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Biomedical subjects

K F Chung

Publications and source records attributed to K F Chung.

At least 19 recordsLinked to original sources
PubMed1992

The effect of anion transport inhibitors and extracellular Cl- concentration on eosinophil respiratory burst activity.

Furosemide has been shown recently to protect asthmatic patients against certain bronchoconstrictor challenges. We investigated the effect of furosemide on eosinophil function. Since furosemide may be exerting its inhibitory effect on the eosinophil by inhibiting anion transport, we also assessed the effects of the anion transport inhibitors 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS). Furosemide, NPPB and DIDS inhibited the eosinophil respiratory burst in response to leukotriene B4 (LTB4) and, to a smaller extent, inhibited the response to opsonized zymosan (OZ). To assess whether the anion transport inhibitors were achieving their inhibitory effect by inhibiting an influx of Cl- ions into the eosinophil, the effect of removing extracellular Cl- on eosinophil function was determined. OZ-induced H2O2 production was inhibited by removing extracellular Cl- whereas the LTB4 response was not affected by the concentration of extracellular Cl-.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1992

Effect of Hoe 140, a new bradykinin receptor antagonist, on bradykinin- and platelet-activating factor-induced bronchoconstriction and airway microvascular leakage in guinea pig.

We have investigated the effect of a new bradykinin receptor antagonist, Hoe 140 (D-Arg- Hyp3,Thi5,D-Tic7,Oic8]-bradykinin), on bradykinin- and platelet-activating factor (PAF)-induced bronchoconstriction and airway microvascular leakage in anesthetized guinea pigs. Extravasation of Evans blue dye and lung resistance were measured simultaneously. Both i.v. (15 nmol/kg) and inhaled bradykinin (1 mM, 45 breaths) caused a significant increase in lung resistance and leakage of dye at all airway levels. Hoe 140 (100 nmol/kg i.v.) almost completely inhibited these airway responses induced by bradykinin except for dye extravasation in trachea induced by inhaled bradykinin. Inhaled PAF (3 mM, 30 breaths) significantly increased lung resistance and leakage of due at all airway levels, but Hoe 140 had no effect on these responses. Bradykinin-induced bronchoconstriction and airway microvascular leakage are predominantly mediated by activation of B2 receptor, since Hoe 140 is a B2 receptor antagonist. Bradykinin receptor-mediated mechanisms do not play an important role on inhaled PAF-induced bronchoconstriction and microvascular leakage.

Administration, Inhalation↗
PubMed1992

Mechanisms of bronchial inflammation in asthma: implications for therapy.

Chronic persistent infiltration of the airway submucosa by inflammatory cells such as eosinophils and lymphocytes is a hallmark of asthma, and may result in airway damage, bronchial obstruction and hyperresponsiveness. Genetic and environmental factors may predispose towards the development of this chronic submucosal airway inflammation. Priming of inflammatory cells by cytokines and growth factors, and release of mediators such as leukotrienes may be important mechanisms by which inflammation results in bronchial obstruction and hyperresponsiveness. The prime aim of asthma management is to prevent and dampen the inflammatory mechanisms, and corticosteroid therapy, which is most effective in the treatment of asthma, may act at several levels of the submucosal inflammatory process.

Adrenal Cortex Hormones↗
PubMed1992

Effect of neutral endopeptidase inhibitor on airway function and bronchial responsiveness in asthmatic subjects.

We determined the effect of an inhibitor of neutral endopeptidase, acetorphan, on the skin responses to substance P and on the bronchostrictor effects of sodium metabisulphite aerosol in asthmatic subjects. One hour following ingestion of acetorphan (200 mg) or placebo tablets, cutaneous responses to substance P were performed in four subjects. In seven subjects, bronchial challenge with increasing concentrations of sodium metabisulphite solutions was performed and the concentration required to cause a 20% fall in baseline FEV1 determined (PC20). On the acetorphan day, there was a significant increase in the wheal and flare responses to substance P and to the diluent (0.9% NaCl) alone. However, there was no significant effect of acetorphan on the PC20 metabisulphite. We conclude that metabisulphite airway challenge in vivo may not invoke the release of endogenous neuropeptides. However, the degree of inhibition of neuropeptide breakdown by the oral dose of acetorphan used may not have been optimal.

