 2Linked to original sources
PubMed2004

Mucin expression in peripheral airways of patients with chronic obstructive pulmonary disease.

AIMS: To study the expression of mucins in peripheral airways in patients with chronic obstructive pulmonary disease (COPD). METHODS AND RESULTS: Peripheral lung sections from smokers with COPD (n = 9) and age-matched controls including smokers (n = 11) and lifelong non-smokers with normal lung function (n = 6) were stained with alcian blue, periodic acid-Schiff (PAS) and by immunohistochemistry of mucins (MUC): MUC2, MUC4, MUC5AC, MUC5B and MUC6. Histochemical staining and immunoreactivity of bronchiolar epithelium were graded and the presence or absence of stained mucus in the bronchiolar lumen was evaluated. There were no differences in alcian blue and PAS epithelial staining between the three groups. Intraluminal PAS staining was significantly more frequent among COPD subjects (P < 0.05). The expression of MUC5AC was significantly higher in the bronchiolar epithelium of patients with COPD (P < 0.05). Within the bronchiolar lumen, the predominant mucin was MUC5B. Intraluminal MUC5B was significantly more frequent among COPD patients (P < 0.05). CONCLUSIONS: COPD is specifically associated with increased expression of MUC5B in the bronchiolar lumen and of the mucin MUC5AC in the bronchiolar epithelium. These changes in mucin production in the peripheral airways may contribute to the pathophysiology of COPD.

Aged↗
PubMed2004

Differential expression of IL-10 receptor by epithelial cells and alveolar macrophages.

BACKGROUND: Interleukin (IL)-10 is a pleiotropic cytokine with a broad spectrum of immunosuppressive and anti-inflammatory effects. IL-10 secretion from alveolar macrophages is defective in patients with asthma and lower concentrations of IL-10 are found in bronchoalveolar lavage (BAL) from asthmatic patients than in normal control subjects. Reduced IL-10 may result in exaggerated and more prolonged inflammatory responses in asthmatic airways. IL-10 acting through the IL-10 receptor (IL-10R) stimulates the transcription factors STAT1 and STAT3. METHODS: We investigated IL-10 and IL-10R expression in normal and asthmatic bronchial epithelium and BAL macrophages using reverse transcription-polymerase chain reaction, immunohistochemistry and Western blotting. The functional effect of IL-10 was examined using granulocyte-macrophage-colony stimulating factor, enzyme-linked immunosorbent assay and Western blotting for phosphorylated STAT1 and STAT3. RESULTS: IL-10 was not expressed in epithelial cells; furthermore these cells did not express the IL-10R and had no functional response to exogenous IL-10. Bronchial epithelial cells expressed variable levels of phosphorylated STAT1 and STAT3 with no change in expression between normal subjects and asthmatics. IL-10 protein and IL-10R expression was detected in alveolar macrophages from all subjects. CONCLUSION: Our study suggests that the bronchial epithelium is not a source of IL-10 and cannot respond to exogenous IL-10 because of a lack of IL-10R expression.

Adult↗
PubMed2004

Failure of sputum eosinophilia after eotaxin inhalation in asthma.

BACKGROUND: Eotaxin is a chemokine specific for eosinophils and may play an important role in eosinophil recruitment in asthma. The effects of eotaxin inhalation on sputum and blood eosinophils, exhaled nitric oxide (NO), and bronchial responsiveness were determined. METHODS: Eotaxin was administered by nebulisation to asthma patients in three studies: (1) an open dose finding study with eotaxin (5, 10 and 20 microg) to two asthmatic subjects; (2) a randomised placebo controlled study with 20 microg eotaxin to five asthmatic subjects and five normal volunteers; and (3) a randomised placebo controlled study with 40 microg eotaxin to nine asthmatics. Forced expiratory volume in 1 second (FEV(1)), exhaled NO, and blood eosinophils were measured before and hourly for 5 hours after nebulisation and at 24 and 72 hours. Methacholine bronchial challenge and sputum induction were performed before and at 5, 24, and 72 hours after nebulisation. RESULTS: In the two placebo controlled studies there was no change in sputum eosinophil count and sputum eosinophilic cationic protein concentration after eotaxin inhalation compared with placebo. FEV(1), exhaled NO, and methacholine PC(20) did not change. However, high dose eotaxin (40 microg) induced an increase in sputum neutrophil count compared with placebo (p<0.05). CONCLUSIONS: Inhaled eotaxin up to 40 microg induced no changes in sputum eosinophil count but at 40 microg it increased the sputum neutrophil count. The significance of this finding is unknown.

