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Biomedical subjects

J G Widdicombe

Publications and source records attributed to J G Widdicombe.

At least 19 recordsLinked to original sources
PubMed1995

Regulation of human airway surface liquid.

Human airways are lined with a film of liquid from 5-100 microns in depth, consisting of a periciliary sol around and a mucous gel above the cilia. Microscopical studies have shown the sol to be invariably the same depth as the length of the cilia, and we discuss possible reasons for this. The composition and sources of the airway surface liquid are also described. In addition the forces regulating its volume are analyzed. Several airway diseases are characterised by dramatic changes in the volume and composition of airway liquid. We review recent research suggesting that the accumulation of airway mucous secretions in cystic fibrosis is caused by alterations in active transport of ions and water across both the surface and gland epithelia.

Animals↗
PubMed1995

Tracheal epithelial damage alters tracer fluxes and effects of tracheal osmolaity in sheep in vivo.

Tracheal osmolaity affects blood flow and the flux of a tracer, technetium-99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA), from tracheal lumen to venous blood in anesthetized sheep. Hyperosmolar liquids increase blood flow and slightly decrease 99mTc-DTPA flux, whereas hyposmolar liquids have no effect on blood flow and greatly increase 99mTc-DTPA flux. We have now investigated whether epithelial damage induced by exposure of the tracheal lumen to a detergent (0.2% Triton X-100) alters these effects. A tracheal artery was perfused, and tracheal venous blood was collected. The initial tracheal volume was 12.8 +/- 0.7 ml. Triton X-100 greatly increased the permeability coefficient for 99mTc-DTPA from -2.1 x 10(-7) to -240 x 10(-7) cm/s. Hyperosmolar Krebs-Henseleit solution (KH; 739 +/- 6 mosmol/kg) increased arterial (+14.3%) and venous (+21.5%) flows and decreased 99mTc-DTPA output by 51.7%. Water flux into the lumen (+0.3 +/- 0.1 ml) was not significant, and the osmolality decreased by 99 +/- 9 mosmol/kg. Hyposmolar KH (124 +/- 2 mosmol/kg) had no effect on arterial and venous flows (-1.3% for both), and the increase in 99mTc-DTPA output (+8.3%) was small and not significant. The volume decreased by 0.4 +/- 0.1 ml, and the osmolaity increased by 36 +/- 4 mosmol/kg. Thus epithelial damage greatly increases the baseline permeability of the tracheal wall to 99mTc-DTPA. It does not alter the qualitative effects of hypersomolar KH on blood flow and 99mTc-DTPA output but does reduce the effect of hyposmolar KH on 99mTc-DTPA output. The latter effect may be a consequence of the reduced net water movement in response to non-isosmolar solutions after epithelial damage.

Animals↗
PubMed1995

Neurophysiology of the cough reflex.

Cough is due to activation of sensory receptors in the larynx and lower respiratory tract, sending impulses to the brainstem. The central organization of cough is poorly understood. The afferent pathways for cough are from receptors in and under the epithelium of the airways. These receptors are rapidly adapting, with thin myelinated fibres in the vagus nerves, which can be directly stimulated by tussive agents. Activation of C-fibre receptors in the airway releases sensory neuropeptides. These cause neurogenic inflammation and may activate rapidly adapting receptors to cause cough. The central connections of the C-fibre receptors inhibit cough. Thus, the sensitivity of the cough reflex and its pattern of response is due to a complex interaction between C-fibre receptors and rapidly adapting receptors, with peripheral and central nervous interactions. How these mechanisms apply to clinical cough in patients is at present poorly understood, but is beginning to be clarified.

Afferent Pathways↗
PubMed1994

Permeability of ferret trachea in vitro to 99mTc-DTPA and [14C]antipyrine.

