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Dive into the research topics where K. F. Chung is active.

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Featured researches published by K. F. Chung.


Thorax | 2008

Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma

Pankaj K. Bhavsar; Mark J Hew; Nadia Khorasani; Alfonso Torrego; P J Barnes; Ian M. Adcock; K. F. Chung

Background: About 5–10% of patients with asthma suffer from poorly controlled disease despite corticosteroid (CS) treatment, which may indicate the presence of CS insensitivity. A study was undertaken to determine whether relative CS insensitivity is present in alveolar macrophages from patients with severe asthma and its association with p38 mitogen-activated protein kinase (MAPK) activation and MAPK phosphatase-1 (MKP-1). Methods: Fibreoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed in 20 patients with severe asthma and 19 with non-severe asthma and, for comparison, in 14 normal volunteers. Alveolar macrophages were exposed to lipopolysaccharide (LPS, 10 μg/ml) and dexamethasone (10−8 and 10−6 M). Supernatants were assayed for cytokines using an ELISA-based method. p38 MAPK activity and MKP-1 messenger RNA expression were assayed in cell extracts. Results: The inhibition of LPS-induced interleukin (IL)1β, IL6, IL8, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α release by dexamethasone (10−6 M) was significantly less in macrophages from patients with severe asthma than in macrophages from patients with non-severe asthma. There was increased p38 MAPK activation in macrophages from patients with severe asthma. MKP-1 expression induced by dexamethasone and LPS, expressed as a ratio of LPS-induced expression, was reduced in severe asthma. Conclusion: Alveolar macrophages from patients with severe asthma demonstrate CS insensitivity associated with increased p38 MAPK activation that may result from impaired inducibility of MKP-1.


Clinical and Experimental Immunology | 2009

T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients

A. Di Stefano; Gaetano Caramori; Isabella Gnemmi; Chiara Vicari; Armando Capelli; Francesca Magno; Silvestro Ennio D'Anna; Andrea Zanini; Paola Brun; Paolo Casolari; K. F. Chung; Peter J. Barnes; Alberto Papi; Ian M. Adcock; Bruno Balbi

There are increased numbers of activated T lymphocytes in the bronchial mucosa of stable chronic obstructive pulmonary disease (COPD) patients. T helper type 17 (Th17) cells release interleukin (IL)‐17 as their effector cytokine under the control of IL‐22 and IL‐23. Furthermore, Th17 numbers are increased in some chronic inflammatory conditions. To investigate the expression of interleukin (IL)‐17A, IL‐17F, IL‐21, IL‐22 and IL‐23 and of retinoic orphan receptor RORC2, a marker of Th17 cells, in bronchial biopsies from patients with stable COPD of different severity compared with age‐matched control subjects. The expression of IL‐17A, IL‐17F, IL‐21, IL‐22, IL‐23 and RORC2 was measured in the bronchial mucosa using immunohistochemistry and/or quantitative polymerase chain reaction. The number of IL‐22+ and IL‐23+ immunoreactive cells is increased in the bronchial epithelium of stable COPD compared with control groups. In addition, the number of IL‐17A+ and IL‐22+ immunoreactive cells is increased in the bronchial submucosa of stable COPD compared with control non‐smokers. In all smokers, with and without disease, and in patients with COPD alone, the number of IL‐22+ cells correlated significantly with the number of both CD4+ and CD8+ cells in the bronchial mucosa. RORC2 mRNA expression in the bronchial mucosa was not significantly different between smokers with normal lung function and COPD. Further, we report that endothelial cells express high levels of IL‐17A and IL‐22. Increased expression of the Th17‐related cytokines IL‐17A, IL‐22 and IL‐23 in COPD patients may reflect their involvement, and that of specific IL‐17‐producing cells, in driving the chronic inflammation seen in COPD.


European Respiratory Journal | 2004

Parameters associated with persistent airflow obstruction in chronic severe asthma

D. Bumbacea; D.A. Campbell; L. Nguyen; D. Carr; Peter J. Barnes; Douglas S. Robinson; K. F. Chung

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 Georges 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±0.03×109cells·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.


Thorax | 1998

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

R G Stirling; Sergei A. Kharitonov; D Campbell; Douglas S. Robinson; Stephen R. Durham; K. F. Chung; P J Barnes

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 (⩾2000 μg 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 β 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.


Thorax | 2004

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

Akio Niimi; L T Nguyen; Omar S. Usmani; B Mann; K. F. Chung

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 μM, 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.


Thorax | 2012

Genome-wide association study to identify genetic determinants of severe asthma

Y.I. Wan; Nick Shrine; M. Soler Artigas; Louise V. Wain; John Blakey; Miriam F. Moffatt; Andrew Bush; K. F. Chung; William Cookson; David P. Strachan; Liam Heaney; B.A.H. Al-Momani; Adel Mansur; S. Manney; Neil C. Thomson; Rekha Chaudhuri; Christopher E. Brightling; Mona Bafadhel; Amisha Singapuri; Robert Niven; Angela Simpson; John W. Holloway; Peter H. Howarth; Jennie Hui; Arthur W. Musk; Alan James; Matthew A. Brown; Svetlana Baltic; Manuel A. Ferreira; Philip J. Thompson

Background The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective To identify common genetic variants affecting susceptibility to severe asthma. Methods A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10(−8) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10(−8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.


