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Biomedical subjects

K F Chung

Publications and source records attributed to K F Chung.

At least 271 records · Page 15Linked to original sources
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↗
PubMed1992

Airway hyperresponsiveness is associated with inflammatory cell infiltration in allergic brown-Norway rats.

The time course of the development of airway hyperresponsiveness (AHR) to inhaled acetylcholine (ACh) and the associated inflammatory cell recovery in bronchoalveolar lavage fluid (BAL) in actively sensitised Brown-Norway rats was studied following challenge with inhaled ovalbumin (OA). IgE for OA was detected in serum obtained from sensitised rats using passive cutaneous anaphylaxis, at titres of 1:10 to 1:30; none was detected in unsensitised animals. There was no significant change in either airway responsiveness to inhaled ACh or in BAL cell counts in rats challenged with saline over the 24 h. Following challenge with a 1% OA aerosol, airway responsiveness to inhaled ACh increased over the 24-hour period, maximal at 18-24 h (saline-challenged group mean -log PC200 1.95 +/- 0.07 M; OA-challenged group mean -log PC200 2.30 +/- 0.05 M; p < 0.01). The composition of the inflammatory cells in the BAL fluid after allergen inhalation varied over the 24-hour period, with an initial neutrophilia at 5-8 h (p < 0.01), followed at 18-24 h by an increase in lymphocytes (p < 0.01) and marked eosinophilia (p < 0.01). There was a significant correlation between airway responsiveness and eosinophil recovery at 5-8 h (p < 0.05), and at 18-24 h after allergen exposure (p < 0.05). At 18-24 h there was also a significant correlation between neutrophils and airway responsiveness (p < 0.05). There was no difference between baseline lung resistance in matched saline- or OA-challenged animals at each time point.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

Effect of dexamethasone and cyclosporin A on allergen-induced airway hyperresponsiveness and inflammatory cell responses in sensitized Brown-Norway rats.

We studied the effects of dexamethasone and cyclosporin A on the airway hyperresponsiveness (AHR) and the influx of inflammatory cells into the bronchoalveolar lavage (BAL) fluid seen 18 to 24 hr after exposure to aerosolized ovalbumin in actively ovalbumin-sensitized Brown-Norway rats. Allergen exposure resulted in an approximately sevenfold increase in bronchial responsiveness to inhaled acetylcholine associated with a significant increase in eosinophils and lymphocytes in BAL fluid. Dexamethasone (0.5 mg/kg administered intraperitoneally for 3 days) abolished the AHR and the increase in eosinophil and lymphocyte counts. However, cyclosporin A at two doses (5 and 50 mg given orally for 5 days) did not significantly prevent the induction of AHR while producing a significant inhibition of the eosinophil and lymphocyte influx. Dexamethasone (0.5 mg/kg for 3 days) or cyclosporin A (5 mg/kg for 5 days) on their own had no effect on airway responsiveness. We conclude that specific inhibition of T-lymphocyte activation in this Brown-Norway rat model is not sufficient to inhibit the induction of AHR despite suppressing allergen-induced eosinophilia in BAL fluid. However, corticosteroids, which have inhibitory effects on a wider range of inflammatory cells, are more effective. Our observations are in line with the potent effect of corticosteroids in airway inflammatory conditions such as asthma.

Acetylcholine↗
PubMed1992

Bronchoconstriction and airway microvascular leakage in guinea pigs sensitized with trimellitic anhydride.

We have developed a guinea pig model of immediate airway responses following intradermal sensitization with free trimellitic anhydride (TMA). Guinea pigs were given an intradermal injection with either 0.1 ml of 0.3% TMA in corn oil (n = 8) or 0.1 ml of corn oil alone (n = 6). A guinea pig serum albumin conjugate of trimellitic anhydride (TMA-GPSA) was prepared with a substitution ratio of 21:1. All sensitized guinea pigs had raised specific serum IgG1 antibodies (ELISA), and IgE antibodies were detected in six of the eight sensitized guinea pigs by passive cutaneous anaphylaxis. On Days 21 to 28, guinea pigs were anesthetized, tracheostomized, and ventilated. Evans blue dye (20 mg/ml), an albumin marker, was injected intravenously to quantify airway microvascular leakage (MVL). TMA-GPSA (50 microliters; 1%) in saline was instilled into the trachea. Lung resistance (RL) was measured for 6 min. The guinea pigs were killed, and the lungs were removed. Peak RL (cm H2O/ml x s-1) was significantly increased in sensitized guinea pigs from 0.26 +/- 0.01, mean +/- SEM to 21.3 +/- 6.9 (p < 0.05), compared with nonsensitized guinea pigs. There was a significant increase in Evans blue at all levels of the tracheobronchial tree in sensitized guinea pigs compared with the controls (p < 0.005). The site of MVL was localized to the postcapillary venules as assessed by extravasation of intravascular Monastral blue dye. We conclude that intradermal sensitization of guinea pigs to TMA induces a polyclonal immune response, associated with bronchoconstriction and airway microvascular leakage, when challenged specifically with TMA-GPSA.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1992

Bronchial hyperreactivity after inhalation of trimellitic anhydride dust in guinea pigs after intradermal sensitization to the free hapten.

