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Biomedical subjects

J Widdicombe

Publications and source records attributed to J Widdicombe.

At least 19 recordsLinked to original sources
PubMed2006

Cough: what's in a name?

The cough reflex (CR) and the expiration reflex (ER) are two defensive reflexes from the respiratory tract, the latter mainly from the larynx. Both are elicited by mechanical and chemical irritation of the airway mucosa, and are a characteristic of airway diseases, but they have different functions. The CR first draws air into the lungs, to accentuate the subsequent expulsive phase; the ER consists of a strong expiration, to prevent aspiration of material into the lungs. They have different sensory pathways, central nervous circuits, and physiological and pharmacological modulations. In practice, coughing often consists of a combination of the two reflexes, a cough bout, epoch or attack. Articles on cough usually do not distinguish between the two reflexes, or whether the coughs are single events or epochs; they usually only measure frequency of expiratory efforts, and neglect other aspects. Current methods for measuring and assessing cough are described, with indications of when the use of these methods may be important.

Bronchi↗
PubMed2001

Airway receptors.

There are many types of afferent receptor in the airways; at least five in the larynx: pressure, drive, cold, irritant and C-fibre; and at least four in the trachea and bronchi: slowly and rapidly adapting stretch receptors (SARs and RARs), C-fibre receptors, and those in neuroepithelial bodies (NEBs). Histologically enough sensory structures have been identified to account for the various patterns of afferent activity, but most correlations are poor. For the larynx, four or more sensory structures have not definitively been identified with afferent discharges and reflex responses. For the trachea and bronchi, only SARs have been clearly identified morphologically and physiologically. The reflexes and afferent discharges from RARs and C-fibre receptors are fairly clear, some at least of the sensory terminals lie in the epithelium, but receptor complexes have not been mapped out. Nerves in NEBs have been identified, but not their local and central reflex actions.

Animals↗
PubMed2001

Reflexes from airway rapidly adapting receptors.

Rapidly adapting receptors (RARs) occur throughout the respiratory tract from the nose to the bronchi. They have thin myelinated nerve fibres, an irregular discharge and adapt rapidly to a maintained volume stimulus, but often slowly to a chemical stimulus. They are polymodal, responding to mechanical and chemical irritant stimuli, and to many inflammatory and immunological mediators. RARs show very varied sensitivities to different stimuli, and diverse reflex responses. Those in the larynx are usually called 'irritant' receptors. They probably cause cough, the expiration reflex and other laryngeal reflexes: cardiovascular, mucus secretion, bronchoconstrictor and laryngoconstrictor. Those in the trachea and larger bronchi are very mechanosensitive; they cause cough, bronchoconstriction and airway mucus secretion. Those in the larger bronchi are more chemosensitive; they may cause cough, but also stimulate hyperventilation, augmented breaths, mucus secretion, bronchoconstriction and laryngeal closure. Most of the stimuli to RARs also affect other airway receptors, especially those with C-fibre afferents, and the total reflex response will be the additive affect of all these reflexes.

Adaptation, Physiological↗
PubMed2001

Airway reflexes, autonomic function, and cardiovascular responses.

In this article, we review the cardiovascular responses to the inhalation of irritants and pollutants. Many sensory receptors in the respiratory system, from nose to alveoli, respond to these irritants and set up powerful reflex changes, including those in the cardiovascular system. Systemic hypotension or hypertension, pulmonary hypertension, bradycardia, tachycardia, and dysrhythmias have all been described previously. Most of the experiments have been acute and have been performed on anesthetized experimental animals. Experiments on humans suggest we have similar sensory systems and reflex responses. However, we must use caution when applying the animal results to humans. Most animal experiments, unlike those with humans, have been performed using general anesthesia, with irritants administered in high concentrations, and often to a restricted part of the respiratory tract. Species differences in the response to irritants are well established. We must be even more careful when applying the results of acute experiments in animals to the pathophysiologic changes observed in prolonged exposure to environmental pollution in humans.

Air Pollutants↗
PubMed1998

Upper airway reflexes.

It is usually assumed that upper airway pressure receptors mediate the reflexes involved in sleep apneas, but many other receptors may be involved, including those responding to chemical stimuli. The reflexes to upper airway negative pressure have been further studied, and the timing of their inputs shown to be important. Their effects on the cardiovascular system, including cerebral blood flow, have been emphasized. The central nervous pathways for the upper airway reflexes and their relationship to the neuronal circuits of the respiratory rhythm generator are being analyzed, but no clear pattern has emerged. Many neurotransmitters have been identified, usually on the motor pathways, which points to possible therapeutic approaches. The central nervous pharmacology and the neuronal pattern for the cough reflex have been described, and a similar approach to other upper airway reflexes, especially those involved in sleep apneas, would be valuable.

