Biomedical subjects

D F Rogers

Publications and source records attributed to D F Rogers.

At least 73 records · Page 4Linked to original sources

PubMed1992

Cigarette smoke-induced airway goblet cell secretion: dose-dependent differential nerve activation.

We studied the effect of acute inhalation of middle-tar cigarette smoke on airway goblet cell secretion in anesthetized guinea pigs. Secretion induced by a low dose of smoke (10 breaths diluted 1:10 in air) was blocked by either hexamethonium or by filtering out the particulate phase of the smoke. The response was partially inhibited by atropine but was not inhibited by propranolol, phentolamine, or capsaicin pretreatment. Cutting the nerve supply to the airways did not inhibit the response to low-dose smoke. In contrast, goblet cell secretion induced by a high dose of cigarette smoke (20 breaths undiluted) was inhibited by capsaicin pretreatment but not by autonomic receptor blockade nor by filtering out the particulate phase. Secretion induced by the vapor phase of the high dose of cigarette smoke was blocked by capsaicin pretreatment but was not inhibited by hexamethonium. We conclude that in guinea pig airways the particulate phase of low doses of smoke activates cholinergic nerves via stimulation of parasympathetic ganglia, whereas the vapor phase of high doses of smoke activates capsaicin-sensitive sensory nerves.

Animals↗

PubMed1991

Effects of a new compound (Zy 15850A) on cigarette smoke-induced bronchitis in the rat.

The effect of 4H-4 phenylthieno-(3,2-C)-(1)-benzopyran-2-carboxylate (Zy 15850A) on mucous cell hyperplasia was examined in vivo using a well established rat model of cigarette smoke-induced bronchitis. Zy 15850A was given by gavage (25 mg/kg body weight) to male rats before and after sub-acute exposure (i.e. daily for 14 days) to an atmosphere of cigarette smoke (CS). CS significantly increased the thickness of the epithelium at three of the four sites studied in the trachea and in both of the intrapulmonary levels examined. CS increased the number of epithelial mucous cells in all intrapulmonary airways and also increased the mass of submucosal gland present in the larynx and upper trachea. Zy 15850A completely inhibited CS-induced increases in epithelial thickness in the upper trachea and the two intrapulmonary airway levels studied, and tended to inhibit CS-induced epithelial mucous cell hyperplasia in all the six intrapulmonary airway levels examined, with statistically significant inhibition in two. Zy 15850A had no inhibitory effect of the CS-induced enlargement of laryngo-tracheal submucosal glands. We conclude that, in the rat, the predominant inhibitory effect of Zy 15850A is on CS-induced epithelial thickening with weaker inhibitory effects on mucous cell hyperplasia and enlargement of submucosal glands. Zy 15850A is less effective than other mucoregulatory drugs or antiinflammatory agents we have tested in the same bronchitic model.

Animals↗

PubMed1991

Corticosteroid inhibition of airway microvascular leakage.

We studied the effect of dexamethasone on microvascular leakage (using Evans blue dye as a marker of plasma exudation) induced in rat airways by platelet-activating factor (PAF). Intravenously administered PAF caused a dose-related increase in plasma leakage over the range 0.1 to 1 micrograms/kg. At 500 ng/kg PAF, the response was maximal in the extrapulmonary airways examined with increases in leakage above those in control animals of 312% in the larynx, 295% in the trachea, and 167% in the main bronchi. A maximal response was not achieved in the intrapulmonary airways at the doses of PAF tested: at 1 microgram/kg the increase was 206% above that in control animals. Dexamethasone, given by intraperitoneal injection 24 h and 4 h before PAF at a dose of 0.2 mg/kg on each occasion, partially inhibited leakage induced by PAF (1 microgram/kg) in all airway levels studied by 43 to 65%. At each level the tissue concentration of dye was reduced to a value that was significantly (p less than 0.05) different from either PAF or control values. We also determined whether a high dose (8 mg/kg) of dexamethasone given intraperitoneally would inhibit plasma leakage of dye induced by either PAF or antigen-challenge of sensitized rats. When given 4 h before antigen, dexamethasone completely prevented allergen-induced leakage in the airways showing significant leakage (larynx, trachea, and intrapulmonary airways). Similarly, dexamethasone (4 h before) partially inhibited PAF-induced leakage in the trachea and main bronchi. In summary, in rat airways, both low and high doses of dexamethasone markedly inhibit mediator-induced plasma exudation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Neurogenic inflammation in the airways: characterisation of electrical parameters for vagus nerve stimulation in the guinea pig.