Adult↗
PubMed1992

Modulation of neurally mediated airway microvascular leakage in guinea-pig airways by beta 2-adrenoceptor agonists.

The effect of two beta 2-adrenoceptor agonists, salbutamol (100 micrograms/kg i.v.) and broxaterol (100 micrograms/kg i.v.), on airway microvascular leakage induced by vagal stimulation was studied in anaesthetised guinea pigs. Airway microvascular leakage was measured by Evans blue extravasation. Broxaterol, but not salbutamol, inhibited Evans blue dye extravasation at all airway levels, an effect prevented by pretreatment with propranolol (1 mg/kg). Neither of the beta 2-agonists had any effect on substance P-induced Evans blue dye extravasation. Broxaterol inhibits the prejunctional release of tachykinins from airway sensory nerves by stimulation of beta-receptors. The mechanism by which beta-adrenoceptor agonists prevent airway microvascular leakage deserves further study.

Adrenergic beta-Agonists↗
PubMed1992

Questions about inhaled beta 2-adrenoceptor agonists in asthma.

The safety of the most widely prescribed antiasthma drugs, beta 2-adrenoceptor agonists, has recently been questioned. Issues such as their suitability for long-term and regular prophylactic use are addressed in this Comment article by Peter Barnes and Fan Chung, who examine the possibility that the beta 2-agonists themselves contribute to worsening symptoms in asthma patients, thus setting up a vicious circle with greater use of the drugs. They conclude that it would be prudent to restrict the use of beta 2-agonists in asthma to on-demand immediate symptom control.

Administration, Inhalation↗
PubMed1992

Role of inflammatory mediators in asthma.

Release of inflammatory mediators such as histamine and products of arachidonic acid metabolism has been demonstrated in bronchoalveolar lavage fluid of patients with asthma. Their precise cellular source is not clear but many cells types such as eosinophils, macrophages and mast cells may contribute to the generation of a wide variety of chemical mediators. These can mimic many of the features associated with asthma including bronchoconstriction, bronchial hyperresponsiveness and airway microvascular leakage. Development of specific mediator receptor antagonists or inhibitors of mediator synthesis may clarify the role of particular inflammatory mediators such as the sulphidopeptide leukotrienes or platelet-activating factor in asthma. It seems unlikely that only one particular mediator is responsible for all the manifestations of asthma.

Asthma↗
PubMed1992

Asthma as an inflammatory disease: clinical perspectives.

Asthma is characterised by a persistent, ongoing airway submucosal inflammatory process which may underlie bronchial hyperresponsiveness and airways obstruction. Indirect assessment of airway inflammation includes examination of sputum or serum for eosinophils or eosinophil-derived products, but examination of bronchial mucosal biopsies or bronchoalveolar lavage fluid or cells remains the gold standard. Lymphocyte and eosinophil activation, with the release of certain cytokines such as interleukin-5, lipid mediators such as leukotrienes and eosinophil products such as major basic protein, may be important mechanisms of inflammation in asthma. Less invasive indirect measures of submucosal inflammation are needed to assess the impact of asthma treatment in the clinic. Antiinflammatory treatment in asthma should be introduced as early as possible. A greater understanding of the inflammatory mechanism or of the actions of corticosteroids may lead to the development of more effective and safer drugs for asthma.

Allergens↗
PubMed1992

Effect of frusemide on the induction and potentiation of cough induced by prostaglandin F2 alpha.

We examined whether inhaled frusemide could reduce the potentiation of capsaicin-induced cough by prostaglandin (PG) F2 alpha. Eight non-smoking normal subjects, after a baseline capsaicin challenge were given inhaled frusemide or saline followed by capsaicin challenge, then PGF2 alpha and finally capsaicin challenge again. PGF2 alpha-induced coughs were reduced after frusemide to 3.6 +/- 1.0 compared with 5.7 +/- 1.2 after saline (P less than 0.05). PGF2 alpha increased capsaicin-induced coughs by 11.1 +/- 3.7 and 7.9 +/- 3.4 after placebo and frusemide, respectively (P less than 0.05). Frusemide had no effect on capsaicin-induced cough alone. Changes in local ionic concentrations by frusemide, particularly chloride ions within the vicinity of epithelial cough receptors, may determine the cough response to low chloride solutions and to PGF2 alpha, but not to capsaicin which acts directly on the cough receptors, and alter the sensitivity of the receptors to capsaicin.

