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Biomedical subjects

K F Chung

Publications and source records attributed to K F Chung.

At least 289 records · Page 16Linked to original sources
PubMed1991

Role for platelet-activating factor in asthma.

Recent studies of the effects of platelet-activating factor (PAF) on human and animal airways would support a putative role for this lipid mediator in asthma. PAF can induce many aspects of the clinical and pathological features seen in asthmatic airways such as airway oedema, eosinophil accumulation in the airway wall, and bronchial hyperresponsiveness. PAF has potent activity as a chemotactic agent and as an activator of eosinophils, which are prominent cells in asthmatic airways, through the activation of specific surface receptors. The interaction between PAF and eosinophils may be crucial in the pathogenesis of bronchial hyperresponsiveness in asthma. A role for PAF in asthma can now be studied using the recently developed antagonists of the PAF receptor.

Animals↗
PubMed1991

Characterization of allergen-induced bronchial hyperresponsiveness and airway inflammation in actively sensitized brown-Norway rats.

Bronchial responsiveness to inhaled acetylcholine (ACh) and inflammatory cell recruitment in bronchoalveolar lavage fluid (BALF) were studied in inbred Brown-Norway rats actively sensitized to, and later exposed to, ovalbumin (OA). We examined animals 21 days after initial sensitization at 18 to 24 hours, or 5 days after a single challenge, or after the last of seven repeated exposures administered every 3 days. BALF was examined as an index of inflammatory changes within the lung. Animals repeatedly exposed to OA aerosols had an increased baseline lung resistance and a significant increase in bronchial responsiveness to inhaled ACh compared to control animals at both 18 to 24 hours and 5 days after the last OA exposure. Sensitized animals receiving a single OA aerosol also demonstrated bronchial hyperresponsiveness (BHR) to inhaled ACh (p less than 0.01) at 18 to 24 hours of a similar order as the multiple-exposed group. There was a significant increase in eosinophils, lymphocytes, and neutrophils in BALF at 18 to 24 hours but not at 5 days after single or multiple exposure to OA aerosol in the sensitized groups. Control animals demonstrated no changes in bronchial responsiveness, although a small but significant increase in inflammatory cells was observed compared to saline-only treated animals. There was a significant correlation between bronchial responsiveness and eosinophil counts in the BALF in the single allergen-exposed group (Rs = 0.68; p less than 0.05). We conclude that (1) BHR after allergen exposure in sensitized rats is associated with the presence of pulmonary inflammation but persists despite the regression of inflammatory cells in BALF after multiple OA exposures, and (2) this rat model has many characteristics of human allergen-induced BHR.

Acetylcholine↗
PubMed1991

Inhibition of cutaneous and platelet responses to platelet-activating factor by oral WEB 2086 in man.

WEB 2086, an antagonist of platelet-activating factor (PAF), was assessed against the cutaneous response in vivo and the aggregation of platelets ex vivo induced by PAF in a double-blind, placebo-controlled, crossover study in 12 normal male volunteers. Wheal-and-flare responses to intradermal PAF (200 ng) and histamine (1 microgram) were measured 1 hour after placebo or control administration. Wheal volumes were significantly reduced by 66% +/- 8.7% (mean +/- SEM), 86% +/- 8.3%, and 90% +/- 6.0% after 10, 40, and 100 mg of WEB 2086 compared to placebo administration (p less than 0.005). Flare responses were correspondingly inhibited by 66% +/- 8.3%, 82% +/- 8.7%, and 84% +/- 7.8% at 10, 40, and 100 mg of WEB 2086, respectively. Cutaneous responses to histamine were unaffected. Ex vivo platelet responses to PAF were significantly inhibited at all three doses of WEB 2086. Oral WEB 2086 is a potent and specific inhibitor of cutaneous and platelet responses to PAF in man.

Administration, Oral↗
PubMed1991

Detection of bronchiectasis by high-resolution computed tomography in the yellow nail syndrome.