We systematically determined the electrical parameters optimal for inducing plasma leakage in the airways of the anaesthetised, unventilated guinea pig but with minimal effects on carotid artery pressure in response to bilateral vagus nerve stimulation. The magnitude of both plasma leakage and of the reductions in blood pressure was dependent upon the frequency, amplitude and pulse width of the stimulus and on the duration for which it was applied. At 7 Hz, 5 V, 5 ms for 3 min leakage was increased above controls by 161% in the lower trachea, by 200% in the main bronchi and by 77% in the proximal intrapulmonary airways, with only a 21% drop in blood pressure. Neither increasing the intensity and duration of the stimulus nor allowing leakage to increase in magnitude with time after a short stimulus caused significant further increases in leakage but did cause concomitant reductions in blood pressure. Vagally-induced leakage and reduced blood pressure were abolished by pretreatment of the animals with capsaicin. Thus, the involvement of non-adrenergic, non-cholinergic mechanisms in the response to these stimulation parameters indicates that they are suitable for the study of neurogenic inflammation in the airways and its modulation by drugs, some of which may affect blood pressure.

Animals↗

PubMed1990

Modulation of neurogenic inflammation: novel approaches to inflammatory disease.

Neurogenic inflammation, which involves the release of neuropeptides from capsaicin-sensitive sensory nerves, may contribute to inflammatory diseases of the airways, joints, bladder, skin, eye and gut. Peter Barnes and colleagues review some of the therapeutic strategies that can be used to inhibit this neurogenic inflammation, with particular reference to the respiratory tract.

Animals↗

PubMed1990

Neural control of airway mucus secretion.

Neural mechanisms contribute to the control of secretion of mucus in the airways of a number of animal species including humans. The nerves involved are adrenergic, cholinergic and non-adrenergic, non cholinergic (NANC) and contribute to greater or lesser degrees, depending upon the species, to secretion from submucosal glands and epithelial goblet cells. Experimental studies implicate abnormalities in neural control in the pathophysiology of certain bronchial diseases in humans which are associated with mucus hypersecretion. New observations indicate a number of novel interventions with therapeutic potential for control of mucus in chronic bronchitis and asthma.

Bronchial Diseases↗

PubMed1990

Bradykinin-induced plasma exudation in guinea-pig airways: involvement of platelet activating factor.

1. We studied the effect of bradykinin on plasma exudation in the airways of the anaesthetized guinea-pig in vivo. Tissue content of extravasated Evans blue dye was used as an index of protein exudation in the larynx, trachea, main bronchi and intrapulmonary airways (i.p.a.). 2. Bradykinin increased the content of Evans blue in all tissues studied in a dose-related manner. The response was greatest in the main bronchi and i.p.a., less in the trachea and least in the larynx. A dose of 47 nmol kg-1 was the lowest tested which caused significant (P less than 0.001) plasma exudation with increases in leakage above control values of 256% in the larynx, 405% in the trachea, 394% in the main bronchi and 485% in intrapulmonary airways. 3. Leakage was significantly (P less than 0.05) increased above control values by 1 min after bradykinin (47 nmol kg-1) in the main bronchi and intrapulmonary airways and was maximal in all airways 5 min after bradykinin. Although reduced by 15 min, the tissue content of dye was still significantly (P less than 0.05) increased 2 h after bradykinin. 4. The prolonged tissue dye retention was due to a later phase of slow and maintained exudation preventing full clearance of dye after the initial response. 5. The initial phase of leakage was partially attenuated by the platelet activating factor (PAF) receptor antagonists WEB 2086 or BN 52021, by indomethacin or by inhibiting sensory nerve activation by opioid anaesthesia: it was not affected by mepyramine and cimetidine nor by the sulphidopeptide leukotriene receptor antagonists FPL 55712 or ICI 198,615. Adrenoceptor blockade of the anti-leakage effects of endogenously-released catecholamines significantly (P < 0.05) enhanced leakage. 6. The later phase of plasma leakage was completely inhibited by the PAF antagonists. 7. We conclude that, in guinea-pig airways in vivo, the initial phase of bradykinin-induced plasma exudation is mediated in part by PAF, sensory nerves and prostaglandins, whereas the later, prolonged phase of leakage is mediated exclusively by PAF. If bradykinin is generated in asthma, its potent and prolonged effects on plasma leakage may contribute significantly to airway oedema and may be involved in the development of bronchial hyperresponsiveness.

