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Biomedical subjects

K F Chung

Publications and source records attributed to K F Chung.

At least 343 records · Page 19Linked to original sources
PubMed1988

Effect of inhaled platelet-activating factor on circulating neutrophils and platelets in vivo and ex vivo in man.

We studied the effect of five successive inhalations of platelet-activating factor (PAF) on airway calibre, circulating neutrophil and platelet counts and the activation of these cells ex vivo in normal subjects. PAF (24 ug) caused a mean maximal fall of the expiratory flow rate at 70% vital capacity from a partial manoeuvre (Vp30) of 46.4 +/- 6.2% (p less than 0.001); there was a tachyphylactic response to further doses of PAF. Circulating neutrophil counts fell by 54.3 +/- 10.6% (p less than 0.005) with immediate recovery and with a rebound neutrophilia by the fifth inhalation. Platelet counts showed no significant changes. Aggregation of platelets in platelet-rich plasma to PAF and ADP in vitro at 15 min after the first, second and fifth PAF inhalations was not significantly altered. Chemiluminescence responses of neutrophils to PAF (0.01, 0.1, 1 and 10 microM) in vitro were reduced at 15 min after the fifth PAF inhalation, but this was only significant at 1 microM PAF. Methacholine inhalation did not cause any changes in responsiveness of neutrophils to PAF ex vivo. We conclude that ex vivo platelet desensitisation cannot be used as an index of endogenous PAF release, but reduced responsiveness of neutrophils ex vivo is not a sensitive indicator.

Administration, Inhalation↗
PubMed1988

Ketotifen inhibits the cutaneous but not the airway responses to platelet-activating factor in man.

We studied the effect of ketotifen, an oral antiallergic and antihistaminic drug, on the airway and cutaneous responses to platelet-activating factor (PAF) in a double-blind, randomized, and crossover study in six normal subjects. Ketotifen (three doses of 2 mg taken during a 14-hour period before PAF) did not alter PAF-induced bronchoconstriction and did not prevent the accompanying flushing and coughing. The transient neutropenia (74.5 +/- 4.8% fall; p less than 0.001) and rebound neutrophilia (104 +/- 55% rise) induced by PAF were not affected by ketotifen. On the day placebo was received, airway responsiveness to methacholine increased after PAF exposure with the concentration needed to cause a 40% fall in baseline partial expiratory flow rate (PC40), decreasing from 69.2 mg/ml (geometric standard error of the mean, 2.69) to 23.3 mg/ml (2.34) on day 3 (p less than 0.001). Ketotifen had no effect, because on the day ketotifen was administered, mean PC40 also decreased from 52.7 mg/ml (2.5) to 21.5 mg/ml (2.14) (p less than 0.01). In the skin, ketotifen reduced the flare area (from 8.05 +/- 3.60 to 1.14 +/- 0.29 cm2; p less than 0.05) and the wheal volume (from 0.068 +/- 0.010 to 0.045 +/- 0.008 cc; p = 0.02) induced by intradermal PAF (200 ng). Cutaneous responses to histamine (1 microgram) were significantly inhibited. Thus, the bronchoconstriction and bronchial hyperresponsiveness induced by PAF are not inhibited by ketotifen. Ketotifen inhibits PAF-induced wheal and flare in the skin, which is probably histamine dependent. The airway effects of PAF are unlikely to be mediated by histamine release.

Adult↗
PubMed1988

Effect of a PAF antagonist, BN52063, on antigen-induced, acute, and late-onset cutaneous responses in atopic subjects.

Platelet-activating factor (PAF) is a potent phospholipid that has been implicated as a mediator of allergic inflammatory responses, since it may induce a biphasic response and eosinophil infiltration in the skin that is reminiscent of antigen-induced reactions after cutaneous administration in man. We have studied the effect of a PAF antagonist, the ginkgolide mixture, BN52063, to determine the role of PAF in antigen-induced cutaneous responses in a double-blind, placebo-controlled, crossover study in 10 atopic subjects. Two hours after ingestion of BN52063 (120 mg), the wheal-and-flare response to intradermal PAF (200 ng), but not to histamine (1 micrograms), was inhibited, as previously described in nonatopic subjects. The late-onset component of the response to allergen (8 hours after injection) was significantly attenuated from 2.89 +/- 0.76 cm3 to 1.41 +/- 0.58 cm3 (p less than 0.05). Although the early wheal response was reduced in 50% of subjects, it was not significant overall, nor was there any significant reduction in the flare response. These observations suggest that PAF contributes to the late inflammatory response to allergen that is known to be associated with an inflammatory cell (predominantly eosinophil) infiltrate. This lends support to the idea that PAF is a mediator of allergic inflammation and that PAF antagonists may have a therapeutic role in allergic diseases.