Female↗
PubMed1998

Drug uptake from the airways and lungs.

This paper reviews the mechanisms and physiological processes that act when drugs or chemicals are administered into the lower airways and lungs. Administration is usually by aerosol. Agents can be given, for example, either to treat pulmonary diseases such as asthma, or the test for airways' responsiveness or other functions, or as a means of access of a drug to the systemic circulation. The first barrier to absorption is the airway surface liquid, including mucus. The thickness of this layer will determine the concentration of the drug in solution, and therefore its rate of entry into the tissue. The agent must then penetrate the airway epithelium, the strongest barrier for hydrophilic agents. Agents must then diffuse through the epithelial basement membrane and the interstitium. Finally, the agent may be taken up into the mucosal vasculature, and changes in blood flow will influence its uptake and distribution. If the drug is to reach a target organ, such as airway smooth muscle or glands, these barriers have first to be traversed.

Animals↗
PubMed1997

Actions of moguisteine on cough and pulmonary rapidly adapting receptor activity in the guinea pig.

With anaesthetized guinea pigs, the actions of moguisteine were tested on the cough reflex, the resting discharge of lung rapidly adapting receptors (RARs), RAR activity induced by aerosols of capsaicin, stimulation of RARs due to i.v. injection of capsaicin, and on the reflex responses to i.v. capsaicin. I.v. moguisteine (20 microg kg(-1)), compared with vehicle, decreased the spontaneous firing of RARs. Intragastric (i.g.) moguisteine (200 mg kg(-1)) had no effect on resting discharge. I.g. moguisteine depressed the cough response due to capsaicin aerosol (0.01(-1) mg ml(-1)) and significantly reduced the increased discharge of the RARs due to the aerosol. I.v. and i.g. moguisteine reduced the proportionate increase in RAR discharge due to i.v. capsaicin (50 microg kg(-1)). It did not appreciably affect the cardiovascular and respiratory responses to i.v. capsaicin, which presumably activated lung C-fibre receptors. We conclude that the antitussive action of moguisteine is mediated at least in part by a decrease in the excitatory response of RARs to tussive stimuli.

Aerosols↗
PubMed1997

Microvascular anatomy of the nose.

The microvasculature of the nose consists of: 1) A dense subepithelial network of capillaries, with fenestrations between the endothelial cells. This network provides nutrients to the epithelium and glands, and allows passage of water into the lumen for evaporation and air-conditioning. 2) A system of capacitance vessels or sinuses, which when they distend, block the nasal lumen, and when they empty, open the nasal passages. Changes in their volume will affect the filtering and air-conditioning functions of the nose. 3) Arteriovenous anastomoses which allow rapid passage of blood through the mucosa. They are probably important in air-conditioning, and in the countercurrent mechanisms that tend to keep the brain cool in a hot dry climate. The anatomical interrelationships between these different systems is not well understood, nor is their differential control in terms of actions of mediators and nerves. In neurogenic inflammation sensory nerves are excited and release local mediators such as substance P via axon reflexes. These sensory neuropeptides will cause vasodilatation, vascular congestion and extravasation of liquid from the postcapillary venules, with resultant oedema and exudate. They may also cause secretion from the submucosal glands.

Arteriovenous Anastomosis↗
PubMed1997

Airway and alveolar permeability and surface liquid thickness: theory.

The thickness of airway surface liquid (ASL) can be calculated as the ratio of the permeability coefficient of an absorbed inert tracer to the percentage rate in which it decreases in content in the airway lumen. The percentage clearance of radiolabeled diethylenetriaminepentaacetic acid (DTPA) from human airways or lungs has been measured many times, with a mean value of 1.04 +/- 0.25 (SD) %/min. Rates of clearance from animal lungs of most species give values of the same order, although they are lower in the sheep and higher in the dog. Permeability coefficients have not been measured simultaneously with percentage clearances and not at all for human tissues. Values for mannitol and sucrose, of which the former gives a permeability coefficient approximately 25% greater than that for sucrose and DTPA in airway tubes and isolated mucosal sheets from experimental animals, give a mean approximately 7.1 x 10(-7) cm/s. This corresponds to thickness of ASl of approximately 20-150 microns for various species. The assumptions underlying this estimate are discussed. It is concluded that ASL thickness in vivo may be considerably greater than in vitro measurements involving rapid freezing of the airway wall. Estimates of alveolar permeability suggest that either it is very considerably lower than that of the airway epithelium, that methods to measure alveolar permeability mainly reflect airway permeability, or both.