Administration, Inhalation↗
PubMed1992

Specific immunological and bronchopulmonary responses following intradermal sensitization to free trimellitic anhydride in guinea pigs.

We have developed a guinea pig model of trimellitic anhydride-induced airway hypersensitivity responses. In one group of guinea pigs, injected intradermally with 0.1 ml 30% trimellitic anhydride (TMA), we examined the specificity of the bronchopulmonary response to TMA comparing the effect of intravenous TMA conjugated to guinea pig serum albumin (GPSA) with a control hapten (procion dye) protein conjugate (PD-GPSA). A significant increase in pulmonary inflation pressure (PIP) was provoked in sensitized animals following intravenous injection with TMA-GPSA (20%; 0-400, median; range) as compared to intravenous injection of PD-GPSA. In the second group we compared three different methods of sensitization: single injection of 0.1 ml of 0.3% TMA; four injections of 0.1 ml of 0.1% TMA; and a single high dose injection of 30% TMA. Following intravenous TMA-GPSA guinea pigs sensitized with a single injection 0.3% TMA had an increase in PIP of 395%; 220-600, while those given four repeat injections of 0.1% TMA had an increase in PIP of 343%; 315-490. These results were significantly higher than the increase in PIP (160%; 0-220) which occurred in guinea pigs sensitized with a single dose of 30% TMA. Four of 11 guinea pigs given low dose injections of TMA had bronchopulmonary responses to inhaled TMA-GPSA. All sensitized guinea pigs had specific IgG1 antibodies demonstrated by enzyme linked immunosorbent assay (ELISA) and confirmed by ELISA inhibition. Four guinea pigs sensitized by low dose injections of TMA had IgE antibodies demonstrated by passive cutaneous anaphylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Pharmacological modulation of inhaled sodium metabisulphite-induced airway microvascular leakage and bronchoconstriction in the guinea-pig.

1. We have investigated the effects of chlorpheniramine, atropine and capsaicin pretreatment on inhaled sodium metabisulphite (MBS)-induced airway microvascular leakage and bronchoconstriction in anaesthetized guinea-pigs in order to clarify the mechanisms involved in these responses. The effects of frusemide and nedocromil sodium were also examined. 2. Lung resistance (RL) was measured for 6 min after inhalation of MBS (20, 40, 80 and 200 mM; 30 breaths), followed by measurement of extravasation of Evans blue dye into airway tissues, used as an index of airway microvascular leakage. MBS caused an increase in RL and leakage of dye at all airway levels in a dose-dependent manner. 3. Chlorpheniramine (10 mg kg-1, i.v.), atropine (1 mg kg-1, i.v.), their combination or inhaled nedocromil sodium (10 mg ml-1, 7 min) had no effect against the airway microvascular leakage induced by 80 mM MBS (30 breaths). Capsaicin pretreatment (50 mg kg-1, s.c.) caused a significant decrease in the leakage of dye in the main bronchi and inhaled frusemide (10 mg ml-1, 7 min) also in the main bronchi and proximal intrapulmonary airway. 4. Chlorpheniramine, atropine, their combination, capsaicin pretreatment and frusemide, but not nedocromil sodium, inhibited significantly the peak RL induced by 80 mM MBS (30 breaths) by approximately 50%. 5. We conclude that a cholinergic reflex and neuropeptides released from sensory nerve endings may participate in the mechanisms of MBS-induced airway responses. Frusemide but not nedocromil sodium may have an inhibitor effect on these neural mechanisms. The inhibitory effect of nedocromil sodium against lower doses of MBS is not excluded.

Administration, Inhalation↗
PubMed1992

Involvement of inflammatory mediators in the airway responses to trimellitic anhydride in sensitized guinea-pigs.