Acute Disease↗
PubMed1988

Effect of a PAF antagonist, BN52063, on PAF-induced bronchoconstriction in normal subjects.

1. The effects of an oral platelet activating factor (PAF) antagonist, BN52063, or matched placebo on inhaled PAF challenge were assessed in a double-blind study in eight normal subjects. 2. PAF (24 micrograms) induced an immediate bronchoconstriction, with a maximum fall in flow at 30% of vital capacity from a partial flow volume manoeuvre (Vp30) of 47.1 +/- 7% (mean +/- s.e. mean) 5 min after inhalation following placebo treatment. Repeated PAF challenges at 15 min intervals resulted in tachyphylaxis of the bronchoconstrictor response. 3. Two hours after the ingestion of BN52063 (120 mg) the maximum bronchoconstriction induced by inhaled PAF was attenuated (35.9 +/- 9% fall at 5 min) with a significant reduction (P less than 0.05) in response after the first and second inhalations. 4. Inhaled PAF induced an immediate neutropenia (73.2 +/- 9% fall 5 min after inhalation) followed by a rebound neutrophilia, which were unaffected by pretreatment with BN52063. 5. Oral ingestion of a dose of BN52063 which is effective in reducing skin responses to PAF gave partial protection against the bronchoconstrictor effect of inhaled PAF in normal subjects.

Adult↗
PubMed1988

Effect of a Paf antagonist, WEB 2086, on airway microvascular leakage in the guinea-pig and platelet aggregation in man.

1. The triazolodiazepine WEB 2086 has been evaluated as an antagonist of platelet-activating factor (Paf) by studying its effects on Paf-induced human platelet aggregation and microvascular leakage in guinea-pigs. 2. WEB 2086 inhibited Paf-induced platelet aggregation in platelet-rich plasma in vitro (IC50 = 117 +/- 35 nM, mean +/- s.d.) but had no effect on adenosine 3',5'-diphosphate-induced aggregation. 3. Paf-induced microvascular leakage, measured by the extravasation of intravenously-injected Evans blue dye, was inhibited in a dose-related fashion in the airways and other tissues by WEB 2086, achieving a maximal inhibitory effect at 10 micrograms kg-1, i.v. 4. However, WEB 2086 (10 micrograms kg-1, i.v.) did not inhibit a comparable increase in vascular permeability induced by ovalbumin in sensitized guinea-pigs. 5. We conclude that WEB 2086 is a potent antagonist of Paf and that Paf does not appear to be responsible for antigen-induced microvascular leakage.

Adenosine Diphosphate↗
PubMed1988

Opioid modulation of non-cholinergic neural bronchoconstriction in guinea-pig in vivo.

1. Opioid receptors have been demonstrated on sensory fibres in the vagus nerve. Non-cholinergic (NC) neural bronchoconstriction in guinea-pig is due to release of neuropeptides from sensory nerve endings. We have therefore studied the effect of opioids on this NC bronchoconstriction in the anaesthetized guinea-pig. 2. Bilateral vagal stimulation (5 V, 5 ms, 10 Hz) caused reproducible bronchoconstriction in guinea-pigs which was reduced by atropine (1 mg kg-1), but the NC component was unaffected by hexamethonium (10 mg kg-1). 3. NC bronchoconstriction was reduced by morphine in a dose-dependent manner (ED50 = 132 micrograms kg-1 with a maximal inhibition of 79 +/- 2.1% at 1 mg kg-1). Yohimbine (0.5 mg kg-1) did not alter the inhibitory effect of morphine (1 mg kg-1). 4. The inhibitory effect of morphine was completely reversed by naloxone (1 mg kg-1) which had no effect on NC bronchoconstriction. Propranolol (1 mg kg-1) significantly increased the NC bronchoconstrictor response but did not significantly alter the inhibition by morphine. 5. The selective mu-opioid receptor agonist Tyr-(D-Ala)-Gly-(N-Me-Phe)-Glyol (DAGOL) was significantly more potent than morphine with an ED50 of 5.4 micrograms kg-1 and complete inhibition at 100 micrograms kg-1. The delta-agonist Tyr-(D-Pen)-Gly-Phe-(D-Pen) (DPDPE) was less potent than DAGOL with an ED50 of 28 micrograms kg-1 and a maximal inhibition of only 50 +/- 5% at 100 micrograms kg-1. The delta-agonist Tyr4D-Pen)-Gly-Phe-D-Pen) (DPDPE) was less potent than DAGOL with an ED5o of 28pgkg-1 and a maximal inhibition of only 50 + 5% at lOOPgkg- . The Kappa-receptor agonist, U-50,488H had no inhibitory effect on the NC bronchoconstrictor response. 6. The bronchoconstrictor responses to exogenous substance P (25 pgkg- 1) or acetylcholine (25 pg kg- 1) were unaffected by morphine (500 pg kg- 1). 7. We conclude that opioids inhibit the NC bronchoconstrictor response to vagal stimulation via an action on mu-opioid receptors localized to sensory nerve endings in the airway.

