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Biomedical subjects

K F Chung

Publications and source records attributed to K F Chung.

At least 145 records · Page 8Linked to original sources
PubMed1998

Proliferation of airway epithelium after ozone exposure: effect of apocynin and dexamethasone.

Ozone is an environmental pollutant with potent oxidizing properties. We investigated whether exposure to ozone-induced cell proliferation in the lungs of rats, and determined the effect of an antioxidant and of a glucocorticosteroid in Brown-Norway (BN) rats. Following single ozone exposure (0.5, 1.0, or 3.0 ppm for 6 h), proliferating cell nuclear antigen (PCNA) expression, as determined with immunohistochemistry, was significantly increased in the bronchial epithelium and alveolar epithelium as compared with controls exposed to filtered air with a maximal effect at 24 to 48 h (p < 0.001). Apocynin (5 mg/kg, orally), a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, reduced the PCNA index in bronchial epithelium induced by ozone (3 ppm, 6 h) from 11.5 +/- 1.3% (percent of nuclear cells expressing PCNA) to 4.4 +/- 1.3% (mean +/- SEM; p < 0.05). Dexamethasone (3 mg/kg, intraperitoneally) also reduced the PCNA index in bronchial epithelium, from 19.2 +/- 2.3% to 10.9 +/- 2.6% (p < 0.05). Dexamethasone but not apocynin inhibited ozone-induced neutrophil influx. Rats exposed repeatedly to ozone (3.0 ppm, 3 h, on three occasions 48 h apart) expressed a lower PCNA index in bronchial epithelium than did rats exposed only once at 1.9 +/- 0.7% versus 6.0 +/- 0.9%, respectively (p < 0.05). The proliferative epithelial response following a single exposure to ozone is modulated through oxidative and inflammatory mechanisms probably involving neutrophils.

Acetophenones↗
PubMed1998

The effects of 5-lipoxygenase inhibition by zileuton on platelet-activating-factor-induced pulmonary abnormalities in mild asthma.

Platelet-activating factor (PAF) has been implicated in the pathogenesis of asthma. We investigated whether PAF-induced neutropenia and lung function disturbances are secondary to activation of the 5-lipoxygenase (5-LO) pathway with the consequent liberation of leukotrienes. The effect of a selective 5-LO inhibitor (zileuton) was examined in 10 mildly asthmatic patients (24 +/- 1 [mean +/- SE] yr; FEV1 = 94 +/- 4% predicted) before and after PAF inhalation, in a randomized, double-blind, placebo-controlled, crossover fashion. Patients were studied at baseline, 3 h after an oral single dose of zileuton (600 mg) or placebo, and then at 5 min, 15 min, and 45 min after PAF (18 microg) inhalation. Compared with vehicle, premedication with zileuton reduced both PAF-induced neutropenia at 5 min (by 43%) (p < 0.005) and the subsequent rebound neutrophilia at 15 min and 45 min (by 50% and 47%, respectively) (p < 0.025 each). In addition, at 5 min after PAF inhalation, zileuton attenuated increases in respiratory system resistance (Rrs) (by 39%) (p < 0.01) and in the alveolar-arterial PO2 difference (A-a)PO2 (by 40%) (p < 0.05), and the decrease in PaO2 (by 27%) (p < 0.005). The protective effect of zileuton against PAF-induced ventilation-perfusion (VA/Q) defects was shown by a parallel improvement (decrease) in an overall marker of VA/Q inequality (dispersion of retention minus excretion of inert gases corrected for dead space; DISP R-E.) (by 43%) 5 min after administration of PAF (p < 0.01). These findings indicate that PAF-induced systemic and pulmonary effects in patients with mild asthma are effectively mediated by the ongoing release of leukotrienes.

Adult↗
PubMed1998

Combined use of exhaled hydrogen peroxide and nitric oxide in monitoring asthma.