Platelet-activating factor (PAF) and vasoactive drugs were tested on permeability of ferret trachea in vitro by measuring fluxes of 99mTc-diethylenetriamine pentaacetic acid (99mTc-DTPA; hydrophilic) and [14C]antipyrine ([14C]AP; lipophilic) across the tracheal wall. Tracheae were bathed on both sides with Krebs-Henseleit buffer, with luminal buffer containing either 99mTc-DTPA or [14C]AP. Luminal and abluminal radioactivities, potential difference, and tracheal smooth muscle tone were measured. Baseline 99mTc-DTPA and [14C]AP permeability coefficients were -4.7 +/- 0.6 (SE) x 10(-7) and -2.2 +/- 0.1 x 10(-5) cm/s, respectively. PAF (10 microM) increased permeability to 99mTc-DTPA to -35.3 +/- 7.6 x 10(-7) cm/s (P < 0.05), but permeability to [14C]AP did not change, suggesting that paracellular but not transcellular transport was affected. Abluminal and luminal applications of methacholine (MCh, 20 microM), phenylephrine (PE, 100 microM), and albuterol (Alb, 100 microM) caused no change in permeability to 99mTc-DTPA before or after exposure to luminal PAF, but abluminal histamine (Hist, 10 microM) significantly increased permeability. Abluminal Hist decreased permeability to [14C]AP before and after exposure to PAF. MCh, PE, and Hist increased smooth muscle tone; Alb and PAF had no effect. Thus, only PAF and Hist altered permeability to 99mTc-DTPA, and MCh, PE, and Hist changed smooth muscle tone. Tracheal permeability changes were greater for the hydrophilic than for the lipophilic agent.

Animals↗
PubMed1994

Osmolality alters tracheal blood flow and tracer uptake in anesthetized sheep.

Changes in the osmolality of airway surface liquid cause bronchoconstriction, mucus secretion, and ion transport, but little is known about the effects on the permeability of the trachea to drugs applied to the tracheal lumen. Using the anesthetized sheep, we have investigated the effects of hyperosmolar (725 +/- 11 mosmol/kg) and hyposmolar (128 +/- 5 mosmol/kg) Krebs-Henseleit (KH) solution in the tracheal lumen (mean volume 13.6 ml) on the uptake of technetium-99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA), a low-molecular-mass hydrophilic tracer that is thought to cross the epithelium via paracellular pathways, and on blood flow. All changes in osmolality were made by altering the NaCl content. We perfused a tracheal artery and collected tracheal venous blood. Hyperosmolar KH increased water movement into the lumen (+2.0 ml) and solute flux out of the lumen. It increased arterial (+24.5%) and venous (+20.6%) flows and decreased 99mTc-DTPA concentration (-26.3%) and output (-12.0%) in venous blood. Hyposmolar KH caused water movement out of the lumen (-0.9 ml) and solute flux into the lumen. It had no effect on arterial (+0.6%) and venous (+5.5%) flows and greatly increased the concentration (+345%) and output (+375%) of 99mTc-DTPA in venous blood. The baseline permeability coefficient for 99mTc-DTPA (-9.1 x 10(-7) cm/s) was not affected by hyperosmolar KH (-8.7 x 10(-7) cm/s) but was increased by hyposmolar KH (-21.4 x 10(-7) cm/s). These results confirm that hyperosmolar liquid in the lumen increases blood flow and indicate that tracer uptake is affected by the bulk flow of water across the airway wall.

Administration, Inhalation↗
PubMed1993

The effects of indomethacin and thiorphan on bradykinin-induced albumin output and submucosal gland secretion in the ferret trachea in vivo.