Acetylcholine↗
PubMed1988

Nonadrenergic bronchodilator mechanisms in normal human subjects in vivo.

In seven normal subjects we investigated whether a nonadrenergic bronchodilator nervous system is demonstrable in humans in vivo. After inhalation of leukotriene D4 (LTD4), respiratory resistance (Rrs) increased by 115 +/- 11% (SE). Subsequent inhalation of 2 nmol of capsaicin induced coughing and a fall in Rrs of 22.1 +/- 2% (P less than 0.01). However, inhalation of the diluent of capsaicin, 10% saline-ethanol, decreased Rrs similarly. These bronchodilator responses were not altered by inhaled ipratropium bromide (120 micrograms) and oral propranolol (80 mg). After ipratropium and propranolol, voluntary coughing alone decreased Rrs by 25 +/- 3% (P less than 0.05). We next investigated whether these bronchodilator responses could be blocked by anesthesia of the airways with inhaled lidocaine. After inhalation of lidocaine and LTD4, capsaicin aerosol induced coughing and a transient increase in Rrs of 18 +/- 6% (P less than 0.05) but no bronchodilation. Inhalation of saline-ethanol (n = 4) and a deep inhalation (n = 6) decreased Rrs by 18 +/- 4% (P less than 0.05) and 34 +/- 3% (P less than 0.001), respectively. We conclude that in normal subjects a nonadrenergic, noncholinergic bronchodilator mechanism exists, which can be activated by inhalation of capsaicin and inhibited by local anesthesia.

Adult↗
PubMed1988

Ozone-induced bronchial hyperresponsiveness in the rat is not accompanied by neutrophil influx or increased vascular permeability in the trachea.

We determined whether ozone-induced bronchial hyperresponsiveness in the rat is accompanied by neutrophil influx or increased vascular permeability in the trachea. Three groups of female Long-Evans rats were studied. One group was exposed to 4 ppm ozone for 2 h and studied immediately thereafter, another group was similarly exposed but was not studied until 24 h after the ozone exposure, and a third group consisted of control rats that breathed room air. Increases in total pulmonary resistance caused by acetylcholine aerosol were measured to assess bronchial responsiveness in these 3 groups. In parallel studies, neutrophil influx into the tracheal mucosa was quantified by counting cells within whole mounts of tracheas that were treated histochemically to stain the myeloperoxidase in neutrophils, and tracheal vascular permeability was quantified by measuring the amount of Evans blue dye extravasated into the trachea. In the rats studied immediately after the ozone exposure, the concentration of acetylcholine required to increase total pulmonary resistance to three-fold the baseline value was only 6% of that required in the controls. In the rats studied 24 h after the ozone exposure, this provocative acetylcholine concentration was not significantly different from that of the controls. Neither the number of neutrophils in the tracheal mucosa nor the amount of Evans blue dye extravasated into the trachea was significantly different from the corresponding control values at either time. We conclude that rats exposed to ozone develop bronchial hyperresponsiveness without detectable neutrophil influx or increased vascular permeability in the trachea.

Acetylcholine↗
PubMed1988

Inflammatory mediators involved in antigen-induced airway microvascular leakage in guinea pigs.