High resolution computed tomography of the lungs was performed in three patients with the yellow nail syndrome to detect bronchiectasis. Standard CT was performed in a fourth patient. Evidence of bronchiectasis with bronchial wall thickening and bronchial dilatation was observed in all four patients. High resolution CT is a non-invasive method for detecting and assessing the extent of airway disease in the yellow nail syndrome.

Aged↗
PubMed1991

Circulating autoantibodies to recombinant lipocortin-1 in asthma.

One of the postulated mechanisms of corticosteroid action is through the de novo synthesis and release of lipocortins. We assayed circulating antibodies to lipocortin-1 in sera obtained from normal (n = 67) and asthmatic (n = 57) subjects using an ELISA technique. Asthmatic subjects with a wide range of severity, with the mildest needing only occasional inhaled beta-agonist therapy to the most severe needing maintenance oral corticosteroid treatment, were recruited from our Asthma Clinic and classified into five categories according to the need of therapy. Median values of IgM and IgG lipocortin-1 antibody for normal subjects were 19.3 (interquartile range (r) = 11.0-30.4) and 16.9 (r = 10.54-29.4) ELISA units (EU) ml-1 respectively. These levels were significantly elevated in asthmatic subjects: IgM = 43.9 EU ml-1 (r = 31.7-64.5) and IgG = 29.0 EU ml-1 (r = 21.2-44.7) (P less than 0.001). There was no significant relationship between the levels of lipocortin antibody and the clinical severity of asthma. Asthmatics with significantly raised levels of antibody were found within all five categories of severity. We conclude that the level of this antibody is not related to severity of asthma, to previous or current corticosteroid therapy or to the development of corticosteroid resistance.

Adolescent↗
PubMed1991

Plasma exudation into airways induced by inhaled platelet-activating factor: effect of peptidase inhibition.

1. To evaluate whether endogenous peptide release is involved in the airway responses to inhaled platelet-activating factor, we measured lung resistance and airway microvascular leakage in anaesthetized guinea pigs pretreated with inhalation of either saline or a combination of the peptidase inhibitors phosphoramidon (0.1 mmol/l: 60 breaths; 7.5 nmol), to inhibit neutral endopeptidase, and captopril (4.6 mmmol/l: 60 breaths; 350 nmol), to inhibit angiotensin-converting enzyme. 2. Airway microvascular leakage was determined by the albumin marker Evans Blue dye injected intravenously (20 mg/kg) before platelet-activating factor or sham challenge. 3. Inhaled platelet-activating factor induced a maximum increase in lung resistance (1.43 +/- 0.33 cmH2O s-1 ml-1) which was not significantly different after pretreatment with phosphoramidon and captopril (1.44 +/- 0.21 cmH2O s-1 ml-1). 4. Inhalation of platelet-activating factor caused a significant increase in extravasated Evans Blue dye at all airway levels, an effect which was not potentiated by peptidase inhibition. Similar results were obtained with dye extravasated into the airway lumen and absorbed by a filter paper placed on the tracheal mucosa. Approximately 11% of the total tracheal dye was found in the lumen. There was a high correlation between tracheal tissue and tracheal lumen Evans Blue dye (r = 0.91; P less than 0.001). 5. We found a significantly lower dry to wet weight ratio in proximal intrapulmonary airways of animals exposed to platelet-activating factor, suggesting that platelet-activating factor caused airway oedema at this airway level.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1991

Eosinophils adhere to and stimulate replication of lung fibroblasts 'in vitro'.

