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Biomedical subjects

K F Chung

Publications and source records attributed to K F Chung.

At least 109 records · Page 6Linked to original sources
PubMed2000

Difficult, therapy-resistant asthma: definition and clinical features.

Difficult therapy-resistant asthma may be defined as poorly controlled asthma in terms of chronic symptoms, episodic exacerbations, persistent and variable airways obstruction despite a continued requirement for short-acting beta 2-agonists despite the use of high doses of inhaled steroids. It is necessary to confirm the diagnosis of asthma, to exclude alternative diagnosis, and to make sure that adequate asthma treatment is given and being adhered to. Difficult therapy-resistant asthma is likely to consist of several clinical subgroups characterized by the temporal sequence of exacerbations and symptoms, the chronicity and rapidity of symptoms and response to treatment, such as brittle asthma, chronic difficult asthma, and fatal asthma. Exacerbating factors such as gastrooesophageal reflux, sinorhinitis, allergen exposure, drugs, respiratory tract infections and psychosocial factors must be addressed.

Asthma↗
PubMed1999

Inhibition of ozone-induced lung neutrophilia and nuclear factor-kappaB binding activity by vitamin A in rat.

Vitamin A binds to retinoic acid receptors, which in turn may interact with other transcription factors. We determined its effect (2500 and 5000 IU/kg) on nuclear factor-kappaB binding activity in the lung, airway inflammation and bronchial hyperresponsiveness in rats exposed to ozone. Ozone (3 ppm, 3 h) caused neutrophil influx into bronchoalveolar lavage fluid (16.2+/-0.8 x 10(5) cells/ml, p < 0.01) and bronchial hyperresponsiveness (-logPC200ACh = 2.54+/-0.19, p < 0.05, compared to control animals, respectively). Vitamin A inhibited this neutrophilia dose-dependently together with the increased DNA-binding activity of nuclear factor-KB in lung extracts. Vitamin A did not affect bronchial hyperresponsiveness at both doses. Vitamin A inhibits ozone-induced neutrophilic inflammation through a reduction in nuclear factor-kappaB DNA binding activity.

Acetylcholine↗
PubMed1999

Non-invasive biomarkers of asthma.

Several non-invasive biomarkers of inflammation in asthma such as exhaled NO and eosinophil numbers in induced sputum have been developed. Their usefulness in experimental asthma models has been validated but there is less experience in their use in clinical practice. Because specific cooperation may be needed from the patient in producing samples from the airways for assay of biomarkers, younger children may not be suitable. Specific experience in these age groups is required. There remains a need to examine these biomarkers in patients from the mild asymptomatic to the more symptomatic difficult asthmatic in longitudinal studies. Is it useful to monitor these biomarkers as a response to treatment rather than the more conventional measures of symptoms and lung function measurements for prevention of exacerbations and long-term reduction in lung function? Answers to such issues will be crucial in adopting the routine measurement of certain biomarkers from the airways in the assessment of asthma severity and control.

Asthma↗
PubMed1999

Previously unrecognized obstructive sleep apnea in Chinese subjects with essential hypertension.

Obstructive sleep apnea (OSA) is found to affect 2-4% of the middle-aged population in several Caucasian studies, whereas the prevalence among other ethnic groups have not been clearly documented. It has been reported that OSA and systemic hypertension are highly associated; we therefore conducted a study on Chinese subjects who were receiving treatment for essential hypertension to assess the prevalence of OSA among this group. Ninety-two consecutive patients being followed up at a hypertension clinic were recruited for a questionnaire survey. The entire study group was aged 54.7 +/- 11.7 years, with 40 men. One male subject had a diagnosis of obstructive sleep apnea on nasal continuous positive airway pressure (nCPAP) treatment and 46 subjects agreed to an overnight sleep study. Those who underwent sleep study showed selection bias with a higher body mass index and more symptoms associated with OSA. Of the 46 who underwent sleep study, 16 (34.8%) had an obstructive apnea-hypopnea (AHI) score of >/=5 and excessive daytime sleepiness, with a median score of 26.2 (range, 8.3-64.9). Patients in the group with obstructive sleep apnea syndrome (OSAS) thus defined compared with those without OSAS had more men (64.7 vs 17.20%, p = 0.001) and an excess of smokers (31.5 vs 3.3%. p = 0.01) and had significantly more symptoms of excessive daytime sleepiness (p = 0.001), daytime fatigue (p = 0.007), and witnessed apneas (p = 0.008). Seven patients accepted treatment with nCPAP and reported improvement in symptoms, but there was no detectable change in clinic blood pressure measurements after 3 months of nCPAP treatment. This study demonstrated a high prevalence of previously unidentified OSAS among Chinese patients with essential hypertension. Increased awareness of both doctors and patients toward this potentially treatable problem is warranted.