1. We examined the effect of various pharmacological agents on the acute bronchoconstrictor response and airway microvascular leakage in a model of guinea-pig sensitization to trimellitic anhydride (TMA) a cause of low molecular weight occupational asthma in man. 2. Guinea-pigs were given intradermal injections of 0.1 ml of 0.3% TMA in corn oil; 21-28 days later, anaesthetized guinea-pigs were challenged with TMA conjugated to guinea-pig albumin by tracheal instillation. Changes in lung resistance were measured and airway microvascular leakage was quantified by measuring the extravasation of Evans blue dye into the airway tissue. 3. Sensitized guinea-pig (n = 9 in each group) were pretreated with chlorpheniramine (2.5 mg kg-1, i.v.), WEB 2086 (10 micrograms kg-1, i.v.), BW 4AC (50 mg kg-1, i.p.), nedocromil sodium (2% aerosol for 60 s) or vehicle alone. 4. Pretreatment with chlorpheniramine inhibited both the acute bronchoconstrictor response and the increase in airway microvascular leakage. WEB 2086 and nedocromil sodium partially inhibited the bronchoconstrictor response but had no significant effect on airway microvascular leakage. BW 4AC caused a non-significant reduction of the bronchoconstrictor response and airway microvascular leakage. 5. These results indicate that both the bronchoconstrictor response and the airway microvascular response in this model of sensitization is mediated to a large extent by histamine. PAF but not 5-lipoxygenase products also partially mediates the bronchoconstrictor response but not the airway microvascular leakage. Nedocromil sodium partially inhibits the bronchoconstrictor response only.

Allergens↗
PubMed1992

Neutrophil influx into guinea-pig airway lumen during cholinergic and non-cholinergic bronchoconstriction.

Sensory nerve activation will produce adherence of neutrophils to tracheobronchial microvessels. The aim of the present study was to investigate whether this adherence would lead to an influx of neutrophils into the airway lumen. To do this, we studied the effects of 20 minutes of vagal stimulation (1 Hz, 5 ms, 5 V) in anaesthetized and tracheostomized guinea-pigs on both lung resistance, and the cell picture in bronchoalveolar lavage. Any changes were compared to those of intravenous methacholine infusion, producing similar changes in lung resistance. Since high pressure ventilation could produce lung damage, we also studied the effects of ventilation through an extracorporeal resistor, producing a similar change in transpulmonary pressure (45 +/- 2 cmH2O) as vagal stimulation (42 +/- 4 cmH2O). The total number of cells recovered in the lavage was not increased by vagal stimulation, methacholine infusion or the extracorporeal resistor. However, both vagal stimulation and methacholine infusion significantly increased the relative number of neutrophils in the lavage compared to sham stimulated animals (21 +/- 11%, 13 +/- 4% and 4 +/- 1% respectively), but the extracorporeal resistor had no effect (4 +/- 2%). Our data suggests that prolonged bronchoconstriction per se may induce an influx of neutrophils into the airway lumen of the guinea-pig.

Animals↗
PubMed1992

Peptide mediator effects on bronchial blood velocity and lung resistance in conscious sheep.

Peptide mediators or neuropeptides released from sensory nerves may induce inflammatory effects in airways, but their effects on airway blood velocity and lung resistance have not been previously studied simultaneously in awake animals. Nine adult sheep were chronically prepared for continuous measurement of blood flow velocity to the distal trachea and bronchi by surgical implantation of a 20-MHz pulsed Doppler flow probe on the common bronchial branch of the bronchoesophageal artery. Awake restrained animals were intubated and connected to a pneumotachograph to measure resistance to airflow across the lung (RL). Doubling doses of bradykinin (BK, 0.02-1.51 nmol/kg), calcitonin gene-related peptide (CGRP, 0.004-0.26 nmol/kg), or substance P (SP, 0.02-1.19 nmol/kg) were injected as a bolus into the right atrium while mean arterial pressure (MAP), bronchial blood velocity (Vbr), and RL were measured. BK at 0.76 nmol/kg caused a transient dose-related increase in Vbr from a baseline of 19.3 +/- 2.5 to 41.4 +/- 4.1 (SE) cm/s (P less than 0.05) despite a decrease in MAP from 118 +/- 6 to 80 +/- 6 mmHg. CGRP at 0.26 nmol/kg caused a transient dose-related increase in Vbr from 16.8 +/- 2.7 to 25.3 +/- 4.7 cm/s (P less than 0.05) despite a decrease in MAP from 113 +/- 5 to 87 +/- 8 mmHg. Neither BK nor CGRP affected RL. SP at 1.19 nmol/kg transiently increased Vbr from 18.3 +/- 2.3 to 45.1 +/- 8.3 cm/s (P less than 0.05), MAP from 138 +/- 9 to 162 +/- 15 mmHg, and RL from 4.5 +/- 1.0 to 106.6 +/- 62.1 cmH2O.l-1.s.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1992