Oxidative stress contributes to airway inflammation and exhaled hydrogen peroxide (H2O2) and nitric oxide (NO) are elevated in asthmatic patients. We determined the concentrations of expired H2O2 and NO in 116 asthmatic (72 stable steroid-naive, 30 stable steroid-treated, and 14 severe steroid-treated unstable patients) and in 35 healthy subjects, and studied the relation between exhaled H2O2, NO, FEV1, airway responsiveness, and eosinophils in induced sputum. Both exhaled H2O2 and NO levels were elevated in steroid-naive asthmatic patients compared with normal subjects (0.72 +/- 0.06 versus 0.27 +/- 0.04 microM and 29 +/- 1.9 versus 6.5 +/- 0. 32 ppb, respectively; p < 0.001) and were reduced in stable steroid-treated patients (0.43 +/- 0.08 microM, p < 0.05, and 9.9 +/- 0.97 ppb, p < 0.001). In unstable steroid-treated asthmatics, however, H2O2 levels were increased, but exhaled NO levels were low (0.78 +/- 0.16 microM and 6.7 +/- 1.0 ppb, respectively). There was a correlation between expired H2O2, sputum eosinophils and airway hyperresponsiveness (methacholine PC20). Exhaled NO also correlated with sputum eosinophils, but not with airway hyperresponsiveness. Our findings indicate that measurement of expired H2O2 and NO in asthmatic patients provides complementary data for monitoring of disease activity.

Administration, Inhalation↗
PubMed1998

Activation and localization of transcription factor, nuclear factor-kappaB, in asthma.

Asthma is associated with increased expression of inflammatory proteins including cytokines, enzymes, and adhesion molecules. Induction of many of the genes for these proteins is regulated by the transcription factor, nuclear factor-kappaB (NF-kappaB). We therefore examined whether airway cells from patients with asthma show increased activation of NF-kappaB. Nuclear proteins were extracted from cells of induced sputum and from bronchial biopsies of normal subjects and patients with asthma. NF-kappaB-binding to its consensus DNA binding site, as investigated with 32P-labeled oligonucleotides and electrophoretic-mobility-shift assay, showed a 2.5-fold increase (p < 0.003) in NF-kappaB-DNA binding in induced sputum of asthma patients. Nuclear staining, representing activated NF-kappaB, was observed in macrophages of induced sputum. Immunohistochemical examination of bronchial biopsy specimens with an antibody to p65, a constituent of NF-kappaB, showed more airway epithelial cells with nuclear staining in asthma patients (45.1 +/- 7.2% versus 20.7 +/- 3.9%; n = 9; p < 0.01), and a 2.5-fold greater number of cells with cytoplasmic staining in the mucosal region (p < 0.05). Pooled nuclear extracts of bronchial biopsy specimens from asthma patients showed a 44% greater level of NF-kappaB-DNA binding. Activation of NF-kappaB may be the basis for increased expression of many inflammatory genes and for the perpetuation of chronic airway inflammation in asthma.

Adult↗
PubMed1998

Prostaglandins E2 and F2alpha reduce exhaled nitric oxide in normal and asthmatic subjects irrespective of airway caliber changes.

Cyclooxygenase products modulate the expression of nitric oxide synthase (NOS) in certain cell types. We determined the effect of prostaglandins (PG) E2 and F2alpha on exhaled nitric oxide (NO) concentrations measured by chemiluminescence. Inhaled PGE2 and PGF2alpha significantly reduced exhaled NO. After the highest dose of PGE2 (100 micrograms), NO concentrations fell from 6.9 +/- 0.5 ppb to 4.0 +/- 0.8 ppb (p < 0.001), and from 22.9 +/- 2.0 ppb to 12.3 +/- 1. 2 ppb (p < 0.001), whereas after PGF2alpha, it fell from 6.5 +/- 0.6 ppb to 3.0 +/- 0.5 ppb (p < 0.001), and from 26.0 +/- 3.4 ppb to 11. 5 +/- 1.4 ppb (p < 0.001) in normal (n = 7) and asthmatic (n = 8) subjects, respectively. Although the prostaglandins did not change FEV1 in normal subjects, PGE2 caused an increase in asthmatics (from 3.6 +/- 0.3 L to 3.8 +/- 0.4 L, p < 0.05) and PGF2alpha caused a transient reduction in FEV1 from 4.0 +/- 0.2 L to 3.5 +/- 0.2 L (p < 0.05). To further determine the relationship between bronchoconstriction and exhaled NO levels, we examined the effect of inhaled methacholine which did not change exhaled NO concentrations in normal and asthmatic subjects despite a greater than 20% fall in FEV1 in asthmatics. Therefore, PGE2 and PGF2alpha reduce exhaled NO, an effect not related to airway caliber changes but which may result from an inhibition of nitric oxide synthase (NOS), particularly inducible NOS (iNOS).