Adult↗
PubMed1999

Increased progenitor cell proliferation in the peripheral blood of patients with bronchial asthma: the role of nitric oxide.

BACKGROUND: Asthma exacerbation is associated with increased numbers of circulating CD34(+) progenitor cells, which may migrate to airways and develop into mature cells under the effects of cytokines and hematopoietic factors. Nitric oxide (NO) generation is enhanced in asthma and is known to suppress human hematopoiesis. OBJECTIVES: We studied circulating progenitor cells in the blood of patients with varying severity of asthma and examined the contribution of NO to their proliferation into eosinophil-forming colonies ex vivo. METHODS: With use of multiparameter flow cytometric analyses, the cell numbers and intracellular inducible NO synthase (iNOS) immunoreactivity of circulating CD34(+) cells in peripheral blood was measured. The serum level of GM-CSF or IL-5 was also determined. The colonies grown from progenitor cells were cultured in methylcellulose either in the presence or absence of growth factors, including GM-CSF, stem cell factor, and IL-3. RESULTS: A significantly greater number of circulating CD34(+) cells increased together with higher intracellular iNOS immunoreactivity in moderate asthmatics compared with mild intermittent asthmatics and healthy subjects. There was no significant difference in iNOS immunoreactivities or CD34(+) progenitor cell numbers between healthy subjects and those with mild intermittent asthma. Serum levels of GM-CSF or IL-5 were significantly higher in all asthmatics compared with healthy subjects and correlated with circulating CD34(+) cells. A greater number of colonies was grown either in the presence or absence of growth factors with a higher percentage of cells of eosinophil lineage in asthmatics than in health subjects. N(G)-nitro-L-arginine methyl ester potentiated and sodium nitroprusside inhibited the colony growth in both asthmatic and healthy subjects without a significant change in the percentage of eosinophil lineage. CONCLUSIONS: The production of NO from progenitor cells or other circulating cells may act in an autocrine or paracrine fashion to regulate progenitor cell growth and colony formation. However, this is not sufficient to control the increased proliferation of progenitor cells observed in asthma.

Adult↗
PubMed1999

Differential regulation of cytokine expression after allergen exposure of sensitized rats by cyclosporin A and corticosteroids: relationship to bronchial hyperresponsiveness.

BACKGROUND: Cyclosporin A and dexamethasone exhibit different effects on allergic airway eosinophilia and bronchial hyperresponsiveness (BHR). OBJECTIVE: We determined whether these were related to alteration of cytokine expression, particularly with regard to the profile of Th1- versus Th2-derived cytokines. METHODS: Brown-Norway rats sensitized with ovalbumin were administered cyclosporine or dexamethasone before ovalbumin aerosol challenge. Bronchial responsiveness was measured 18 to 24 hours after aerosol exposure. Airway cellular influx was determined by bronchoalveolar lavage and tissue immunohistochemistry. The expression of Th1 and Th2 cytokine messenger RNA (mRNA) was analyzed by reverse transcriptase-PCR. RESULTS: Ovalbumin exposure induced significant BHR, with increases in eosinophils, lymphocytes, and neutrophils in bronchoalveolar lavage fluid and an increase in eosinophils, CD2(+) and CD8(+), but not CD4(+) T cells, in the airway submucosa. IL-2, IFN-gamma, IL-4, and IL-5 mRNA expression in the lungs of sensitized ovalbumin-exposed rats was increased (P <.05) compared with controls. Cyclosporin A had no significant effect on BHR and neutrophil accumulation but reduced the number of bronchoalveolar lavage eosinophils (P <.002), airway submucosal eosinophils, and CD4(+) and CD8(+) T cells (P <.02). It also suppressed the induced mRNA expression of IL-2, IL-4, IL-5, and IFN-gamma. By contrast, the inflammatory cell influx and mRNA expression for IL-2, IL-4, and IL-5, as well as BHR, were suppressed by dexamethasone. However, an increase in IL-10 and IFN-gamma mRNA expression was found. CONCLUSION: The differential activities of cyclosporin A and dexamethasone on inflammatory cell influx, particularly neutrophils, or cytokine expression such as IL-10 and IFN-gamma may underlie their contrasting effects on BHR.