Animals↗

PubMed1990

Capsaicin and sensory neuropeptide stimulation of goblet cell secretion in guinea-pig trachea.

1. We studied the effect of capsaicin and sensory neuropeptides on tracheal goblet cell secretion in anaesthetized guinea-pigs using a semi-quantitative morphometric technique whereby the magnitude of discharge of stained intracellular mucus, expressed as a mucus score (MS), was related inversely to discharge. 2. Capsaicin (i.v.) induced goblet cell secretion: a decrease of 50% in MS below control (indicative of increased secretion) was maximal at 3.3 x 10(-9) mol/kg. 3. Capsaicin-induced secretion was unaffected either by prior vagus nerve section or by pre-treatment with atropine, propranolol and phentolamine which suggests that local axon reflexes with release of sensory neuropeptides are involved in the response. 4. Intravenous substance P (SP), neurokinin A (NKA), neurokinin B (NKB), and calcitonin gene-related peptide (CGRP) produced dose-related increases in goblet cell secretion, with SP the most potent. Doses (mol/kg) causing a 50% decrease in MS from control were 3.5 x 10(-12) for SP; 72 x 10(-10) for NKA; 1.6 x 10(-9) for NKB; and 1.2 x 10(-8) for CGRP. The maximal increase in goblet cell secretion was 75% of control and occurred with SP at 10(-10) mol/kg. 5. SP-induced mucus discharge was not inhibited by atropine or the histamine receptor antagonists mepyramine or cimetidine. 6. We conclude that in guinea-pig trachea, goblet cell secretion is under the control of capsaicin-sensitive sensory nerves and release of neuropeptides from these nerves may induce mucus discharge via tachykinin receptors of the NK-1 subtype (indicated by an order of potency of SP greater than NKA greater than NKB).

Anesthesia, General↗

PubMed1990

Effect of platelet activating factor on formation and composition of airway fluid in the guinea-pig trachea.

1. We studied the effect of platelet activating factor (PAF) on leakage of albumin, and secretion of fucose (a marker for mucus glycoprotein) and protein into the tracheal lumen of the guinea-pig isolated in situ, and on bioelectric properties and fluxes of mannitol in vitro. We also studied the effect of PAF on mucus secretion in human bronchi in vitro. 2. In guinea-pig, intravenous PAF markedly increased the luminal concentration of protein but did not significantly increase fucose concentrations. Increased albumin leakage (274% above controls at a dose of 50 ng/kg PAF) was associated with the increased luminal content of protein (248% above controls at the same dose of PAF). 3. Leakage of albumin was maximal 10 min after PAF, was significantly reduced by 20 min and had returned to baseline by 30 min. This pattern of leakage could be repeated with successive administrations of PAF. 4. PAF induced small but significant biphasic changes in bioelectric properties in vitro. The initial response was rapid in onset and characterized by maximal increases in short-circuit current (Isc) of 6.5% above controls at 7.5 min and in conductance (G) of 7% at 20 min. Both responses were blocked by the PAF receptor antagonist WEB 2086. Amiloride blocked the increase in Isc. Permeability of the tissue to mannitol (Pmann) was unaltered. The delayed response was characterized by maximal increases in Isc and G of 10% above controls at 60-90 min which were not significantly affected by WEB 2086 or amiloride. Pmann was increased by 38% at 90 min. 5. PAF increased fucose secretion in human bronchi in vitro. 6. Lyso-PAF in vitro caused changes similar to those induced by PAF on bioelectric properties and mucus secretion, but had no significant effects in vivo. 7. Light microscopy showed no evidence of epithelial disruption in animals given intravenous PAF at a dose causing significant albumin transudation. 8. We conclude that PAF increases the protein content of guinea-pig tracheal fluid principally by inducing plasma leakage rather than mucus secretion and that the small changes in ion transport and epithelial conductance may reduce the tendency to epithelial disruption during plasma leakage.

Action Potentials↗

PubMed1990

Neural control of goblet cell secretion in guinea pig airways.