Administration, Inhalation↗
PubMed1998

Expression and release of interleukin-8 by human airway smooth muscle cells: inhibition by Th-2 cytokines and corticosteroids.

Interleukin (IL)-8 is a C-X-C chemokine that potently chemoattracts and activates neutrophils. We determined whether IL-8 could be produced by human airway smooth muscle cells in culture and examined its regulation. TNF-alpha stimulated IL-8 mRNA expression and protein release in a time- and dose-dependent manner, whereas IFN-gamma alone had no effect. Both cytokines together did not induce greater IL-8 release compared to TNF-alpha alone. IL-1beta was more potent in inducing IL-8 release and, together with TNF-alpha, there was a synergistic augmentation of IL-8 release. IL-8 release induced by TNF-alpha and IFN-gamma was partly inhibited by the Th-2-derived cytokines IL-4, IL-10, and IL-13, as well as by dexamethasone. In addition to its contractile responses, airway smooth muscle cells have synthetic and secretory potential with the release of IL-8 and subsequent recruitment and activation of neutrophils in the airways. Release of IL-8 can be modulated by Th-2-derived cytokines and corticosteroids.

Adrenal Cortex Hormones↗
PubMed1998

Increased exhaled nitric oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in alveolar macrophages.

Nitric oxide (NO) plays an important role in resistance to Mycobacterium tuberculosis infection. Our aim was to determine whether inducible NO synthase (iNOS) expression and generation of reactive nitrogen intermediates (RNI) by alveolar macrophages (AM) are increased in patients infected with M. tuberculosis. NO levels in the exhaled air of 19 active pulmonary tuberculosis (TB) and 14 control subjects were measured using a chemiluminescence NO analyser. The expression of iNOS on AM was studied by labelling AM with anti-mac iNOS polyclonal antibody analysed with a flow cytometer. The spontaneous generation of RNI by cultured AM was also measured. Data are presented as mean+/-SEM. The level of NO in exhaled air was higher in patients with active TB (16.2+/-1.2 parts per billion (ppb)) compared to control subjects (6.5+/-0.9 ppb), p<0.0001. Exhaled NO decreased with anti-TB treatment. Compared to control subjects (29.0+/-4.5 fluorescence intensity (FI)), iNOS expression on AM was upregulated in TB patients (86.3+/-12.5 FI) p<0.001 and the capacity for spontaneous generation of nitrite was enhanced. Nitrite production was inhibited by N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of iNOS. The expression of iNOS on AM was related to the concentration of exhaled NO (r=0.66, p<0.001) and the nitrite generation capacity of AM (r(s)=0.77, p<0.001). We conclude that the increase in exhaled nitric oxide observed in patients with active pulmonary tuberculosis is due to an upregulation of inhaled NO synthase expression in alveolar macrophages which have an enhanced capacity for nitric oxide production.

Cells, Cultured↗
PubMed1998

Effect of a platelet-activating factor (PAF) antagonist, SR 27417A, on PAF-induced gas exchange abnormalities in mild asthma.

