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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↗
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↗
PubMed1992

Tracheal blood flow and luminal clearance of 99mTc-DTPA in sheep.

Tracheal blood flow and 99mTc-labeled diethylenetriamine pentaacetic acid (DTPA) clearance were measured in the sheep trachea in vivo. The tracheal arteries were isolated and perfused. An isolated segment of tracheal lumen was filled with Krebs-Henseleit solution containing 99mTc-DTPA, and radioactivity was measured in blood from a catheterized tracheal vein. Infusions at constant pressure of methacholine (n = 5), albuterol (n = 6), and histamine (n = 5) increased arterial inflow [+250 +/- 73.0, +74.2 +/- 22.9, +68.9 +/- 39.2% (SE), respectively] and venous outflow (+49.5 +/- 13.8, +11.6 +/- 4.5, +6.2 +/- 13.9%) but decreased 99mTc-DTPA output (-36.8 +/- 8.4, -20.4 +/- 6.2, -58.1 +/- 11.7%) and concentration (-53.9 +/- 10.1, -27.3 +/- 7.5, -49.3 +/- 14.4%). Phenylephrine (n = 9) decreased arterial inflow (-49.4 +/- 10.0%) and venous outflow (-4.1 +/- 5.9%) but increased 99mTc-DTPA output (+74.6 +/- 44.2%) and concentration (+94.4 +/- 56.6%). When the tracheal arteries were initially perfused at constant flow and the flow rate was then changed, 50% increases in flow (n = 5) increased perfusion pressure (+35.9 +/- 2.2%) and venous outflow (+10.5 +/- 3.8%) but decreased 99mTc-DTPA output (-24.4 +/- 7.8%) and concentration (-30.4 +/- 8.8%). Decreases in flow of 50% (n = 3) and 100% (n = 10) decreased perfusion pressure (-34.2 +/- 4.2, -80.1 +/- 3.5%, respectively) and venous outflow (-11.0 +/- 4.8, -29.7 +/- 7.2%) but increased 99mTc-DTPA output (+45.9 +/- 27.5, +167.4 +/- 70.4%) and concentration (+64.7 +/- 26.7, +305.7 +/- 110.2%).(ABSTRACT TRUNCATED AT 250 WORDS)

Albuterol↗
PubMed1991

The actions of bradykinin and lys-bradykinin on tracheal blood flow and smooth muscle in anaesthetized sheep.

The actions of bradykinin and the related compound lys-bradykinin have been studied on the tracheal circulation and tracheal smooth muscle of the sheep. Cranial tracheal arteries of ten anaesthetised and paralysed sheep were isolated and perfused at systemic arterial pressure; arterial inflow was measured with an electromagnetic flow probe. Tracheal smooth muscle tone was assessed by measuring the external diameter of the cranial trachea. Close arterial injection of bradykinin and lys-bradykinin (0.1 to 1000 pmoles) produced potent dose-dependent falls in tracheal vascular resistance: for bradykinin a maximum fall of -56.4% (52.3-60.5%, 95% confidence interval) and for lys-bradykinin -52.8% (46.5-59.1%). The ED50 values were 0.69 (0.51-1.32) and 1.46 (1.19-2.28) pmoles respectively. Small and inconsistent relaxation of tracheal smooth muscle was seen with the higher doses (greater than 1.9 pmoles) of both kinins. Intravenous indomethacin (5 mg.kg-1) increased the vasodilation produced by bradykinin and lys-bradykinin. Oxyhaemoglobin (4 microns at 0.35 ml.min-1) infused into the tracheal circulation almost abolished the responses to bradykinin and methacholine. The results indicate that in the sheep trachea bradykinin has little action on airway smooth muscle but is a potent dilator of the vasculature; bradykinin and lys-bradykinin are of similar potency suggesting the action may be via B2 receptors. While the vascular responses may be modulated by vasoconstrictor cyclo-oxygenase products the vasodilation is likely to be endothelium-dependent and not prostanoid-mediated.