Eosinophils have been implicated in several disorders associated with the development of fibrosis. This led us to investigate the interactions between eosinophils and fibroblasts in vitro. Adhesion between purified guinea pig peritoneal eosinophils and monolayers of human fetal lung fibroblasts was assessed using the rose bengal dye staining assay. Fibroblast replication was assessed using a colorimetric assay based upon the uptake and subsequent release of methylene blue. Addition of phorbol myristate acetate induced a rapid, time-dependent increase in eosinophil adhesion (127% and 328% over basal adhesion after 10 and 30 min, respectively). Phorbol myristate acetate-induced adhesion was inhibited by the peptides RGDS and GRGDS (48% and 42%, respectively using 1 mM peptide) and by nordihydroguaiaretic acid, an inhibitor of the lipoxygenase pathway of arachidonic acid metabolism (46% inhibition at 15 microM). In addition, 24 h culture of fibroblast monolayers with interleukin 1 alpha (IL-1 alpha) or tumour necrosis factor alpha (TNF alpha) resulted in enhanced adhesion (10 U/ml IL-1 alpha stimulated adhesion by 55% of control, 500 U/ml TNF alpha by 75% of control). Conditioned media from cultured eosinophils stimulated fibroblast replication in a time-dependent fashion with maximal stimulation at 3 h. In contrast, media from guinea pig peritoneal macrophages in culture did not show such an effect. This study indicates that eosinophils are capable of both adhering to and releasing mitogens for fibroblasts in vitro. These observations suggest that eosinophils have the capacity to play a role in the development of fibrosis in disorders where they have been shown to be present.

Amino Acid Sequence↗
PubMed1991

Capsaicin pretreatment does not inhibit allergen-induced airway microvascular leakage in guinea pig.

We have studied the effects of tachykinin-depletion on airway microvascular leakage induced by allergen challenge in ovalbumin-sensitised guinea pigs. Tachykinin-depletion was obtained by capsaicin pretreatment 1 week before inhaled allergen challenge. Capsaicin pretreatment did not change airway microvascular permeability induced by allergen challenge. Thus, sensory neuropeptides may not be important in allergen-induced acute airway microvascular leakage in guinea pig in vivo.

Airway Obstruction↗
PubMed1991

Differential effects of phosphoramidon on neurokinin A- and substance P-induced airflow obstruction and airway microvascular leakage in guinea-pig.

1. The effects of the inhaled neuropeptides, neurokinin A (NKA) and substance P (SP) on lung resistance (RL) and airway microvascular permeability were studied in anaesthetized guinea-pigs. 2. Single doses of inhaled NKA (3 x 10(-5), 1 x 10(-4), 3 x 10(-4) M; 45 breaths) and SP (1 x 10(-4), 3 x 10(-4), 1 x 10(-3); 45 breaths) caused a dose-dependent increase in both RL and airway microvascular leakage, assessed as extravasation of the albumin marker, Evans blue dye. 3. NKA at 1 x 10(-4) and 3 x 10(-4) M resulted in a significantly higher increase in RL than SP at the same doses. 4. Inhaled SP (3 x 10(-4) M; 45 breaths) caused significantly higher Evans blue dye extravasation in main bronchi and proximal intrapulmonary airways compared to the same dose of NKA. 5. Pretreatment with the specific inhibitor of neural endopeptidase (NEP24.11), phosphoramidon, caused an approximately 100 fold leftward shift of the RL responses to inhaled NKA and SP. 6. Phosphoramidon significantly potentiated both NKA- and SP-induced airway microvascular leakage at proximal intrapulmonary airways, but not at any other airway level. 7. Inhibition of NEP24.11 potentiate both the SP- or NKA-induced airflow obstruction to a larger extent than the induced airway microvascular leakage, suggesting that NEP24.11 is more important in the modulation of the airflow obstruction observed after these mediators.

Administration, Inhalation↗
PubMed1991

Peptidase modulation of noncholinergic vagal bronchoconstriction and airway microvascular leakage.