Inhaled platelet-activating factor (PAF), both in normals and in asthmatic patients, provokes transient systemic effects, neutropenia, bronchoconstriction and arterial oxygenation abnormalities similar to those shown in spontaneous exacerbations of asthma. To investigate the efficacy of a new PAF-receptor antagonist, SR 27417A, on all these changes after PAF challenge, 12 nonsmoking patients (four females and eight males) (mean+/-SEM) age 24+/-1 yrs with mild asthma (forced expiratory volume in one second (FEV1) 93+/-3% predicted) were studied in a double-blind, placebo-controlled, cross-over fashion 2 weeks apart. PAF aerosol challenge (18 microg) was carried out 3 h after oral administration of either SR 27417A (20 mg) or placebo. Respiratory system resistance (Rrs) and arterial blood gases and neutrophil cell counts were measured at baseline, before compound/placebo administration, and at 5, 15 and 45 min after PAF. Compared to vehicle, SR 27417A brought about moderate attenuation of PAF-induced neutropenia at 5 min (by 140%; p<0.025), and rebound neutrophilia at 15 and 45 min (p<0.025), increases of Rrs (by 90-65%) (p<0.01) and of alveolar-arterial pressure difference for oxygen (PA-a,O2) at 5 min (by 68%) and 15 min (by 63%), and decreases of arterial oxygen tension (Pa,O2) at 5 min (by 57%; p<0.025, each). Furthermore, systemic effects and platelet aggregation tests (p<0.001) were abolished after the administration of the compound. We conclude that SR 27417A is effective in inhibiting systemic, cellular and pulmonary effects after platelet-activating factor challenge in patients with mild bronchial asthma.

Adult↗
PubMed1998

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

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.

Administration, Inhalation↗
PubMed1998

Zafirlukast (Accolate).

Cysteinyl-leukotrienes are important mediators in the pathogenesis of asthma. Zafirlukast is a selective and competitive leukotriene receptor antagonist that has been developed for the treatment of asthma. It inhibits exercise-induced asthma, both the early- and late-phase response after allergen challenge in asthmatic subjects, and aspirin-induced asthma in aspirin-sensitive asthmatic patients. Published data indicate that zafirlukast 20 mg twice daily causes an improvement in lung function (FEV(1) and peak expiratory flow measurements) and symptom control, together with a reduction in the use of short-acting beta-agonist inhaled therapy in patients with mild to moderate asthma. Studies presented in abstract form have shown that zafirlukast 20 mg twice daily had similar efficacy as sodium cromoglycate aerosol or dry powder inhalation; in one of the studies, no advantage of the active drugs was reported over placebo. Compared to inhaled beclomethasone dipropionate therapy (200-250 microg b.i.d.), improvements in morning peak flow, FEV(1) and daytime symptom score were significantly less with zafirlukast 20 mg twice daily than with inhaled steroids. A steroid-sparing effect of zafirlukast (20 mg b.i.d.) was not observed in studies of 12-20 weeks duration in patients on inhaled steroid therapy. A significant improvement in lung function and symptom control was observed on addition of zafirlukast 80 mg twice daily in symptomatic patients maintained on high-dose inhaled steroid therapy. Meta-analysis of 5 large studies indicate that there is a significant reduction in the number of asthma exacerbations compared to placebo. Zafirlukast at 20 mg twice daily dosage appears to be well-tolerated comparable to placebo. High doses of 80 mg twice daily have been associated with reports of elevated liver enzymes. Zafirlukast is a useful addition to existing antiasthma therapies. It may be used in combination with inhaled or oral corticosteroid therapy. Further investigation of its efficacy and antiinflammatory effects will clarify its use as a first-line antiinflammatory agent in mild asthma. Zafirlukast is administered orally and may therefore be useful in patients poorly compliant with inhaled steroid therapy and with a poor inhaler technique.

Journal Article↗
PubMed1998

Drug trials.

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Administration, Inhalation↗
PubMed1998

Increased sensitivity of the cough reflex in progressive systemic sclerosis patients with interstitial lung disease.