Antigen challenge of ovalbumin (OA)-sensitized guinea pigs results in significant (p less than 0.05) increases in vascular permeability to Evans blue (EB) dye in the airways, esophagus, and bladder. Mean values +/- SEM in ng EB/mg wet weight tissue for unsensitized versus sensitized animals were: trachea, 23.6 +/- 6.6 versus 92.5 +/- 11.1; main bronchi, 31.1 +/- 12.2 versus 153.1 +/- 14.9; "central" intrapulmonary airways (ipa), 34.6 +/- 11.2 versus 101.3 +/- 6.2; and "peripheral" ipa, 26.2 +/- 6.8 versus 93.5 +/- 13.6. We investigated the involvement of several mediators of inflammation in this process. FPL 55712, a sulfidopeptide leukotriene receptor antagonist, caused significant inhibition of leakage in trachea (to 55.1 +/- 9.8) and main bronchi (91.7 +/- 15.8). Blockade of the cyclooxygenase and lipoxygenase pathways with BW 755C, but not of the cyclooxygenase pathway alone with indomethacin, also significantly reduced EB dye extravasation in trachea (55.1 +/- 18.0), main bronchi (71.7 +/- 23.0), and "central" ipa (62.7 +/- 16.4). The histamine antagonists, chlorpheniramine and cimetidine, only inhibited microvascular leakage in main bronchi (94.4 +/- 20.0). PAF-receptor blockade with the ginkgolide mixture BN 52063 had no effect. Nedocromil sodium, a mast cell stabilizer and an inhibitor of inflammatory cell activation, caused significant inhibition throughout the airways: trachea, 50.4 +/- 10.6; main bronchi, 72.0 +/- 15.3; "central" ipa 61.0 +/- 8.6; "peripheral" ipa 41.9 +/- 12.2. Thus, histamine and lipoxygenase products (in particular, leukotrienes), but not PAF, may mediate the antigen-induced increase in vascular permeability to different degrees in differing regions of the respiratory tract in guinea pigs.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1988

Influence of airway calibre on the intrapulmonary dose and distribution of inhaled aerosol in normal and asthmatic subjects.

We investigated the relationship between airway calibre and the dose and distribution of inhaled aerosol in ten normal and six asthmatic subjects. Subjects inhaled saline aerosol containing 99mTcO4 delivered from a nebulizer connected to a dosimeter, and the lung fields were scanned with a gamma-camera. Right lung dose (RLD) was calculated as percentage of total dose. Intrapulmonary distribution was measured as penetration index (PI) (peripheral zone counts/central zone counts). Asthmatics had a significantly lower PI than normal subjects and there was a linear relationship between PI and baseline specific airway conductance (sGaw, p less than 0.001), and forced expiratory volume in one second (FEV1, p less than 0.05). After bronchodilatation with salbutamol (delta sGaw 101 +/- 31%, mean +/- SEM), PI increased from 0.73 +/- 0.11 to 1.09 +/- 0.15 (p less than 0.05); after bronchoconstriction with methacholine (delta sGaw 62.6 +/- 2.9%), PI decreased from 1.42 +/- 0.24 to 1.06 +/- 0.22 (p less than 0.05). Changes of PI were correlated with changes in sGaw and FEV1 (n = 20, p less than 0.001) but changes of RLD and changes in airway calibre were not. The distribution of inhaled aerosol, but not the dose, is largely dependent on airway calibre. The differences in PI between normal and asthmatic subjects may at best be explained by the differences in central airway calibre.

Administration, Inhalation↗
PubMed1988

Platelet-activating factor induces eosinophil peroxidase release from purified human eosinophils.

The degranulation response of purified human eosinophils to platelet-activating factor (PAF) has been studied. PAF induced release of eosinophil peroxidase (EPO) and beta-glucuronidase from highly purified human eosinophils with an EC50 of 0.9 nM. The order of release was comparable with that induced by phorbol myristate acetate (PMA). The new specific PAF antagonist 3-[4-(2-chlorophenyl)-9-methyl-H-thieno[3,2-f] [1,2,4]triazolo-[4,3a][1,4]-diazepin-2-yl](4-morpholinyl)- 1-propane-one (WEB 2086) inhibited the PAF-induced enzyme release by human eosinophils in a dose-dependent manner. The viability of eosinophils were unaffected both by PAF and WEB 2086. The results suggest that PAF may amplify allergic and inflammatory reactions by release of preformed proteins from eosinophil granules.

Azepines↗
PubMed1987

Effect of a ginkgolide mixture (BN 52063) in antagonising skin and platelet responses to platelet activating factor in man.

Antagonism of the effects of platelet activating factor (PAF) by the ginkgolide mixture BN 52063 was assessed in a double-blind, placebo-controlled, crossover study in 6 normal subjects. Weal and flare responses to 400 ng PAF, examined 2 h after ingestion of BN 52063 (80 mg, 120 mg) were inhibited in a dose-related manner. After 120 mg the flare area was reduced by a mean 62.4% (p less than 0.005) and the weal volume by a mean 60% (p less than 0.05). Both doses of BN 52063 significantly inhibited PAF-induced platelet aggregation in platelet-rich plasma (p less than 0.001). In vitro, BN 52063 inhibited PAF-induced but not ADP-induced platelet aggregation. Thus BN 52063 seems to be an antagonist of PAF in man.

Adult↗