We investigated whether inhibition of neutral endopeptidase 24.11 (NEP) and/or angiotensin-converting enzyme (ACE) modifies vagally induced nonadrenergic noncholinergic (NANC) airflow obstruction and airway microvascular leakage as measured by extravasation of Evans blue dye (intravenous) in anesthetized guinea pigs. We gave phosphoramidon to inhibit NEP and enalapril maleate or captopril to inhibit ACE. Animals pretreated with inhaled phosphoramidon (7.5 or 75 nmol), enalapril maleate (87 or 870 nmol), or captopril (350 nmol) reached higher peak lung resistance (RL) values (14.3 +/- 2.7, 15.7 +/- 3.8, 16.7 +/- 3.8, 11.4 +/- 1.6, and 24.6 +/- 3.5 cmH2O.ml-1.s, respectively) than saline-treated animals (5.9 +/- 1.1; P less than 0.05) after bilateral vagus nerve stimulation (5 Hz, 10 V, 10 ms, 150 s). Intravenous phosphoramidon (1 mg/kg), but not intravenous captopril (6 mg/kg), potentiated peak RL (22.9 +/- 6.9 and 7.1 +/- 1.5 cmH2O.ml-1.s, respectively). Vagal nerve stimulation (1 and 5 Hz) increased the extravasation of Evans blue dye in tracheobronchial tissues compared with sham-stimulated animals, but this was not potentiated by inhaled enzyme inhibitors or intravenous captopril. However, intravenous phosphoramidon significantly augmented the extravasation of Evans blue dye in main bronchi and intrapulmonary airways. We conclude that degradative enzymes regulate both NANC-induced airflow obstruction and airway microvascular leakage.

Acetylcholinesterase↗
PubMed1991

Role of thromboxane A2 in airway microvascular leakage induced by inhaled platelet-activating factor.

We studied the effects of OKY-046 (1, 10, and 30 mg/kg iv), a selective thromboxane synthase inhibitor, and of ICI 192605 (0.5 mg/kg), a selective thromboxane A2 receptor antagonist, on airflow obstruction and airway microvascular leakage induced by inhaled platelet-activating factor (PAF). Extravasated Evans blue dye content was measured as a reflection of airway microvascular leakage. In control animals, PAF caused a significantly higher increase in extravasation of dye and significantly less increase in lung resistance (RL) than histamine. OKY-046 significantly inhibited both changes in RL and airway microvascular leakage after PAF in a dose-dependent manner, whereas it inhibited histamine-induced airway microvascular leakage only at main bronchi, without any significant effect on RL. ICI 192605 significantly inhibited both RL and airway microvascular leakage induced by PAF, but not after histamine. After both PAF and histamine, changes in RL correlated significantly with the degree of microvascular leakage. Airway microvascular leakage and airflow obstruction after PAF, but not after histamine, may be dependent on thromboxane A2 generation.

Administration, Inhalation↗
PubMed1991

Attenuation of inhaled allergen-induced airway microvascular leakage and airflow obstruction in guinea pigs by a 5-lipoxygenase inhibitor (A-63162).

Leukotrienes, products of the 5-lipoxygenase pathway in the metabolism of arachidonic acid, are potent mediators of airway microvascular leakage and smooth muscle contraction in guinea pigs. We studied the effect of a specific 5-lipoxygenase inhibitor, A-63162, on airway microvascular leakage and airflow obstruction following inhaled ovalbumin in actively sensitized guinea pigs. Airway microvascular leakage was assessed by extravasation of Evans blue dye into airway tissues. Inhaled ovalbumin caused increased lung resistance (RL) with decreased dynamic compliance (CL) and increased extravasation of Evans blue dye at all airway levels. A-63162 reduced the changes in RL and CL at 1.0 mumol/kg (p less than 0.05) but not at lower doses of 0.1 and 0.3 mumol/kg. A-63162 reduced Evans blue dye extravasation in airway tissues at all three doses, however, being most effective in the distal airways (p less than 0.01), and these reductions were greater than those in RL and CL. A 5-lipoxygenase inhibitor thus reduced airway microvascular leakage to a greater extent than airflow obstruction, suggesting that leukotrienes have a larger contribution to changes in airway microvascular permeability than smooth muscle contraction following inhaled allergen challenge in actively sensitized guinea pigs in vivo.