We studied the neural control of goblet cell secretion in the lower airways of anesthetized guinea pigs using a semiquantitative morphometric technique. The magnitude of discharge of intracellular mucus was determined in histological sections of the trachea and main bronchi stained for mucus glycoproteins. Bilateral electrical stimulation of the cervical vagus nerves induced goblet cell secretion. The magnitude of the effect was dependent on the frequency, voltage, and pulse width of the stimulus, and the duration of stimulation. At 10 Hz, 5 V, and 5 ms for 3 min, there was a 62% decrease in the amount of intracellular mucus below that with sham stimulation. The secretion was blocked either by atropine or by pretreatment with capsaicin but was not significantly inhibited by idazoxan, an alpha-adrenoceptor antagonist. The magnitude of goblet cell discharge in animals pretreated with propranolol was intermediate between that in controls and that with nerve stimulation, although not significant to either. These results demonstrate that goblet cell secretion is under neural control in guinea pig airways and suggest that cholinergic, nonadrenergic-noncholinergic, and possibly adrenergic neural pathways, may contribute to the secretion.

Adrenergic alpha-Antagonists↗

PubMed1990

Bleomycin-induced lung injury in the rat: effects of the platelet-activating factor (PAF) receptor antagonist BN 52021 and platelet depletion.

Bleomycin is a highly effective antitumor agent, but pulmonary toxicity, characterized by an acute inflammatory reaction and associated pulmonary edema, limits clinical use of the drug. Platelets and platelet-activating factor (PAF), a membrane-derived phospholipid, have been implicated in the mechanisms that can mediate pulmonary microvascular injury. We sought to investigate the role of PAF in bleomycin-induced lung injury in the rat, using the PAF receptor antagonist BN 52021; and the role of platelets though the use of an anti-platelet antibody. Lung injury was induced by intratracheal bleomycin (1.5 mg) and assessed by measurements of lung wet weight and total pulmonary extravascular albumin space (TPEAS). Bleomycin caused a significant increase in both indices after 48 hr, compared with control animals (p less than 0.05). A single dose of BN 52021 (20 mg/kg orally) significantly reduced the bleomycin-induced increase in lung weight, but not the rise in TPEAS (p greater than 0.05). Increasing the dose of BN 52021 (20 mg/kg/12 hr, orally) had no additional effect. Reducing circulating platelet numbers by approximately 75% had no effect on either the increase in lung weight or TPEAS, observed 48 hr after bleomycin (p greater than 0.05). PAF may partially contribute to the acute inflammatory reaction seen after intratracheal bleomycin in rats.

Administration, Inhalation↗

PubMed1990

Effects of treatment on airway microvascular leakage.

Microvascular leakage, an essential component of inflammation, probably plays a critical role in asthma in producing plasma exudation and thickening of the bronchial mucosa which may underlie airway hyperresponsiveness. Several therapeutic approaches are possible to reduce this leakage, by blocking either the effects or the release of inflammatory mediators which induce the leakage. Drugs with these actions might be too specific to be of therapeutic value if many mediators are involved, as seems increasingly likely. Reduction of blood flow using selective vasoconstrictors is a more attractive approach and alpha 1-adrenoceptor agonists may be of value. Drugs that act directly on endothelial cells are probably the most useful, since they would be effective irrespective of the mechanism of leakage. Corticosteroids probably have this property, but whether beta-agonists or theophylline are clinically effective against airway microvascular leakage is not yet certain. The development of new drugs which can inhibit microvascular leakage is an important therapeutic approach for the future.

Adrenal Cortex Hormones↗

PubMed1990

Endotoxin-induced plasma exudation in guinea-pig airways in vivo and the effect of neutrophil depletion.

The contribution of neutrophils to the action of endotoxin on plasma exudation in the airways of anaesthetized guinea-pigs was quantified by measuring the extravasation of Evans blue dye. Endotoxin (Salmonella enteritidis) caused a dose-dependent increase in microvascular leakage to Evans blue dye which was maximal after 25 min (p less than 0.05). The minimum dose tested that induced a significant rise in leakage was 1.5 mg.kg-1 for "central" intrapulmonary airways (ipa); 4.5 mg.kg-1 for trachea and main bronchi and 7.5 mg.kg-1 for nasal mucosa, larynx and "peripheral" ipa. Depletion of circulating neutrophil numbers by 97% using an antibody to guinea-pig neutrophils caused no significant diminution of the effects of endotoxin on leakage in any part of the airway. There was no significant influx of neutrophils into the airway interstitium at the time of maximum extravasation of Evans blue. We conclude that endotoxin-induced airway microvascular permeability is dependent upon mechanisms other than circulating neutrophils.

Animals↗

PubMed1990

The role of increased airway microvascular permeability and plasma exudation in asthma.