In the ferret liquid-filled trachea in vivo, intraluminal bradykinin (BK, 3-300 microM) produced concentration-dependent increases in the output of lysozyme from submucosal gland serous cells and albumin movement into the lumen. Baseline outputs of albumin and lysozyme were not altered significantly by intraluminal indomethacin (10 microM) or thiorphan (10 microM). However, intraluminal indomethacin completely blocked the BK-induced increase in albumin output. Intraluminal thiorphan (10 microM) did not significantly potentiate BK-induced albumin output, although mean output was higher. Neither indomethacin nor thiorphan significantly altered BK-induced lysozyme output, although mean output was reduced in the presence of indomethacin. Thus BK increases albumin output and may increase lysozyme output via the action of cyclooxygenase products. Inhibition of neutral endopeptidase activity may enhance the action of BK on albumin output.

Albumins↗
PubMed1993

Influence of simulated mucus on cough sounds in cats.

Although in the clinic the presence of mucus in the airways is known to be an important factor influencing the sound of coughing in pathological conditions, this observation has not been established experimentally. We have substituted mucus in the airways of anaesthetized cats with 0.5 ml of natural undiluted egg albumin (EA) from hens' eggs, or with 1 ml of 10% pig gastric mucin (PGM) in saline. There were obvious changes in the character of cough sounds and significant increases in the intensity of the sounds (+76% with EA, +36% with PGM). The intensity of cough efforts significantly increased but only in the cats with addition of PGM (mean 30%). Removal of EA or PGM caused the opposite effects, a decrease in cough sounds (-41%) and intensity of cough effort (-52%), with simultaneous changes in the character of the cough sounds. There were no clear-cut patterns of cough sounds as has been described for humans. The cough sounds were often present not only during the expiratory phase of cough but also during the inspiratory phase. The results establish an important role of mucus in the airways in the creation of cough sounds.

Animals↗
PubMed1993

Effect of experimental lung oedema on cough sound creation.

We have assessed the importance of changes in lung structure on the pattern of cough sound and its creation with 13 anaesthetized cats. Acute lung injury with oedema was induced by i.v. administration of a mixture of fatty acids. Cough was elicited by mechanical stimulation of the mucous membranes of the airways and was evaluated by its intensities of effort and sound before and up to 2 h after administration of the fatty acids. Changes of cough sound pattern were not definitive, there being no typical alterations. The cough effort and sound intensities, induced from the trachea, consistently decreased (by 70-80% in both cases). The cough efforts immediately after induction of oedema were transiently abolished in some cats. The cough values induced from the larynx similarly decreased at 5 min (51-57%) but subsequently gradually returned to control values. There were significant correlations, both for coughs induced from the trachea and from the larynx, and for changes in intensity of efforts compared with sounds. Thus, pathological changes in the lungs modify the intensities both of cough efforts and their associated sounds.

Animals↗
PubMed1993

Osmolality affects ion and water fluxes and secretion in the ferret trachea.

Nonisosmolar solutions were placed in the lumen of the ferret trachea in vitro in an organ bath. Hyposmolar (150 mmol/kg) solutions progressively increased in osmolarity over 1 h. Increases in luminal concentration of impermeant blue dextran occurred only after 5 min, suggesting that the initial changes were due to ion rather than water fluxes. With hyperosmolar solutions the osmolarity decreased over 1 h with no change in blue dextran concentration, indicating that ion but not water fluxes were taking place. Cooling the preparation to 4 degrees C greatly reduced the osmolaity changes with hyperosmolar solutions and halved those with hyposmolar solutions, suggesting that active ion transport was involved. Hyposmolar (75-150 mmol/kg) and hyperosmolar (450-900 mmol/kg) solutions both increased albumin output into the lumen, but the response was prevented by cooling the trachea to 4 degrees C. Hyposmolar and hyperosmolar solutions both increased the output of lysozyme from glandular serous cells into the lumen. The response to hyposmolar solutions was stronger. Cooling the trachea abolished the lysozyme response to hyperosmolar solutions. Thus hypo- and hyperosmolar solutions promote ion transport in directions to restore isosmolarity. Both nonisosmolar solutions promote albumin movement by active transport across the mucosa and lysozyme secretion from submucosal glands, responses inhibited by tracheal cooling and therefore dependent on metabolically active processes.