Administration, Inhalation↗
PubMed2004

Reduced pH and chloride levels in exhaled breath condensate of patients with chronic cough.

BACKGROUND: Increased hydrogen and reduced chloride ionic environments of the airways are conducive to the stimulation of cough. However, the constituents of the local milieu of the airways of patients with chronic cough are unknown. METHODS: The pH and chloride levels in exhaled breath condensate and capsaicin cough threshold (C5) were measured in 50 patients with chronic cough and in 16 healthy controls. pH and chloride measurements were repeated after capsaicin challenge in those with cough. The cause of cough was asthma (n = 13), postnasal drip/rhinitis (n = 7), gastro-oesophageal reflux (n = 5), bronchiectasis (n = 5), but remained unidentified in 20. RESULTS: Compared with controls, patients with chronic cough had lower pH (mean 7.9 v 8.3, 95% CI of difference -0.5 to -0.2, p<0.0001), chloride levels (median 4 v 6 mmol/l, 95% CI -3.1 to -0.2, p = 0.007), and C5 (median 3.9 v 125 micro M, 95% CI -270.0 to -17.6, p = 0.002). The pH levels were different in the six subgroups including controls, and were reduced in all diagnostic subgroups of patients with cough compared with controls but did not differ between them. Chloride levels were significantly different in the six subgroups but were lower than controls in only the gastro-oesophageal reflux subgroup. There was a weak but significant correlation between chloride levels and C5 when all participants were analysed together, but not between pH and C5 or chloride levels. pH and chloride levels did not change after capsaicin challenge. CONCLUSIONS: The epithelial lining fluid of patients with chronic cough has a reduced pH and reduced chloride levels which could contribute to the enhanced cough reflex.

Adult↗
PubMed2004

Formoterol protects against platelet-activating factor-induced effects in asthma.

Platelet-activating factor (PAF) is an inflammatory mediator that provokes neutropaenia, bronchoconstriction and gas exchange defects due to exudation of bulk plasma within the airways. While the inhibitory effects of short-acting beta2-agonists on PAF-induced disturbances have been consistently shown, those of long-acting beta2-agonists are less convincing. To further explore the mechanisms involved in PAF challenge in asthma, 12 patients (forced expiratory volume in one second, 90 +/- 4% predicted) were investigated 2 h after inhaled formoterol (18 microg), in a double-blind, placebo-controlled, crossover design following PAF (18 microg) inhalation. Compared with the placebo, at 5 min, premedication with formoterol reduced PAF-induced cough and dyspnoea, and attenuated increased respiratory system resistance (by 67%) and arterial deoxygenation (by 50%). Likewise, ventilation-perfusion (V'A/Q') inequality improved, as reflected by the dispersion of pulmonary blood flow (by 63%) and an overall index of V'A/Q' heterogeneity (by 71%). In contrast, PAF-induced facial flushing, neutropaenia and subsequent rebound neutrophilia remained unchanged. The improvement in gas exchange abnormalities shown after platelet-activating factor in patients with asthma pretreated with formoterol at the recommended clinical dose may reflect, in addition to its class effects, an anti-exudative effect of formoterol in the airways.

Administration, Inhalation↗
PubMed2004

Parameters associated with persistent airflow obstruction in chronic severe asthma.

The significance of severe airflow obstruction in severe asthma is unclear. The current study determined whether severe airflow obstruction is related to inflammatory or structural changes in the airways. Patients with severe asthma from a tertiary referral clinic were divided into two groups according to their postbronchodilator forced expiratory volume in one second (FEV1): severe persistent airflow limitation (FEV1 <50% predicted; group S; n=37) and no obstruction (FEV1 >80% pred; group N; n=29). Smoking history, atopic status, lung function tests, exhaled NO, blood eosinophil count, quality of life scores using St George's Respiratory Questionnaire and high resolution computed tomography (HRCT) of the lungs were assessed. Patients from group S were older and had longer disease duration. There was no difference in smoking history, atopic status, hospital admissions, quality of life scores and amount of treatment with inhaled or oral corticosteroids. Exhaled NO and peripheral blood eosinophils were higher in group S (21.0 +/- 2.4 versus 12.8 +/- 2.3 ppb; 0.41 +/- 0.06 versus 0.15 +/- 0.03 x 10(9) cells x L(-1) respectively). HRCT scores for bronchial wall thickening and dilatation were higher in group S with no differences in air trapping. Peripheral blood eosinophilia and bronchial wall thickening on HRCT scan were the only parameters significantly and independently associated with persistent airflow obstruction. Patients with severe asthma and irreversible airflow obstruction had longer disease duration, a greater inflammatory process and more high resolution computed tomography airway abnormalities suggestive of airway remodelling, despite being on similar treatments and experiencing equivalent impairment in quality of life.