Bronchial vasodilation by histamine in sheep: characterization of receptor subtype.

Histamine has been shown to mediate features of pulmonary allergic reactions including increased tracheobronchial blood flow. To determine whether the increase in blood flow was due to stimulation of H1- or H2-histamine receptors, we gave histamine base (0.1 micrograms/kg iv) or histamine dihydrochloride as an aerosol (10 breaths of 0.5% "low dose" or 5% "high dose") before and after H1- or H2-receptor antagonists. Blood velocity in the common bronchial branch of the bronchoesophageal artery (Vbr) was continuously measured using a chronically implanted Doppler flow probe. Pretreatment with H2-receptor antagonists cimetidine, ranitidine, or metiamide did not affect the increase in Vbr induced by intravenous histamine [106 +/- 45% (SD)]. Addition of the H1-receptor antagonists diphenhydramine or chlorpheniramine, however, reduced the Vbr response to 16 +/- 22, 21 +/- 28, 23 +/- 23, and 37 +/- 32% of the unblocked responses (P less than 0.05) when intravenous histamine was given at 3, 10, 20, and 30 min, respectively, after the H1 antagonist. At 40, 50, and 60 min the H1-receptor blockade appeared to attenuate, but subsequent continuous infusion of chlorpheniramine (2 mg.kg-1.min-1) then blocked the histamine response for 60 min. Low-dose histamine aerosol did not change mean arterial or pulmonary arterial pressures, cardiac output, or arterial blood gases but increased Vbr transiently from 15.2 +/- 3.4 to 37.6 +/- 8.4 (SE) cm/s. After chlorpheniramine, the Vbr response to histamine, 16.3 +/- 2.2 to 22.6 +/- 3.6 cm/s, was significantly reduced (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1992

A thromboxane mimetic, U-46619, produces plasma exudation in airways of the guinea pig.

Thromboxane A2 (TxA2) has been implicated in airway responses to allergen and in the bronchial hyperresponsiveness observed in asthma. Furthermore a TxA2 receptor antagonist and a TxA2 synthase inhibitor inhibit plasma exudation in airways induced by inhaled platelet-activating factor. To evaluate whether TxA2 has any direct effect on plasma exudation in the airways, we studied the effect of a stable TxA2 mimetic (U-46619; 2, 20, and 200 nmol/kg iv) on lung resistance (RL) and Evans blue dye extravasation (marker of plasma albumin; 20 mg/kg iv) at the airway levels of trachea, main bronchi, and proximal and distal intrapulmonary airways in anesthetized, tracheostomized, and mechanically ventilated guinea pigs. Injection of U-46619 produced an immediate and marked dose-dependent increase in RL, which peaked at approximately 30 s. At the highest dose of U-46619, we also observed a later increase in RL, starting at approximately 3 min and reaching a second peak at approximately 8 min. Mean systemic blood pressure increased in a dose-dependent manner [maximum 82 +/- 8 (SE) mmHg]. U-46619 also produces dose-dependent plasma exudation, measured as Evans blue dye extravasation, at all airway levels as well as into the tracheal lumen. Airway responses to U-46619 (200 nmol/kg iv) were abolished in animals pretreated with the TxA2 receptor antagonist ICI-192605 (0.5 mg/kg iv). We conclude that U-46619, despite being a vasoconstrictor, is potent in inducing plasma exudation in airways and that this effect is mediated via a TxA2 receptor.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