Albumins↗
PubMed1993

Asymmetric reflex responses of the nasal and tracheal vasculatures of the dog.

Both sides of the nasal vasculature of the dog in vivo were perfused separately, with measurement of vascular resistance responses to stimulation of various nerves. Stimulation of the central end of a cut superior laryngeal nerve caused an ipsilateral vasodilation (-4.98%) and a contralateral vasoconstriction (+3.96%), the difference being statistically significant (P < 0.01). Stimulation of a glossopharyngeal nerve caused vasodilation on both sides, the ipsilateral (-17.52%) being greater than the contralateral (-6.33%) response (P < 0.05). Mechanical stimulation of the nasal mucosa caused little ipsilateral change (+0.47%) and a weak contralateral vasoconstriction (+3.78%; P < 0.01). Stimulation of the central end of a cervical vagus nerve caused vasodilations on both sides, the ipsilateral (-9.75%) being greater than the contralateral (-5.73%) change (P < 0.05). With bilateral perfusions of the cervical tracheal arteries, stimulation of a superior laryngeal nerve caused vasodilation on both sides, the ipsilateral (-10.1%) being greater than the contralateral (-7.4%) response (P < 0.05). Stimulation of the central end of a vagus nerve caused vasoconstrictions on both the sides, the ipsilateral (+37.4%) being greater than the contralateral (+10.8%) change (P < 0.05). Thus various nervous inputs from the nose, pharynx, larynx, and vagal distribution cause asymmetric vascular responses both in the nose and in the cervical trachea.

Animals↗
PubMed1993

Reflex control of the tracheal vasculature of sheep.

Arteries to the cervical trachea were perfused at constant flow in anesthetized sheep. Perfusion pressures (PP), blood pressure (BP), and changes in tracheal smooth muscle tone (Ptr) were measured. Stimulation of pulmonary C-fiber receptors decreased PP (-6.5%) and BP (-16.8%) and increased Ptr (+61.5%), changes prevented by vagotomy and therefore reflex. Stimulation of cardiac receptors and slowly adapting pulmonary stretch receptors decreased PP (-7.9%) and BP (-21.0) and increased Ptr (+19.0%), changes reversed by vagotomy and therefore reflex. Stimulation and inhibition of slowly adapting pulmonary stretch receptors had no vagal-dependent effect on PP and BP, but inflation decreased (-20.3%) and deflation increased Ptr (+35.2%), effects abolished by vagotomy and therefore reflex. Systemic hypoxia increased PP and BP before and after vagotomy (+12.2 and +40.3%), effects greatly reduced by cutting the carotid body nerves; it increased Ptr (+29.8%), an effect abolished by vagotomy and cutting the carotid body nerves. Systemic hypercapnia increased PP (+16.9%), BP (+20.5%), and Ptr (+36.2%), the first two responses being unaffected by vagotomy and the last almost abolished. Stimulation of carotid body chemoreceptors by KCN increased PP (+22.5%), BP (+104.7%), and Ptr (+8.5%), all responses prevented by cutting the carotid body nerves. Responses to intravenous injections of KCN were similar.

Animals↗
PubMed1992

Chemoreceptor control of the airways.

The peripheral chemoreceptors act reflexly not only on respiration, but also on many motor systems in the respiratory tract. They cause a reflex bronchoconstriction, although this may be modified or even reversed by secondary dilator reflexes such as that from pulmonary stretch receptors. They promote a reflex secretion of mucus from submucosal glands in the trachea, and possibly other parts of the airways. They cause systemic reflex vasoconstriction both in nose (with reduction in airflow resistance) and trachea, and probably in the bronchi. There is also a reflex pulmonary vasoconstriction, although the strength of this has not been determined. The larynx dilates during peripheral chemoreceptor stimulation, as does the oropharynx. All these changes affect airway calibre, most components increasing it but some having the opposite effect. In turn these airway responses will affect lung ventilation and blood-gas tensions. The whole respiratory tract seems to be an important target organ for reflexes from the peripheral chemoreceptors.