Administration, Inhalation↗
PubMed2004

STAT4 activation in smokers and patients with chronic obstructive pulmonary disease.

Activation of the transcription factor signal transducer and activator of transcription (STAT)-4 is critical for the differentiation of T-helper 1 cells/type-1 cytotoxic T-cells and the production of interferon (IFN)-gamma. Expression of STAT4, phospho-STAT4, IFN-gamma and T-box expressed in T-cells (T-bet) proteins in bronchial biopsies and bronchoalveolar lavage (BAL)-derived lymphocytes, obtained from 12 smokers with mild/moderate chronic obstructive pulmonary disease (COPD) (forced expiratory volume in one second (FEV1) 59 +/- 16% predicted), 14 smokers with normal lung function (FEV1 106 +/- 12% pred) and 12 nonsmoking subjects (FEV1 111 +/- 14% pred), was examined by immunohistochemistry and immunocytochemistry. In bronchial biopsies of COPD patients, the number of submucosal phospho-STAT4+ cells was increased (240 (22-406) versus 125 (0-492) versus 29 (0-511) cells mm(-2)) when compared with both healthy smokers and control nonsmokers, respectively. In smokers, phospho-STAT4+ cells correlated with the degree of airflow obstruction and the number of IFN-gamma+ cells. Similar results were seen in BAL (2.8 (0.2-5.9) versus 1.03 (0.09-1.6) versus 0.69 (0-2.3) lymphocytes x mL(-1) x 10(3)). In all smokers who underwent lavage, phospho-STAT4+ lymphocytes correlated with airflow obstruction and the number of IFNgamma+ lymphocytes. T-bet expression was not altered in bronchial biopsies and BAL-derived lymphocytes between the three groups. In conclusion, this study suggests that stable mild/moderate chronic obstructive pulmonary disease is associated with an active T-helper 1 cell/type-1 cytotoxic T-cell inflammatory process involving activation of signal transducer and activator of transcription 4 and interferon-gamma production.

Aged↗
PubMed2004

Effect of smoking on MAP kinase-induced modulation of IL-8 in human alveolar macrophages.

Inflammatory cytokine production by alveolar macrophages (AMs) is regulated by transcriptional activation and may be increased by cigarette smoking. The smoking-induced regulation of interleukin (IL)-8 by extracellular signal-regulated kinase (ERK)-1 and -2, p38 mitogen-activated protein kinase (MAPK) and the transcription factor nuclear factor-kappaB (NF-kappaB) in lipopolysaccharide-stimulated AMs was assessed in nine smokers compared with nine healthy nonsmokers. IL-8 production was dependent on phosphorylation of ERK-1 and -2 and p38 MAPK, as examined by PD 098059 (10 microM), an inhibitor of the upstream activator of MAPK kinase (MKK)-1, and SB 203580 (10 microM), an inhibitor of p38 MAPK. IL-8 release and the inhibitory effect of PD 098059 were increased in AMs from smokers. Moreover, ERK-2 messenger ribonucleic acid expression, as examined by reverse transcriptase polymerase chain reaction and phosphorylation of ERK-2 using Western blots, were increased in AMs from smokers, indicating a smoking-induced modulatory role of ERK-1 and -2. Lipopolysaccharide-induced IL-8 production was dependent on activation of NF-kappaB, as examined by SN 50 (100 microM), an inhibitor of NF-kappaB translocation, and the specific NF-kappaB inhibitor kinase-2 inhibitor, AS 602868 (10 microM), with no differences in AMs from smokers and nonsmokers. SN 50 but not PD 098059 and SB 203580 blocked NF-kappaB deoxyribonucleic acid-binding, and this occurred to the same extent in AMs from smokers and nonsmokers, as examined by electromobility shift assay. It is concluded that cigarette smoking enhances mitogen-activated protein kinase activation more than nuclear factor-kappaB activation to increase lipopolysaccharide-induced interleukin-8 production in alveolar macrophages.