Allergens↗
PubMed1999

Effects of inhaled furosemide on platelet-activating factor challenge in mild asthma.

Furosemide (Fur) may have an anti-inflammatory effect on airways in patients with asthma although its intrinsic mechanism remains elusive. Platelet-activating factor (PAF) is a potent proinflammatory mediator that induces systemic and respiratory effects in normal control subjects and asthmatics. The aim of this study was to assess whether pretreatment with nebulized Fur (40 mg) was able to modulate PAF-induced systemic and respiratory effects in asthma. Eleven patients were studied (mean+/-sem 22+/-0.8 yrs) with mild asthma (forced expiratory volume in one second, 95+/-4%) in a randomized, double-blind, placebo-controlled, cross-over fashion, one week apart. PAF challenge (18 microg) was carried out 15 min after administration of Fur or placebo. Peripheral blood neutrophils, respiratory system resistance, and arterial blood gases were measured at baseline, and 5, 15 and 45 min after PAF; urinary cysteinyl leukotriene E4 (uLTE4) was also measured, at baseline and 120 min after PAF challenge. Although Fur did not alter PAF-induced systemic and respiratory effects, it did partially inhibit (63%; p<0.04) the increments of uLTE4 levels shown after PAF inhalation. It is concluded that furosemide is not effective in protecting against platelet-activating factor challenge in patients with asthma despite its potential inhibition of leukotriene synthesis. These findings reinforce the view that the pulmonary effects of platelet-activating factor are mediated through different pathways.

Administration, Inhalation↗
PubMed1999

Gas exchange response to a PAF receptor antagonist, SR 27417A, in acute asthma: a pilot study.

The pathogenic role of platelet-activating factor (PAF) in asthma has been questioned due to the limited or negative efficacy of PAF antagonists; however, in acute asthma (AA), where the endogenous release of PAF may be enhanced, the effects of PAF antagonist receptors have not been investigated. It was postulated that inhaled PAF provokes gas exchange defects in mild asthma likely to be related to airway vascular leakage. The response to a potent, selective PAF receptor antagonist, SR 27471A, on pulmonary gas exchange was studied, more specifically ventilation-perfusion (VA'/Q') distributions, in patients with AA within 48 h of hospitalization. A randomized, double-blind, placebo-controlled, parallel group (n=6, each) design was used. After baseline measurements, either placebo or SR 27417A (20 mg, orally) was administered and measurements were repeated 3 h later. Conventional anti-asthma medication was not interrupted. Despite a near-complete inhibition of the in vitro, platelet aggregation tests by 40 nM PAF (mean+/-SEM from 72+/-9 to 6+/-2%) and 80 nM PAF (from 81+/-7 to 6+/-3% both p<0.01) by SR 27471A indicating a good bioactivity of the compound, no significant changes in baseline forced expiratory volume in one second, (40+/-6%), respiratory system resistance (6.2+/-0.7 cmH2O x L(-1) x s), alveolar-arterial pressure difference for oxygen (5.2+/-0.4 kPa), arterial oxygen tension (9.0+/-0.5 kPa) or VA'/Q' distributions, as expressed by the dispersion of pulmonary blood flow (LogSD Q, 1.07+/-0.09; normal values <0.60), were observed. It is concluded that SR 27417A has limited value when added to the conventional treatment of acute asthma. These findings minimize the potential pathogenic role of endogenous platelet-activating factor as a relevant mediator of airway inflammation during acute asthma.