Animals↗
PubMed1992

The effects of intraluminal and extraluminal drug application on secretion and smooth muscle tone in the ferret liquid-filled trachea in vitro.

With the ferret liquid-filled trachea in vitro, intraluminal methacholine (MCh), phenylephrine (PE) and histamine (Hist) increased smooth muscle tone and salbutamol (Salb) decreased tone. Lysozyme output was increased by intraluminal MCh and PE. Albumin transport into the lumen was not altered by intraluminal Hist, Salb or PE. The concentration-response curves for smooth muscle contraction and for lysozyme output to extraluminal MCh lay to the left of those for intraluminal MCh. Indomethacin shifted the smooth-muscle response curves to MCh significantly to the left but did not significantly alter lysozyme output. Extraluminal MCh produced a concentration-dependent increase in albumin output whilst intraluminal MCh did so in one of three studies. Albumin output in response to MCh was not significantly altered by indomethacin. Thus, MCh has a less potent effect on smooth muscle and lysozyme secretion and, to a lesser extent, on epithelial albumin transport when given intraluminally. This may be because the epithelium restricts diffusion of the drug or due to the production of a non-prostanoid factor which inhibits smooth muscle responsiveness. Smooth muscle responsiveness is enhanced by blocking cyclooxygenase activity, suggesting MCh-induced release of a prostanoid with relaxant activity.

Animals↗
PubMed1992

An in vivo preparation for measurement of plasma protein and lysozyme output in the ferret tracheal lumen.

An in-vivo ferret tracheal preparation has been developed to study the appearance in the liquid-filled trachea of fluorescein-labelled plasma proteins (FLP) and of lysozyme from submucosal gland serous cells. In order to investigate the influence of nervous activity on the appearance of FLP and lysozyme in the tracheal lumen, the effects of intraluminal bradykinin (an inflammatory mediator and sensory nerve stimulant), intraluminal capsaicin (a stimulant of C-fibres) and electrical stimulation of the cut peripheral end of the right cervical vagus nerve have been measured. Vagal stimulation (10 V, 10 Hz, 1 ms, 90-120 s) increased the secretory rate of lysozyme. It had no effect on FLP rate of output. Intraluminal bradykinin (100 microM) produced a small but significant increase in FLP output but had no effect on lysozyme secretion. Intraluminal capsaicin (33 microM) had no effect on FLP output and had variable effects on lysozyme output. Tracheal pressure was increased by vagal stimulation but was unaffected by bradykinin and capsaicin. Thus, bradykinin increases plasma protein output, probably by an action on the epithelium, whilst vagal stimulation and capsaicin stimulate submucosal glands. This method could be used to determine the factors which alter the rate of movement of plasma proteins into the airway lumen and the secretion of submucosal glands in vivo.

Animals↗
PubMed1992

Asthma. Tracheobronchial vasculature.

The tracheobronchial vasculature consists of a subepithelial capillary network and a deeper system of blood sinuses or capacitance vessels. There seem to be no arteriovenous anastomoses. Sympathetic nerves constrict the vasculature by the transmitters noradrenaline and neuropeptide-Y, parasympathetic nerves dilate it by acetylcholine and vasoactive intestinal polypeptide, and sensory nerves release neuropeptides including substance P that are dilator. Most inflammatory mediators are also vasodilator. In asthma there is mucosal vasodilation due to the direct action of mediators on vascular smooth muscle, neuropeptides released by axon reflexes in sensory nerve receptors, and possibly reflex vasodilation due to stimulation of sensory nerves. The vasodilation increases the thickness of the mucosa, both by vascular engorgement and by increased interstitial liquid volume. This mucosal thickening will narrow the airways and increase the rigidity of their walls. The vascular bed is also dilated by cold and hyperosmolality, and this change may be a component of the bronchoconstriction due to hyperventilation, inhalation of cold air and exercise. Changes in mucosal blood flow influence the uptake of chemical agents from the lumen, and the success of aerosol therapy in asthma may to some extent depend upon the influence of mucosal blood flow.