Acetamides↗
PubMed1991

Effect of inhaled furosemide and bumetanide on adenosine 5'-monophosphate- and sodium metabisulfite-induced bronchoconstriction in asthmatic subjects.

Inhaled furosemide, a high ceiling diuretic, inhibits bronchoconstrictor responses to sodium metabisulfite (MBS) and other indirect challenges by unknown mechanisms. Furosemide acts by inhibition of Na+/Cl- transport in renal tubules and may exert similar effects on asthmatic airways. To evaluate this hypothesis we compared the effects of nebulized furosemide with those of bumetanide, another high ceiling diuretic that inhibits Na+/Cl- transport, on bronchial challenge with adenosine 5'-monophosphate (AMP) and MBS in 16 asthmatic subjects. We also studied the effects of furosemide on histamine-induced bronchoconstriction in seven of these subjects. Nine subjects inhaled furosemide (30 mg) or placebo (P) 30 min before challenge with nebulized AMP (0.39 to 400 mg/ml). Seven returned for similar study with histamine (0.125 to 32 mg/ml). In another study, seven subjects inhaled bumetanide (2 mg) or P 5 and 30 min before AMP and MBS (0.3 to 80 mg/ml) challenge. The provocative concentration causing a 20% fall in FEV1 (logPC20) was calculated by linear interpolation of log dose-response curves. Furosemide (F) significantly attenuated responses to AMP: mean +/- SEM logPC20, 1.59 +/- 0.24 (geometric mean PC20 [GM], 39.0 mg/ml) after F and 0.98 +/- 0.29 (GM, 9.5 mg/ml) after P (p less than 0.01), but it did not alter responsiveness to histamine: logPC20, 0.09 +/- 0.17 (GM 1.2 mg/ml) after F and 0.09 +/- 0.20 (GM, 1.2 mg/ml) after P.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Monophosphate↗
PubMed1991

Loop diuretics inhibit cholinergic and noncholinergic nerves in guinea pig airways.

Furosemide, a loop diuretic, is known to inhibit the response to a variety of indirect bronchial challenges in humans but does not inhibit bronchoconstriction induced by inhaled methacholine or histamine. We have investigated the effects of the two loop diuretics, furosemide (10(-6) to 10(-3) M) and bumetanide (10(-7) to 10(-4) M), on airway smooth muscle contraction in vitro induced by electrical field stimulation (EFS), or exogenously applied acetylcholine (ACh) or substance P (SP) in guinea pig tracheal and bronchial smooth muscle strips pretreated with indomethacin (10(-5) M) and propranolol (10(-6) M). Both furosemide and bumetanide caused a concentration-dependent inhibition of cholinergically mediated neural contraction in the trachea. The effect of furosemide was not influenced by the presence of airway epithelium. Furthermore, both furosemide and bumetanide inhibited in a concentration-dependent fashion nonadrenergic, noncholinergic (NANC) contraction induced by electrical field stimulation of bronchi pretreated with atropine (10(-5) M). Neither drug at the highest concentration inhibited the responses to exogenous acetylcholine (10(-8) to 10(-2) M) or substance P (10(-9) to 10(-5) M). Thus loop diuretics inhibit the neurally induced contraction of guinea pig airways without a direct effect on airway smooth muscle. We conclude that loop diuretics inhibit both cholinergic and excitatory NANC neurotransmission in guinea pig airways and that this effect may be related to their inhibitory effects on the sodium-potassium-chloride cotransporter.

Animals↗
PubMed1991

Mechanism of airway narrowing caused by inhaled platelet-activating factor. Role of airway microvascular leakage.