Airway oedema and inflammation are recognized as cardinal features of asthma, resulting from increase microvascular permeability of the bronchial circulation with the exudation of plasma and inflammatory cells into the airway lumen. Resistance to airflow is increased and the epithelium is disrupted either directly or by cytotoxic proteins derived from migrating inflammatory cells. Such mediators include bradykinin, platelet-activating factor (PAF), leukotrienes and histamine. Antigen-induced and neurogenic inflammation, generated by immunoglobulin E (IgE) and neuropeptides respectively, may also contribute to oedema generation. Assessment of increased bronchial vascular permeability in animals has largely involved measurement of the extravasation of radiolabelled albumin or protein-bound dyes. Non-invasive techniques are less reliable in humans, but measurement of the rate of clearance of inhaled particles labelled with isotope may prove successful. Airway oedema appears to be an important feature of asthma and future research may be aimed at developing drugs that specifically prevent airway microvascular leakage.

Animals↗

PubMed1989

Effects of tachykinins on mucus secretion in human bronchi in vitro.

We examined the effects of mammalian tachykinins on human bronchial secretion in vitro using fucose as an endogenous marker for mucus. Substance P (SP, 10(-9)-10(-5) M) increased secretion in a dose-related manner and was more potent than neurokinin A or neurokinin B. The enkephalinase (endopeptidase 24.11) inhibitor phosphoramidon (10(-5) M) potentiated the effect of SP (10(-7) M). SP is a potent stimulant of secretion in human bronchi and enkephalinase may modulate its effects.

Adolescent↗

PubMed1989

Opioid inhibition of neurally mediated mucus secretion in human bronchi.

Capsaicin, which induces release of neuropeptides such as substance P from sensory nerves, stimulated mucus secretion in surgically resected human bronchi in vitro. Pretreatment of the tissue with the opioid antagonist naloxone significantly enhanced secretion, possibly by blocking the inhibitory effect of opiate premedication before surgery. Capsaicin-induced mucus secretion was completely blocked by morphine, and this effect was reversed by naloxone. Thus, sensory nerve stimulation increases mucus secretion in human airways, which might contribute to the mucus hypersecretion seen after inhalation of irritants such as cigarette smoke. Secretion can be completely inhibited by opioid drugs, so they may represent a new therapeutic approach to airway hypersecretion in chronic bronchitis and asthma, in which axon reflex mechanisms have been implicated.

Aged↗

PubMed1989

Plasma exudation. Correlation between Evans blue dye and radiolabeled albumin in guinea pig airways in vivo.

We quantified the tissue exudation and luminal transudation of two plasma markers, Evans blue (EB) dye and [125I]-human serum albumin (HSA), into the airways of the anesthetized guinea pig in response to platelet activating factor (PAF). There was a highly significant correlation between the tissue content of EB and [125I]-HSA in all airways studied. Significant correlation for transudation of the two markers was limited to high rates of plasma leakage. [125I]-HSA was the more sensitive marker for the association between exudation and transudation and the effect of PAF on transudation. EB was the better marker for assessing the relationship between the dose of PAF and plasma exudation.

Animals↗

PubMed1989

Regional and time-dependent effects of inflammatory mediators on airway microvascular permeability in the guinea pig.

1. Airway oedema resulting from increased microvascular permeability is a characteristic pathological finding of asthma. The regional effects of putative mediators involved in asthma on airway microvascular permeability have been studied. 2. The effects of histamine, leukotriene (LT) D4 and platelet-activating factor (PAF) on microvascular permeability in the nasal mucosa, larynx, trachea, main bronchi and intrapulmonary airways of the guinea pig were assessed by measuring the extravasation of intravenously administered Evans Blue dye. 3. PAF and LTD4 caused increased microvascular leakage throughout the respiratory tract, although their effects were maximal in different regions. Histamine had no significant effect on intrapulmonary airways. PAF was more potent than LTD4 and histamine at all airway levels. For example, in the trachea the doses required to cause leakage of 50% of maximal (ED50) were 10.4 nmol/kg, 138 nmol/kg and 11.2 mumol/kg, respectively, for PAF, LTD4 and histamine. 4. The effect of the three mediators was maximal 5 min after intravenous administration. Histamine, but neither LTD4 nor PAF, still caused significant leakage 30 min after administration. 5. The increased microvascular leakage induced by the mediators was inhibited by their respective specific receptor antagonists, suggesting that the effect was mediated via specific receptors. 6. Histamine, LTD4 and PAF have varying potencies in increasing microvascular permeability in the guinea-pig respiratory tract, exert their maximal effect in different regions and have varying durations of action.

Animals↗