Acute Disease↗
PubMed1999

Repeated allergen exposure of sensitized Brown-Norway rats induces airway cell DNA synthesis and remodelling.

Chronic inflammation in asthmatic airways can lead to characteristic airway smooth muscle (ASM) thickening and pathological changes within the airway wall. This study assessed the effect of repeated allergen exposure on ASM and epithelial cell deoxyribonucleic acid (DNA) synthesis, cell recruitment and airway wall pathology. Brown-Norway rats were sensitized and then exposed to ovalbumin or saline aerosol every 3 days on six occasions. After the final exposure, rats were administered twice daily for 7 days with the DNA S-phase marker bromodeoxyuridine (BrdU). Using a triple immunohistochemical staining technique, BrdU incorporation into ASM and epithelium was quantified employing computer-assisted image analysis. There were >3-fold mean increases in BrdU incorporation into ASM from 1.3% of cells (95% confidence interval (CI) 1.0-1.6) in saline controls to 4.7% (95% CI 2.6-6.7) after allergen exposure (p<0.001), and in airway epithelium, from 1.3 (95% CI 0.6-2.0) BrdU-positive cells x mm basement membrane(-1) in saline controls to 4.9 (95% CI 3.0-6.7) after allergen exposure (p<0.001). There was increased subepithelial collagen deposition and mucus secretion along with a significant eosinophil and lymphocyte recruitment to the airways. Increased rates of deoxyribonucleic acid synthesis in both airway smooth muscle and epithelial cells along with changes to the airway wall pathology may precede the establishment of smooth muscle thickening and airway remodelling after repeated allergen exposure in rats. This model seems to be appropriate for studying structural changes within the airways as observed in asthma.

Actins↗
PubMed1999

Induction of eotaxin expression and release from human airway smooth muscle cells by IL-1beta and TNFalpha: effects of IL-10 and corticosteroids.

Eotaxin is a novel C-C chemokine with selective chemoattractant activity for eosinophils. We determined whether eotaxin could be produced by human airway smooth muscle (HASM) cells in culture and examined its regulation by interleukin-10 (IL-10) and the corticosteroid, dexamethasone. Stimulation of the cells with interleukin-1beta (IL-1beta) or tumour necrosis factor (TNFalpha) each at 10 ng ml(-1) induced the release of eotaxin protein with maximal accumulation by 24 h. Interferon-gamma (IFNgamma) alone at 10 ng ml(-1) had no effect and there was no synergy between these cytokines on the release of eotaxin. Reverse phase high performance liquid chromatographic (HPLC) analysis of supernatents from cells treated with TNFalpha (10 ng ml(-1) for 96 h showed immunoreactivity to eotaxin which eluted with the expected retention time of 34.5-35 min. Both IL-1beta and TNFalpha-induced release of eotaxin was not inhibited by dexamethasone (1 microM), however IL-10 (10 ng ml(-1)) had a significant inhibitory effect. Dexamethasone and IL-10 did not inhibit the induction of eotaxin mRNA induced by IL-1beta or TNFalpha. Thus, human airway smooth muscle cells can release eotaxin and could be an important source of chemokine production during airway inflammatory events.

Adolescent↗
PubMed1999

Involvement of cysteinyl leukotrienes in airway smooth muscle cell DNA synthesis after repeated allergen exposure in sensitized Brown Norway rats.