In order to study the mechanism of airway narrowing after inhaled platelet-activating factor (PAF) we measured concomitant changes in lung resistance (RL) and in airway microvascular leakage in anesthetized guinea pigs. RL and its recovery after hyperinflation at 5 min were measured until 6 min after PAF aerosol (0.1, 0.3, 1, and 3 mM), and in the case of 3 mM PAF also until 10 min. Microvascular leakage in trachea, main bronchi, and proximal and distal intrapulmonary airways was determined by measurement of extravasated Evans blue dye content. For comparison, the responses to inhaled histamine (3 mM) and 5-hydroxytryptamine (5HT) (3 mM), which act directly on airway smooth muscle, were also examined. Inhaled PAF increased RL dose-dependently, with a maximal response (peak RL) at 4 min after the inhalation, whereas the response to histamine or 5HT was maximal within a few seconds after the inhalation. Peak RL (cm H2O/ml/s) was significantly less after PAF (1.03 +/- 0.09) than after histamine (8.39 +/- 1.07) or 5HT (18.3 +/- 6.48), although there was no significant difference in RL after hyperinflation (recovery RL). No additional increase in RL was seen between 5 and 10 min after exposure. PAF caused a dose-dependent increase in Evans blue dye extravasation; 3 mM PAF induced significantly higher leakage than did histamine or 5HT at all airway levels at 6 min. PAF did not cause any additional extravasation of Evans blue dye at 10 min compared with that at 6 min after exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1991

Airway obstruction and bronchial hyperresponsiveness in left ventricular failure and mitral stenosis.

Small and large airways narrow in LVF and the term cardiac asthma is often used. However, current usage of this term is inconsistent and its meaning is therefore ambiguous. The term is better avoided despite several emerging similarities with bronchial asthma. Airway narrowing may be precipitated by acute elevation of pulmonary or bronchial vascular pressures. This appears to be mainly due to reflex bronchoconstriction. The afferents of this reflex are C-fibers with their endings in the lung parenchyma, bronchi, and pulmonary blood vessels and RAR in the larger airways, and they run in the vagus nerves, as do the efferent bronchoconstrictor fibers. Chronic elevation of pulmonary vascular pressures, as in mitral stenosis, are also associated with airway narrowing. Pulmonary edema (in the absence of vascular hypertension) also causes reflex bronchoconstriction. Bronchial responsiveness to bronchoconstrictor drugs is increased in LVF, partly, at least, due to reflex mechanisms. Bronchial mucosal swelling may also contribute. Narrowing by nonreflex mechanisms definitely occurs and there is direct evidence that decreased lung volume caused by pulmonary edema may cause this. There is little evidence for bronchial narrowing due to the mechanical effect of peribronchial edema, or by swelling of the bronchial mucosa. However, edema foam may terminally cause grave obstruction. Patients with LVF are commonly treated with bronchodilator drugs, but the basis for this approach needs further clarification.

Airway Obstruction↗
PubMed1991

Long-acting beta 2-adrenoceptor agonists: a new perspective in the treatment of asthma.

New long-acting beta 2-adrenoceptor agonists, formoterol and salmeterol, may soon appear in several European countries for treatment of asthma. This review examines currently available information and compares the basic pharmacology and describes the clinical effects of these new drugs. The long duration of bronchodilation seen in clinical studies seems to be similar, whereas in isolated tissues there might be a difference in the binding characteristics to the beta 2-adrenoceptor. Long-acting beta 2-agonists could have an inhibitory effect on inflammatory events related to asthma, but the clinical relevance of these effects is not clear at present. Long-term studies up to one year with both new drugs have not shown any unexpected side-effects, and no tachyphylaxis to beta-adrenoceptor stimulation has been reported. Patients appear to strongly prefer the new drugs compared to the short-acting beta 2-agonists. The potential place for these drugs in the treatment of asthma is discussed and some pitfalls pointed out. It is likely that the long-acting beta 2-agonists will be beneficial to many asthmatic patients.

Adrenergic beta-Agonists↗