We have developed in the guinea pig, an animal model of bronchial hyperreactivity provoked by inhalation of trimellitic anhydride (TMA) dust, a known cause of occupational asthma in humans, after intradermal sensitization to the free hapten. Male Dunkin-Hartley guinea pigs (n = 6) were injected intradermally with 0.1 ml of 30% TMA in corn oil. Control animals (n = 7) were injected with 0.1 ml corn oil alone. On Days 21 to 28 after sensitization, guinea pigs were challenged (nose only) to 12 mg/m3 of inhalable TMA dust for 30 min. Bronchial reactivity was measured in sensitized animals and in control animals at 8 h after exposure to the dust. We also measured bronchial reactivity in sensitized exposed guinea pigs at 2 h (n = 5) and at 24 h (n = 5). Pulmonary inflation pressure (PIP) was used to assess bronchopulmonary response. Blood samples were taken for assessment of IgG-1 antibodies to TMA conjugated to guinea-pig albumin. The concentration of acetylcholine required to induce a 100% increase in PIP was used to assess bronchial reactivity. The lungs were eviscerated for histologic examination. All guinea pigs injected intradermally with TMA had high titers of specific IgG-1 antibodies to TMA conjugated to guinea-pig albumin. There was a significant increase in bronchial reactivity in sensitized guinea pigs 8 h after exposure to the TMA dust compared with that in the control animals. There was also a significant eosinophilic inflammatory influx in the subepithelium of the sensitized groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Air Pollutants↗
PubMed1992

Attenuation of platelet-activating factor induced bronchoconstriction by nedocromil sodium.

We assessed the effect of nedocromil sodium on bronchoconstriction and airway responsiveness induced by platelet-activating factor (PAF) in eight normal subjects, in a double-blind, placebo-controlled cross-over study. Subjects inhaled PAF by a dosimeter method in 5 doses of 18 micrograms each, separated by an interval of 15 min, (total dose of 90 micrograms). Airway calibre was measured by partial expiratory flow at 30% of vital capacity (Vp30) before and at 1, 3, 5, 10 and 15 min after each dose of PAF. The bronchoconstrictor response was assessed by measuring the area under the curve of the percentage fall in Vp30 over time. There was a significant reduction in PAF-induced bronchoconstriction after nedocromil sodium (1,225 +/- 392 arbitrary units; mean +/- SEM) compared to placebo (2,395 +/- 598; p < 0.01). There was no significant difference in the fall in peripheral neutrophil count measured at 5 min after PAF with nedocromil sodium (48.5 +/- 9.5%) compared to placebo (43.3 +/- 6.8%). In conclusion, nedocromil sodium significantly attenuates PAF-induced bronchoconstriction but not the peripheral neutropenia in normal subjects. Since PAF is not a direct constrictor of human airway smooth muscle, this effect of nedocromil sodium may indicate inhibition of release of bronchoconstrictor mediators.

Administration, Inhalation↗
PubMed1992

Nonadrenergic, noncholinergic airway inhibitory nerves.

Nonadrenergic, noncholinergic (NANC) nerves, which cause relaxation of airway smooth muscle, have been described in several species including man. Stimulation of efferent vagus nerves during cholinergic and adrenergic blockade induces a pronounced bronchodilation in the cat. In more recent studies in man, capsaicin inhalation or mechanical irritation of the larynx, under conditions of cholinergic and adrenergic blockade, have been shown to cause a transient bronchodilator response. There is some evidence that neuropeptides such as vasointestinal peptide (VIP) or peptide histidine methionine (PHM) may be the neurotransmitter of NANC nerves, but this is not conclusive. Nitric oxide may be another neurotransmitter. In mild asthma, the NANC bronchodilator response is similar to that observed in normal subjects; on the other hand, a reduction in VIP immunoreactivity has been reported in more severe patients. The contribution of NANC dilator nerves in pathophysiological situations is not known, but their effect may be modulated during allergic responses. Use of antagonists or inhibitors of putative neurotransmitters, and molecular biological techniques will be useful in defining both the physiological and pathophysiological roles of NANC inhibitory nerves in the airways.