Airway smooth muscle thickening is a characteristic feature of airway wall remodelling in chronic asthma. We have investigated the role of the leukotrienes in airway smooth muscle (ASM) and epithelial cell DNA synthesis and ASM thickening following repeated allergen exposure in Brown Norway rats sensitized to ovalbumin. There was a 3 fold increase in ASM cell DNA synthesis, as measured by percentage bromodeoxyuridine (BrdU) incorporation, in repeatedly ovalbumin-exposed (4.1%, 3.6-4.6; mean, 95% c.i.) compared to chronically saline-exposed rats (1.3%, 0.6-2.1; P<0.001). Treatment with a 5-lipoxygenase enzyme inhibitor (SB 210661, 10 mg kg(-1), p.o.) and a specific cysteinyl leukotriene (CysLT1) receptor antagonist, pranlukast (SB 205312, 30 mg kg(-1), p.o.), both attenuated ASM cell DNA synthesis. Treatment with a specific leukotriene B4 (BLT) receptor antagonist (SB 201146, 15 mg kg(-1), p.o.) had no effect. There was also a significant, 2 fold increase in the number of epithelial cells incorporating BrdU per unit length of basement membrane after repeated allergen exposure. This response was not inhibited by treatment with SB 210661, pranlukast or SB 201146. A significant increase in ASM thickness was identified following repeated allergen exposure and this response was attenuated significantly by SB 210661, pranlukast and SB 201146. Rats exposed to chronic allergen exhibited bronchial hyperresponsiveness to acetylcholine and had significant eosinophil recruitment into the lungs. Treatment with SB 210661, pranlukast or SB 201146 significantly attenuated eosinophil recruitment into the lungs, whilst having no significant effect on airway hyperresponsiveness. These data indicate that the cysteinyl leukotrienes are important mediators in allergen-induced ASM cell DNA synthesis in rats, while both LTB4 and cysteinyl leukotrienes contribute to ASM thickening and eosinophil recruitment following repeated allergen exposure.

Acetylcholine↗
PubMed1999

Effect of CD8+ T-cell depletion on bronchial hyper-responsiveness and inflammation in sensitized and allergen-exposed Brown-Norway rats.

We examined the role of CD8+ T cells in a Brown-Norway rat model of asthma, using a monoclonal antibody to deplete CD8+ T cells. Ovalbumin (OA)-sensitized animals were given anti-CD8 antibody (0.5 mg/rat) intravenously 1 week prior to exposure to 1% OA aerosol and were studied 18-24 hr after aerosol exposure. Following administration of anti-CD8 antibody, CD8+ cells were reduced to <1% of total lymphocytes in whole blood and in spleen. In sensitized animals, OA exposure induced bronchial hyper-responsiveness (BHR), accumulation of eosinophils, lymphocytes and neutrophils in bronchoalveolar lavage (BAL) fluid, and also an increase in tissue eosinophils and CD2+, CD4+ and CD8+ T cells in airways. Anti-CD8 antibody caused a further increase in allergen-induced BHR (P<0.03, compared with sham-treated animals), together with a significant increase in eosinophil number in BAL fluid (P<0.05). While CD2+ and CD4+ T cells in airways were not affected by anti-CD8 treatment, the level of CD8+ T cells was significantly reduced in sensitized, saline-exposed animals (P<0.04, compared with sham-treated rats), and sensitized and OA-challenged rats (P<0.002, compared with sham-treated rats). Using reverse transcription-polymerase chain reaction, an increase of T helper (Th)2 cytokine [interleukin (IL)-4 and IL-5], and also of Th1 cytokine [interferon-gamma (IFN-gamma) and IL-2], mRNA in the lung of sensitized and OA-exposed animals was found; after CD8+ T-cell depletion, Th1 cytokine expression was significantly reduced (P<0.02), while Th2 cytokine expression was unchanged. CD8+ T cells have a protective role in allergen-induced BHR and eosinophilic inflammation, probably through activation of the Th1 cytokine response.

Acetylcholine↗
PubMed1999

Inhibitory effects of endogenous and exogenous interferon-gamma on bronchial hyperresponsiveness, allergic inflammation and T-helper 2 cytokines in Brown-Norway rats.