Animals↗
PubMed1992

Platelet-activating factor relaxes ferret tracheal smooth muscle and reduces transepithelial potential difference in vitro.

1. The effects of platelet activating factor (PAF) were examined on the smooth muscle tone, mucus volume, lysozyme and albumin outputs and potential difference (PD) across the ferret tracheal wall. 2. PAF (0.1-10 microM) had no direct effect on mucus volume, lysozyme or albumin output from the ferret trachea. PAF produced concentration-dependent relaxations of the tracheal smooth muscle and reductions in PD across the tracheal wall. There was no change in the histological appearance of the trachea after exposure to PAF. 3. The PAF-induced smooth muscle relaxation was not affected by FPL55712, a combination of mepyramine and cimetidine, or by a combination of the oxygen free-radical scavengers catalase and superoxide dismutase (SOD); but was abolished by indomethacin or the PAF-receptor antagonist WEB2086. 4. The PAF-induced reduction in PD was not affected by indomethacin, FPL55712 or mepyramine and cimetidine, but was prevented by catalase and SOD, and by WEB2086. 5. We conclude that PAF relaxes ferret tracheal smooth muscle in vitro by receptor-mediated release of a bronchodilator prostaglandin, possibly PGE2. PAF also reduces PD across the trachea suggesting changes in epithelial function; however, there is no histological epithelial damage after PAF. The reduction in PD with PAF is probably produced by receptor-mediated release of oxygen free-radicals. The cellular source of these free-radicals and of the dilator prostaglandin is unclear.

Animals↗
PubMed1992

PAF-induced muscarinic cholinoceptor hyperresponsiveness of ferret tracheal smooth muscle and gland secretion in vitro.

1. The effects of exposure of the ferret trachea in vitro to platelet activating factor (PAF) were examined on methacholine-induced smooth muscle contraction, mucus volume and lysozyme outputs, and albumin transport across the tracheal epithelium. 2. Methacholine (0.1-30 microM) produced concentration-dependent increases in tracheal smooth muscle tone and mucus volume, lysozyme and albumin outputs from the trachea. 3. The concentration-response curves for methacholine-induced smooth muscle contraction, mucus volume and lysozyme outputs were all shifted upwards after exposure of the trachea to PAF (1 microM) with a significant increase in maximum response for each variable. The EC50 values for methacholine-induced smooth muscle contraction and mucus volume output were significantly reduced after PAF exposure suggesting an increase in the potency of methacholine. The concentration-response curve for methacholine-induced albumin output was shifted downwards after PAF exposure with a greatly reduced maximum but no change in the EC50 for methacholine. 4. PAF-induced hyperresponsiveness of methacholine-induced smooth muscle contraction, mucus volume and lysozyme outputs was not affected by indomethacin, FPL55712, or mepyramine and cimetidine, but was prevented by catalase and superoxide dismutase (SOD), and by WEB2086. Similarly, PAF-induced inhibition of methacholine-stimulated albumin output was prevented by catalase and SOD, and by WEB2086. 5. We conclude that PAF induces hyperresponsiveness of ferret tracheal smooth muscle and submucosal gland secretion (including lysozyme secretion from serous cells) to methacholine. This hyperresponsiveness is probably produced by receptor-mediated release of oxygen free-radicals. The inhibition of methacholine-induced albumin flux suggests a loss of epithelial function which is also probably mediated by release of free-radicals. The mechanism by which the free-radicals produce the changes in responsiveness to methacholine, and the cellular source of the free-radicals, remain to be established.

Albumins↗