Anesthesia↗
PubMed1991

The effect of hydrogen peroxide on smooth muscle tone, mucus secretion and epithelial albumin transport of the ferret trachea in vitro.

The effect of hydrogen peroxide (H2O2) was examined on baseline and on methacholine- and phenylephrine-stimulated smooth muscle tone, mucus volume and lysozyme outputs, and epithelial albumin transport of the ferret whole trachea in vitro. H2O2 (10 microM-10 mM) had no significant effect on tracheal smooth muscle tone but produced concentration-dependent increases in mucus volume, lysozyme and albumin outputs. The potential difference (P.D.) across the trachea was not changed by H2O2. Exposure of the trachea to H2O2 (1 mM) for 2 h reduced the smooth muscle contractions and lysozyme outputs due to methacholine (1 microM) and phenylephrine (10 microM). Methacholine-induced albumin output was significantly increased by H2O2 but that due to phenylephrine was not significantly affected. Exposure to H2O2 had no significant effect on the mucus volume output produced by methacholine or phenylephrine. Thus H2O2 directly stimulates submucosal gland secretion, including secretion from serous cells, and epithelial albumin transport across the ferret trachea but has no effect on tracheal smooth muscle tone. H2O2 reduces methacholine- and phenylephrine-induced smooth muscle contractions and serous cell secretion. H2O2 causes hyperresponsiveness of albumin output to methacholine but not to phenylephrine.

Animals↗
PubMed1991

Veratrine-induced reflexes and cough.

With cats anaesthetized with sodium pentobarbital we studied how veratrine-induced reflexes interact with cough. Cough was elicited by mechanical stimulation of tracheobronchial mucosa and its intensity was evaluated from the changes in oesophageal pressure. Veratrine injected intravenously produced apnoea, bradycardia and long-lasting hypotension. With each dose the intensity of cough was significantly decreased during the apnoea. When the mechanical stimulus was repeated during the breathing following apnoea with remaining hypotension, cough intensity parameters were not changed from control. Veratrine injected intracardially caused bradycardia, hypotension, and decreases in respiratory rate and tidal volume. The intensity of cough elicited just after injection of veratrine was also significantly decreased. We suggest that veratrine-induced reflexes depress the cough reflex mainly by inhibitory reflexes arising from cardiac receptors. The inhibition of cough is probably mediated indirectly via the inhibition of medullary respiratory neurons.

Animals↗
PubMed1991

Mechanisms of platelet activating factor-induced changes in sheep tracheal blood flow.

1. The effects of platelet activating factor (PAF) have been studied on the cervical tracheal vasculature and smooth muscle of anaesthetized sheep. 2. The predominant action of PAF (2 pmol-2nmol) was a dose-dependent fall in tracheal vascular resistance. The maximum fall in resistance was -41.6% (-38.5 to -44.7%, 95% confidence interval) and the ED50 was 17 pmol (12-28 pmol). Lyso-PAF (200 pmol) did not change vascular resistance. 3. PAF had no effect on tracheal smooth muscle tone assessed by measuring changes in the external diameter of the trachea. 4. The fall in vascular resistance produced with PAF was unaffected by the anti-asthma drug nedocromil sodium (1 mg, i.a.), the cyclo-oxygenase inhibitor indomethacin (5 mg kg-1, i.v.), the leukotriene receptor antagonist FPL55712 (2 mg kg-1, i.v.), or a combination of the histamine H1- and H2-antagonists mepyramine (2 mg kg-1, i.v.) with cimetidine (5 mg kg-1, i.v.). The PAF antagonist WEB 2086 (300 micrograms kg-1, i.v.) significantly reduced the vasodilatation produced by PAF (before, -40.8 +/- 4.2%; after -16.5 +/- 5.9%, P less than 0.05). 5. Thus in this model, PAF is a potent vasodilator of the tracheal circulation but has no action on tracheal smooth muscle. The vasodilatation is mediated by specific PAF receptors and is not due to the release of prostanoids, leukotrienes or histamine.

Animals↗