Interferon-gamma (IFN-gamma) is an important cytokine involved in the regulation of allergen-induced immune responses. We examined the role of IFN-gamma in a Brown-Norway rat model of bronchial hyperresponsiveness (BHR) and airway eosinophilia, and its effects on the mRNA expression of T helper type 1 (Th1)/Th2 cytokine. Ovalbumin (OA)-sensitized animals were given either exogenous IFN-gamma (105 U/rat over 3 days, intraperitoneally) or anti-IFN-gamma blocking antibody (DB-1 0.3 mg/rat, intravenously) prior to exposure to OA aerosol and were studied 18-24 hr later. In sensitized animals, OA induced significant BHR, accumulation of eosinophils, T lymphocytes and neutrophils in bronchoalveolar lavage (BAL) fluid, and also increased eosinophils and CD8+ T cells in the airways. Exogenous IFN-gamma attenuated allergen-induced BHR (P<0.02, compared with sham-treated animals) together with a significant reduction in eosinophil and neutrophil numbers in BAL fluid (P<0. 005), and eosinophils and CD8+ T cells in airways (P<0.05). By contrast, anti-IFN-gamma antibody increased airway CD4+ T cells and BHR. Using reverse transcriptase-polymerase chain reaction, significant increases in Th2 [interleukin-4 (IL-4), IL-5 and IL-10], and IFN-gamma cytokine mRNA were found in the lungs of sensitized and OA-exposed animals, while exogenous IFN-gamma significantly suppressed IL-4, IL-5 and IL-10 mRNA expression, and anti-IFN-gamma antibody increased IL-4 and IL-5 mRNA expression. These results indicate that Th1 effects, such as those mediated by IFN-gamma, play a down-regulatory role to suppress the Th2 responses associated with allergen-induced BHR and eosinophilic inflammation.

Analysis of Variance↗
PubMed1999

Constitutive expressions of type I NOS in human airway smooth muscle cells: evidence for an antiproliferative role.

In airway diseases, smooth muscle cells can proliferate at exaggerated rates; thus, the identification of endogenous pathways that limit proliferative responses is important. Here we show that human airway smooth muscle express type I nitric oxide synthase (NOS), which results in inhibition of DNA synthesis and cell proliferation. In addition, superoxide dismutase (SOD), a cell-permeable mimetic that increases the biological half-life and therefore enhances the biological activity of endogenously released nitric oxide (NO), or NO-releasing drugs also greatly reduce DNA synthesis and cell proliferation. Observations in this study have important clinical implications: 1) NOS inhibition may exacerbate airway disease and 2) inhaled SOD/mimetics or NO/nitrovasodilators may be therapies for the treatment of asthma or chronic obliterative pulmonary disease.

Adolescent↗
PubMed1999

Increased neutrophils and cytokines, TNF-alpha and IL-8, in induced sputum of non-asthmatic patients with chronic dry cough.

BACKGROUND: The pathogenesis of non-asthmatic chronic dry cough remains unclear. METHODS: A study was undertaken to determine whether airway inflammation could be a contributing factor by analysing inflammatory cells and cytokines in induced sputum from 19 patients with chronic dry cough of varying aetiology, excluding asthma and bronchiectasis, and from 10 normal controls. The associated causes for the chronic cough were postnasal drip (n = 5), gastro-oesophageal reflux (n = 4), and idiopathic (n = 10). All patients had an enhanced cough reflex to capsaicin. RESULTS: Sputum neutrophilia (median (interquartile range)) was found in the patients with chronic cough (59.4 (27.1)%) compared with the normal controls (28.4 (22.0)%; p < 0.01, 95% CI 11.3 to 42.2). Sputum levels of interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) were also significantly increased compared with normal controls (0.57 (1.08) and 0.25 (0.72) ng/ml; p < 0.05 (95% CI 0.05 to 1.75) for IL-8; 48.3 (34.4) and 12.6 (33.6) pg/ml, p < 0.01 (95% CI 8.8 to 69.8) for TNF-alpha). CONCLUSION: Neutrophils and cytokines associated with neutrophil chemotaxis and activation may contribute to the pathogenesis of non-asthmatic chronic dry cough.

Chemotaxis, Leukocyte↗