Cough is a common presenting symptom of interstitial lung disease (ILD). The aim of this study was to examine the cough reflex in patients with progressive systemic sclerosis (PSS), with and without associated ILD. The cough reflex to inhalation of chloride deficient solutions and capsaicin was determined in patients with PSS with associated ILD (n=12), compared to patients with PSS without ILD (n=12). In addition, patients with a chronic dry cough (n=12) and healthy subjects (n=10) without cough were studied. Cough responses to inhalation of isotonic solutions containing 150, 75, 37.5 and 0 mM Cl- ions and of capsaicin (0.9-500 mM) were measured. PSS patients with ILD reported a significantly higher cough score than PSS patients without ILD (p<0.03). ILD patients coughed more than those without ILD to Cl- of 37.5 and 0 mM (19.1+/-5.0 vs 6.2+/-1.9 coughs x min(-1) (p<0.03), and 29.2+/-5.0 vs 14.1/-4.1 coughs x min(-1) (p<0.04), respectively). The log concentration of capsaicin causing two or five coughs was lower in PSS with ILD compared to PSS without ILD (0.74+/-0.15 mM vs 2.12+/-0.26 mM; p<0.002). Patients with chronic dry cough had a similar degree of response to low-chloride and capsaicin solutions as patients with PSS and ILD, whilst healthy controls had a similar degrees of response to PSS patients. There is an increased cough reflex in patients with interstitial lung disease, which may represent sensitization of airway sensory nerves. This may be the basis for the chronic dry cough in patients with interstitial lung disease.

Bronchial Provocation Tests↗
PubMed1997

A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma.

BACKGROUND: Inhaled glucosteroids and oral theophylline are widely used to treat asthma. We compared the benefits of adding theophylline to inhaled glucosteroid with those of doubling the dose of inhaled glucosteroid in patients with persistent symptoms despite the use of inhaled glucosteroid. METHODS: In a double-blind, placebo-controlled trial, we randomly assigned 62 patients to receive either 400 microg of inhaled budesonide (low-dose budesonide) with 250 or 375 mg of theophylline (depending on body weight) or 800 microg of inhaled budesonide (high-dose budesonide). All doses were given twice daily for three months. Lung function was measured serially, and patients kept records of peak expiratory flow, symptoms, and albuterol use. The effects of treatment on endogenous cortisol levels were also assessed. RESULTS: Both treatments resulted in improvements in lung function that were sustained throughout the study. As compared with treatment with high-dose budesonide, treatment with low-dose budesonide plus theophylline resulted in greater improvements in forced vital capacity (P=0.03) and forced expiratory volume in one second (P= 0.03). There were significant and similar reductions in beta2-agonist use and the variability of peak expiratory flow, a correlate of bronchial hyperresponsiveness and the severity of asthma. Serum cortisol concentrations were significantly reduced in the group given high-dose budesonide (from a mean [+/-SE] of 18.4+/-2.4 microg per deciliter to 15.9+/-2.1 microg per deciliter, P=0.02) but were unchanged in the other group. The median serum theophylline concentration was 8.7 microg per milliliter (therapeutic range, 10 to 20) among those who received theophylline. Both treatments were well tolerated. CONCLUSIONS: For patients with moderate asthma and persistent symptoms, low-dose inhaled budesonide with theophylline and high-dose inhaled budesonide produced similar benefits. Effects were achieved at theophylline concentrations below the recommended therapeutic range. The addition of low-dose theophylline to inhaled glucosteroid may be preferable to and cheaper than increasing the dose of inhaled glucosteroid.

Administration, Inhalation↗
PubMed1997

Effect of 5-HT1A receptor agonist, 8-OH-DPAT, on cough responses in the conscious guinea pig.