Animals↗
PubMed1992

Protective effect of loop diuretics, piretanide and frusemide, against sodium metabisulphite-induced bronchoconstriction in asthma.

We determined whether the loop diuretic, piretanide, had a similar inhibitory action against sodium metabisulphite (MBS)-induced bronchoconstriction in asthmatic subjects as frusemide and, if so, its duration of action. In the first study, we compared the effect of inhaled placebo, piretanide (24 mg), or frusemide (40 mg), on the provocative concentration of MBS needed to cause a 20% fall in baseline forced expiratory volume in one second (FEV1) (PC20MBS) in 12 mild asthmatic subjects before, immediately after, and at 1.5, 3, 6, and 24 h, after inhalation. Both piretanide and frusemide induced a significant diuresis lasting at least 24 h. Frusemide caused a mean 3.8 fold (95% confidence interval: 2.3-6.3 fold), piretanide a 2.5 fold (1.8-3.4 fold) and placebo a 1.7 fold (1.5-1.9 fold) increase in PC20MBS. The effects of frusemide and piretanide were significantly greater than that of placebo. At later time points, tachyphylaxis to the bronchoconstrictor effects of MBS was observed during the placebo limb. In the second study, we measured PC20MBS at 90 min after inhalation of either placebo, piretanide (24 mg), or frusemide (40 mg). No significant difference in PC20MBS was observed. We conclude that piretanide in addition to frusemide significantly inhibits MBS-induced bronchoconstriction and that this action is short-lived over less than 90 min. Frusemide was more potent in inhibiting MBS-induced bronchoconstriction despite causing a smaller diuretic effect than piretanide. The basic mechanism of action of the loop diuretics in the airways remains unclear.

Administration, Inhalation↗
PubMed1991

Bradykinin-induced airway microvascular leakage is potentiated by captopril and phosphoramidon.

Bradykinin can be inactivated by the peptidases angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), both of which are present in the airways. We evaluated the role of these enzymes in bradykinin-induced airway microvascular leakage and lung resistance in anesthetized and mechanically ventilated guinea pigs. We studied the effects of captopril (inhaled; 350 nmol), a specific ACE inhibitor, and phosphoramidon (inhaled; 7.5 nmol), a specific NEP inhibitor. Airway microvascular leakage was measured with the albumin marker Evans Blue dye (20 mg/kg i.v.), and airflow obstruction was measured as lung resistance (RL). Bradykinin was given by inhalation (0.1, 0.3 and 1 mM; 45 breaths), and caused a dose-dependent increase in both RL and airway microvascular leakage. Inhibition of NEP or ACE potentiated the bradykinin-induced microvascular leakage in main bronchi and proximal and distal intrapulmonary airways. However, only NEP inhibition significantly potentiated the extravasation of Evans Blue dye into the tracheal wall and lumen. The combined inhibition of NEP and ACE significantly potentiated plasma leakage at all airway levels, as well as the increase in RL induced by inhaled bradykinin. Recovery RL after one lung inflation significantly correlated with the extravasation of Evans Blue dye in the tissue at all airway levels, indicating that airway edema may have contributed to airway narrowing. We conclude that in the guinea pig, both NEP and ACE modulate bradykinin-induced airway microvascular leakage.

Acetylcholine↗
PubMed1991

Inhaled formoterol inhibits histamine-induced airflow obstruction and airway microvascular leakage.

We studied the effects of inhaled formoterol (0.75 mg/ml, 60 breaths = 26 micrograms), a long-acting beta 2-adrenoceptor agonist, or of the more short-acting drug, salbutamol (25 mg/ml, 60 breaths = 875 micrograms), on acute airflow obstruction and airway microvascular leakage (MVL) induced by inhaled histamine in anesthetized guinea pigs. Lung resistance (RL) and its recovery following hyperinflation (recovery RL) were measured for 6 min after histamine (1 or 2 mg/ml, 30 breaths) in animals pretreated with either inhaled beta 2-adrenoceptor agonist or inhaled saline (0.9%, 60 breaths). MVL was measured by determining the amount of extravasated Evans blue dye at various airway levels. Histamine increased RL dose dependently with a mean peak RL (+/- S.E.M.) of 13.1 +/- 2.41 cmH2O/ml per s after 2 mg/ml of histamine. Both formoterol and salbutamol significantly inhibited both peak and recovery RL and MVL to a similar degree. There was a significant correlation between the degree of extravasated dye and both peak and recovery RL, suggesting that MVL partly contributes to histamine-induced airflow obstruction. Formoterol is approximately 35 times more potent than salbutamol to inhibit both MVL and airflow obstruction induced by histamine aerosol.

Administration, Inhalation↗