Adult↗
PubMed2003

Fundamentals of pulmonary drug delivery.

Aerosol administration of peptide-based drugs plays an important role in the treatment of pulmonary and systemic diseases and the unique cellular properties of airway epithelium offers a great potential to deliver new compounds. As the relative contributions from the large airways to the alveolar space are important to the local and systemic availability, the sites and mechanism of uptake and transport of different target compounds have to be characterized. Among the different respiratory cells, the ciliated epithelial cells of the larger and smaller airways and the type I and type II pneumocytes are the key players in pulmonary drug transport. With their diverse cellular characteristics, each of these cell types displays a unique uptake possibility. Next to the knowledge of these cellular aspects, the nature of aerosolized drugs, characteristics of delivery systems and the depositional and pulmonary clearance mechanisms display major targets to optimize pulmonary drug delivery. Based on the growing knowledge on pulmonary cell biology and pathophysiology due to modern methods of molecular biology, the future characterization of pulmonary drug transport pathways can lead to new strategies in aerosol drug therapy.

Administration, Inhalation↗
PubMed2003

Regulation of protease-activated receptor-1 in mononuclear cells by neutrophil proteases.

Neutrophils and mononuclear cells are implicated in the pathogenesis of several inflammatory conditions including chronic obstructive pulmonary disease (COPD). Neutrophil-derived serine proteases, such as cathepsin G (CG) and neutrophil elastase (NE), may interact with mononuclear cells via protease-activated receptors (PARs) which are seven-transmembrane G protein-coupled receptors activated by proteolytic cleavage of the extracellular N-terminus, and which, on activation, induce the release of several mediators and cytokines. We determined whether CG and NE could affect PAR-1 expression and function in mononuclear cells. Human blood mononuclear cells were isolated from 20 healthy donors. Surface and intracellular receptor expression and calcium mobilisation (using the calcium chelator, FLUO3-AM) were studied by fluorescence-assisted cell sorting (FACS analysis). Positive controls, i.e. thrombin (0.1-100 mU/ml) and the PAR-1-activating peptide SFLLRN (100 microM) induced a rapid and transient intemalisation of PAR-1 in monocytes and lymphocytes. CG but not NE had a similar effect. By contrast, in monocytes intracellular calcium mobilisation was induced by thrombin and SFLLRN but not by CG and NE. Thus, CG can induce intracellular PAR-1 sequestration without activation of the receptor, and may act as an antagonist and prevent subsequent activation of PAR-1 in mononuclear cells. These findings may be of relevance to the pathogenesis of COPD.

Calcium↗
PubMed2003

Severe acute respiratory syndrome: global initiatives for disease diagnosis.

We present a retrospective analysis of the available articles on severe acute respiratory syndrome (SARS) published since the outbreak of the disease. SARS is a new infectious disease caused by a novel coronavirus. Originating in Guangdong, Southern China, at the end of 2002, it has spread to regions all over the world, affecting more than 8000 people. With high morbidity and mortality, SARS is an important respiratory disease which may be encountered world-wide. The causative virus was identified by a WHO-led network of laboratories, which identified the genome sequence and developed the first molecular assays for diagnosis. For the respiratory physician, detecting SARS in its earliest stages, identifying pathways of transmission, and implementing preventive and therapeutic strategies are all important. The WHO and the CDC have published helpful definitions of 'suspected' and 'probable' cases. However, the symptoms of the disease may change, and laboratory tests and definitions are still limited. Even in a situation of no new cases of infection, SARS remains a major respiratory health hazard. As with influenza virus outbreaks, new epidemics may arise at the end of each year.

Antibodies, Viral↗
PubMed2003

Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations.

BACKGROUND: Exacerbations represent an important feature of the clinical manifestation and natural history of chronic obstructive pulmonary disease (COPD). Nuclear localisation of p65 is a signal of nuclear factor-kappaB (NF-kappaB) activation. A study was undertaken to evaluate whether NF-kappaB activation is modified in sputum cells during COPD exacerbations. METHODS: Total and nuclear p65 immunoreactivity was measured by immunocytochemistry in the sputum cells of 11 smokers with moderate COPD during an exacerbation and after 6-8 weeks of clinical stability. RESULTS: Total sputum cell count was significantly increased during exacerbations from a median (IQR) of 880 (510-1865) to 1914.5 (1065-3205) x 10(3)/ml (p<0.05). The main inflammatory cells in the sputum were neutrophils (83.2 (75.4-92.3)%) and macrophages (14.7 (2.6-21.6)%) and their relative proportion did not change during exacerbations. Nuclear staining for p65 was absent in sputum neutrophils, both during exacerbations and in the stable phase. In contrast, the percentage of macrophages expressing nuclear p65 increased significantly during exacerbations from a median (IQR) of 16 (7-24)% to 41.4 (6-69)% (p<0.05). CONCLUSIONS: NF-kappaB appears to be activated in sputum macrophages but not in sputum neutrophils during exacerbations of COPD

Aged↗
PubMed2003

Systematic assessment of difficult-to-treat asthma.