Animals↗
PubMed1997

Estimation of thickness of airway surface liquid in ferret trachea in vitro.

The tracheae of ferrets and rabbits were mounted in vitro in organ baths. While the tracheae were liquid filled, the permeability coefficient ( P) was determined, and then while the tracheae were air filled, the percent clearance for 99mTc-labeled diethylenetriaminepentaacetic acid (DTPA) was determined. The thickness of airway surface liquid (ASL) was estimated by three methods. 1) The initial concentration of 99mTc-DTPA and the total amount of 99mTc-DTPA (the sum of that entering the outside medium, that draining from the trachea, and that washed out at the end of 40 min) gave the initial volume of ASL and thus its thickness. Mean values were 45.7 micron for the ferret and 41.9 micron for the rabbit. 2) Estimates of ASL thickness at the end of the 40-min period, based on the final 99mTc-DTPA concentration and the amount in the washout, were 42.9 micron for ferret and 45.4 micron for rabbit. 3) The ratio of P to percent clearance gave mean ASL thickness values of 49.2 micron for the ferret and 40.3 micron for the rabbit. Thus three separate methods for determining ASL thickness give very similar results, with means in the range 40-49 micron. Administration of methacholine or atropine to ferret tracheae did not significantly change ASL thickness.

Animals↗
PubMed1996

Drug uptake in the trachea.

For hydrophilic drugs and agents the major barrier to diffusion from the airway lumen into the mucosa is the epithelium, but for lipophilic agents epithelial permeability is high. Destruction of the epithelium increases the permeability of hydrophilic but not lipophilic agents. Changes in mucosal blood flow, induced either by vasoactive drugs or by changing the rate of arterial perfusion, lead to changes in drug uptake from the lumen to venous blood. Increases in flow decrease uptake, and vice versa for decreases in flow. The most likely explanation of this apparently paradoxical result is that increases in vascular pressure and flow result in a greater interstitial liquid volume and thus perfusion barrier, and induce solvent drag across the vascular endothelial wall, which will limit uptake of agents into the vascular lumen.

Aerosols↗
PubMed1996

The tracheobronchial vasculature: a possible role in asthma.

The tracheobronchial microcirculation consists of a subepithelial capillary network and in some species deeper capacitance vessels and an adventitial network. Postcapillary venules are the main site of plasma extravasation in inflammatory conditions. There are surprising species differences. The subepithelial capillary network is dense in species such as sheep and dog but relatively scanty in rabbit and humans. Sheep have conspicuous capacitance vessels or blood sinuses, especially in the trachea and at points of bronchial branching with walls that lack smooth muscle. The rabbit also has a well-developed capacitance system but the blood sinuses have thick muscular walls. Although the capacitance system in humans has not been studied much it is probably present with muscular walls. It is absent in rats but present in guinea pigs. Thus, in some species the tracheobronchial vasculature may give the mucosa an erectile capacity, as in the nose of each species. Arteriovenous anastomoses (AVA) cannot be demonstrated physiologically in sheep but they seem to be present as thoroughfare vessels in rats and guinea pigs. Whether they exist in humans is not known. The absence of AVA might indicate a weak or absent thermoregulatory and air conditioning role for the lower airway vasculature. Extensive studies of neurogenic inflammation in rodents show that sensory neuropeptides can open gaps between the endothelial cells of postcapillary venules and the same change can be caused by a large number of inflammatory mediators. These opened gaps cause extravasation of plasma into the interstitium. Small increases in interstitial pressure lead to spaces opening between the epithelial cells and exudation of plasma into the airway lumen. The role of the airway microvasculature in asthma is controversial. Cold and hyperosmolar solutions cause vasodilatation as do the mediators released in the mucosal inflammation of asthma. However, quantitation of the thickening of the airway wall due to vascular engorgement, mucosal edema, or increased luminal liquid does not prove that these changes are a cause of airway obstruction. The contraction of airway smooth muscle superimposed on the mucosal inflammatory pathology might lead to a synergistic mechanism to increase airway resistance.

Airway Resistance↗