Histopathology | 2004

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

Gaetano Caramori; C Di Gregorio; Ingemar Carlstedt; Paolo Casolari; Ippolito Guzzinati; Ian M. Adcock; Peter J. Barnes; Adalberto Ciaccia; Giorgio Cavallesco; K. F. Chung; Alberto Papi

Aims:  To study the expression of mucins in peripheral airways in patients with chronic obstructive pulmonary disease (COPD).


European Respiratory Journal | 1998

An inhaled steroid improves markers of airway inflammation in patients with mild asthma

A. Jatakanon; Sam Lim; K. F. Chung; P J Barnes

Airway inflammation can be demonstrated in mildly asthmatic patients who are not treated with inhaled steroids. Current guidelines recommend that inhaled steroids should be introduced in mild asthmatics who use an inhaled beta2-agonist more than once daily. It was postulated that inhaled steroids can have anti-inflammatory effects in patients with even milder disease. The effect of 4 weeks of treatment with budesonide (800 microg twice daily by Turbohaler) was studied in 10 steroid-naive mildly asthmatic patients (forced expiratory volume in one second (FEV1) = 96+/-1.4% predicted) who required an inhaled beta2-agonist less than one puff daily, in a double-blind, placebo-controlled, crossover fashion. Spirometry, exhaled nitric oxide (NO), bronchial responsiveness (provocative concentration causing a 20% fall in FEV1 (PC20)), and sputum induction were performed before and after each treatment period. Following budesonide treatment, there were significant improvements in FEV1, and PC20, in association with a significant reduction in the percentage of eosinophils in induced sputum. Exhaled NO levels tended towards reduction, but the change was nonsignificant. There were also nonsignificant reductions in sputum eosinophil cationic protein and tumour necrosis factor-alpha levels. In conclusion inhaled budesonide can lead to improvements in noninvasive markers of airway inflammation, in association with a small improvement in lung function, even in mildly asthmatic patients who require an inhaled beta2-agonist less than once daily. This suggests a potential benefit of inhaled corticosteroids, even in relatively asymptomatic asthma.


Clinical & Experimental Allergy | 2001

Decreased T lymphocyte infiltration in bronchial biopsies of subjects with severe chronic obstructive pulmonary disease

A. Di Stefano; Armando Capelli; Mirco Lusuardi; Gaetano Caramori; Piero Balbo; F. Ioli; S. Sacco; Isabella Gnemmi; Paola Brun; Ian M. Adcock; Bruno Balbi; P J Barnes; K. F. Chung; Claudio F. Donner

Background Studies on the inflammatory process in the large airways of patients with mild/moderate COPD have shown a prevalent T lymphocyte and macrophage infiltration of the bronchial mucosa. However, bronchial inflammation in more severe disease has not been extensively studied.


European Respiratory Journal | 2001

Expression of GATA family of transcription factors in T-cells, monocytes and bronchial biopsies

Gaetano Caramori; Sam Lim; K. Ito; Katsuyuki Tomita; Timothy Oates; Elen Jazrawi; K. F. Chung; P J Barnes; Ian M. Adcock

GATA-binding proteins are a subfamily of zinc finger transcription factors with six members (GATA-1-6) that interact with the GATA deoxyribonucleic acid (DNA) sequence. This sequence is found in the regulatory regions of many genes including those encoding T-helper 2 (Th2)-like cytokines, receptors, adhesion molecules and enzymes, which may be important in the pathogenesis of bronchial asthma. The expression of GATA-3, 4 and -6 was investigated in peripheral blood T-lymphocytes and monocytes and bronchial biopsies from 11 normal subjects and 10 steroid-naive asthmatic patients. Using Western blot analysis, T-cells from asthmatic subjects expressed 5 times the level of GATA-3 compared to that in normals. Confocal microscopy indicated that GATA-3 expression was both nuclear and cytoplasmic. GATA DNA binding complex containing GATA-3 was elevated in Th2 cells as determined by electrophorectic mobility shift assay. In contrast, monocytes from normal and asthmatic subjects expressed GATA-4 and -6 in equal amounts, but no GATA-3 was found. Using immunohistochemistry in bronchial biopsies, epithelial cells expressed high levels of GATA-3, GATA-4 and GATA-6 proteins. Comparison of Western blots of bronchial biopsies showed no significant differences between normal and asthmatic subjects. In conclusion, the increased expression of GATA-3 in asthmatic T-cells may underlie augmented T-helper 2-like cytokines in this disease. However, the unaltered GATA-3 expression in epithelial cells suggests a distinct role for GATA-3 in these cells unrelated to T-helper 2-like cytokine release. Finally, no evidence was found for an increased expression of GATA-4 and GATA-6 in asthma.

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Ian M. Adcock

National Institutes of Health

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P J Barnes

Imperial College London

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Peter J. Barnes

National Institutes of Health

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Nadia Khorasani

National Institutes of Health

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Sergei A. Kharitonov

National Institutes of Health

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Sam Lim

Imperial College London

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