We have studied the role for 5-hydroxytryptamine (5-HT) in the modulation of the cough reflex by examining the effect of a selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on cough and respiratory rate in conscious guinea pigs. Animals were placed in a box and exposed to the tussive agent citric acid (0.5 M) for 10 min, 3 min after terbutaline (0.05 mg/kg i.p.) was administered to prevent bronchoconstriction. 8-OH-DPAT inhibited at low doses (0.008 and 0.016 mg/kg) but potentiated at high doses (0.25 and 0.5 mg/kg) the citric acid-induced number of coughs, but dose-dependently increased respiratory rate. Methysergide (0.05-5 mg/kg), a 5HT1 and 5HT2 receptor antagonist, and ketanserin (0.005 mg/kg), a 5HT2 receptor antagonist, had no effects on cough or respiratory rate. Methysergide inhibited the increased cough responses and respiratory rate induced by 8-OH-DPAT at high doses, while ketanserin was without effect. These results suggest that 8-OH-DPAT may induce both in inhibition and activation of the cough reflex, the latter involving central 5HT1-receptor activation.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

Human airway smooth muscle cells express and release RANTES in response to T helper 1 cytokines: regulation by T helper 2 cytokines and corticosteroids.

RANTES is a basic 8-kDa polypeptide of the C-C chemokine subfamily with strong chemotactic activity for eosinophils, lymphocytes, and monocytes. We determined the regulation of RANTES production by human airway smooth muscle cells in culture. While TNF-alpha, but not IFN-gamma, increased RANTES mRNA expression and protein release, the combination of TNF-alpha and IFN-gamma caused a greater degree of expression and release in a time- and dose-dependent manner. Sequential treatment of airway smooth muscle cells with TNF-alpha and IFN-gamma showed that IFN-gamma sensitized the cells to the stimulatory effect of TNF-alpha. Using a modified Boyden chamber technique, RANTES separated by reverse-phase liquid chromatography from cell culture supernatants of airway smooth muscle cells stimulated by TNF-alpha and IFN-gamma showed a strong chemoattractant effect on human eosinophils, an effect inhibited by an anti-RANTES Ab. RANTES production induced by TNF-alpha and IFN-gamma was inhibited partly by the Th2-derived cytokines, IL-4, IL-10, and IL-13, as well as by dexamethasone. Our studies indicate that, in addition to contractile responses and mitogenesis, airway smooth muscle cells have synthetic and secretory potential with the release of RANTES. They may participate in chronic airway inflammation by interacting with both Th1- and Th2-derived cytokines to modulate chemoattractant activity for eosinophils, activated T lymphocytes, and monocytes/macrophages.

Adrenal Cortex Hormones↗
PubMed1997

Airway inflammation despite loss of bronchial hyper-responsiveness after multiple ozone exposures.

The effect of single and multiple exposures to ozone (O3) on airway responsiveness and inflammation was examined in guinea pigs. Airway responsiveness, measured as acetylcholine concentration needed to increase baseline airway resistance (RL) by 250% (PC250), increased 1 h after exposure to ozone at 3 ppm for 3 h (-log PC250 from 3.88 +/- 0.17 to 4.78 +/- 0.18; P < 0.05), but returned to baseline at 8 h. An increase in neutrophil numbers was found at 8 h in bronchoalveolar lavage fluid (BALF). After O3 exposure on 4 successive days, baseline RL increased and airway responsiveness decreased at 1, 8 and 72 h (-log PC250 = 2.88 +/- 0.17, 2.83 +/- 0.10 and 3.12 +/- 0.08, respectively, compared to control value of 3.48 +/- 0.05). Repeated exposures to O3 also increased neutrophil numbers in bronchoalveolar lavage fluid and in bronchial submucosa. Thus, single exposure to O3 caused a rapid and transient increase in airway responsiveness, while multiple exposures induced a rapid but prolonged decrease in airway responsiveness associated with persistent bronchoconstriction. Both single and multiple exposures induced airway inflammation as evidenced by an increase in neutrophil influx. These studies demonstrated a dissociation between ozone-induced changes in airway responsiveness and neutrophil influx, and indicate that multiple exposures to O3 induce persistent bronchoconstriction with airway hyporesponsiveness.

Adaptation, Physiological↗