Five per cent of asthmatics remain symptomatic despite high-dose treatment. The aim of the study was to investigate how often such difficult-to-treat asthma is due to intractable asthma, misdiagnosis, non-adherence with therapy, or psychiatric problems. Difficult asthma was defined as persistence of symptoms despite treatment at step 4 of British guidelines or requirement for long-term oral glucocorticoids (step 5). One-hundred patients with a respiratory physician diagnosis of asthma were investigated in a single tertiary respiratory unit in an open and descriptive study. Twelve of the patients studied did not have asthma and a further seven had additional diagnoses. Of the remainder, 55 had an asthma diagnosis confirmed by demonstration of reversible airflow narrowing or peak flow variability, whilst 20 did not. Non-compliance with prednisolone therapy was more frequent in the 55 with confirmed asthma (nine of 18 prescribed oral prednisolone at a dose of > or = 15 mg x day(-1)) and was not detected in the "unconfirmed asthma" group. There were no other significant differences between these groups. A major psychiatric component was detected in 10 patients. Systematic evaluation of difficult asthma is useful as it can identify alternative or additional diagnoses, psychiatric illness or nonconcordance with therapy in a substantial proportion of cases (32% in the present series).

Administration, Oral↗
PubMed2003

Murine models of asthma.

In vivo animal models can offer valuable information on several aspects of asthma pathogenesis and treatment. The mouse is increasingly used in these models, mainly because this species allows for the application in vivo of a broad range of immunological tools, including gene deletion technology. Mice, therefore, seem particularly useful to further elucidate factors influencing the response to inhaled allergens. Examples include: the role of immunoregulatory mechanisms that protect against T-helper cell type 2 cell development; the trafficking of T-cells; and the contribution of the innate immunity. However, as for other animal species, murine models also have limitations. Mice do not spontaneously develop asthma and no model mimics the entire asthma phenotype. Instead, mice should be used to model specific traits of the human disease. The present task force report draws attention to specific aspects of lung structure and function that need to be borne in mind when developing such models and interpreting the results. In particular, efforts should be made to develop models that mimic the lung function changes characteristic of asthma as closely as possible. A large section of this report is therefore devoted to an overview of airway function and its measurement in mice.

Animals↗
PubMed2003

Neutrophil airway influx by platelet-activating factor in asthma: role of adhesion molecules and LTB4 expression.

Platelet-activating factor (PAF)-induced neutrophil lung sequestration may require cell surface adhesion molecules (macrophage-1 antigen (MAC-1) and lymphocyte function-associated antigen-1 (LFA-1)). In this randomised, double-blinded, crossover study, the neutrophil kinetics after PAF and Lyso-PAF (L-PAF) airway challenge were investigated in nine mild-intermittent asthmatics. Neutrophils were measured in peripheral blood (PB) before and at 5, 15, 45 and 240 min after bronchoprovocation, and in induced sputum before and at 240 min after challenge. MAC-1 and LFA-1 expression were assessed by immunocytochemistry, and leukotriene B4 (LTB4) was measured by enzyme-immunoassay in induced-sputum supernatants. Compared with baseline, neutrophils in PB decreased 5 min after PAF, while at 240 min neutrophils in induced sputum increased. Compared with baseline and L-PAF, PAF decreased the percentages of MAC-1- and LFA-1-positive neutrophils in PB at 5 min, but increased the percentages of MAC-1 and LFA-1 in neutrophil-induced sputum. Moreover, compared with baseline and L-PAF, PAF-induced sputum revealed higher LTB4 levels, a finding that correlated with the elevated number of neutrophils in induced sputum. These findings suggest that macrophage-1 antigen and lymphocyte function-associated antigen-1 are involved in platelet-activating factor-induced neutrophil lung traffic, and that this process is modulated by enhanced leukotriene B4 release within the airways.

Adult↗