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Biomedical subjects

R C Boucher

Publications and source records attributed to R C Boucher.

248 records · Page 14Linked to original sources
PubMed1981

Measurements of nasal transepithelial electric potential differences in normal human subjects in vivo.

Nasal transepithelial electrical potential difference (PD) was estimated in vivo in normal human subjects. The PD between a bridge perfused with Ringer's solution placed on the nasal mucosal surface and a reference electrode in a subcutaneous space was recorded. The magnitude of the PD depended upon the region of the nasal cavity touched by the exploring bridge. The PD values ranged from -4 mV (lumen negative) on the anterior tip of the inferior turbinate to approximately -30 mV on the inferior surface of the turbinate. Biopsies of the anterior turbinate were characterized by squamous epithelial cells, whereas ciliated cells dominated the epithelium from regions of higher PD. Epithelial abrasion abolished PD. No differences in PD were noted between the left and right nasal cavities, and repetitive measurements of PD at the same site yielded comparable values. No differences in nasal PD were noted between young male or female subjects but PD declined as a function of age. Amiloride (10(-4)M) and lidocaine (10(-1)M) reduced PD (-59% and -30%, respectively), whereas amphotericin B (5 X 10(-5)M) raised PD (+29%). We concluded that nasal PD can be accurately measured in vivo in humans, and that measurements of nasal bioelectric properties may serve as a relatively noninvasive index of respiratory epithelial function.

Action Potentials↗
PubMed1981

Effects of a viral laryngotracheitis on the epithelial barrier of chicken airways.

The effects of a virus infection on the barrier function of tracheal epithelium were compared to the effects of a chemical agent (methacholine) which selectively increases membrane permeability, and both were compared to controls. The disruption of the airway epithelium induced by the virus infection caused an increased permeation of horseradish peroxidase (HRP) through this barrier. Methacholine enhanced HRP uptake from the airway lumen to the blood as compared to controls. Visualization of HRP in the tracheal epithelium by transmission electron microscopy correlated with the radioimmunoassay measurements in the blood. Serial anti-HRP antibody titers were measured by a competitive binding technique. The antigen permeation induced by methacholine was associated with an enhanced anti-HRP antibody production. The larger increase in antigen permeation seen with the viral infection was associated with depressed anti-HRP titers. It was concluded that viral disruption of the airway epithelial barrier may contribute to an increased uptake of orally inhaled antigens. The relationship, however, between the increased antigen penetration consequent to the viral infection and the development of allergy remains unclear.

Animals↗
PubMed1981

Mechanisms of pollutant-induced airways toxicity.

The paper has focused on interactions of inhaled agents with airway surfaces. The respiratory mucosa is directly exposed to relatively high concentrations of inhaled substances and pollutant-related increases in incidence of infections and bronchospasm may reflect dysfunction of this barrier. Although the description of the mechanisms of toxicity to this surface are preliminary, it is clear that the challenge for the future will be to identify such toxic mechanisms. Too many environmental compounds are of concern and too many protocols are required to thoroughly study the toxicology and human health effects of individual compounds. An understanding of mechanisms is needed to categorize these compounds toxicologically to predict interactions between compounds in their effects on airways, and perhaps, to deal with the genetic variability of response demonstrated by individual subjects. A challenging need in future research will be to utilize observations on mechanisms made in animal models and in vitro to design well-focused experiments with human subjects.

Afferent Pathways↗
PubMed1980

Airway transepithelial electric potential in vivo: species and regional differences.

A technique for measurement of transmural bioelectric potential difference (PD) in vivo was adapted for use in mammalian airways. PD was measured between a Ringer-perfused exploring bridge positioned on the airway furface and a reference Ringer-agar bridge in the subcutaneous space. The in vivo PD of canine trachea from 50 dogs was 30.8 +/- 9.5 (SD) mV, lumen negative, indistinguishable from the peak in vitro transmural PD of the excised canine trachea. Liquid junction potentials between bridge perfusate and tracheal liquid were negligible. The response pattern to drugs applied to the mucosal surface in vivo was similar to that observed in vitro. The PD in canine bronchi 3-6 cm distal to the carina were substantially lower. Tracheal PDs of rabbit (-23 mV), guinea pig (-8 mV), and rat (-14 mV) were higher than bronchial PDs of the same species. PD across airway epithelia can be accurately and reliably measured in vivo and the lower bronchial PD suggests regional differences in electrolyte transport and/or permeability.

Acetylcholine↗
PubMed1980

Chemical modulation of airway epithelial permeability.

The mucosal surface of the conducting airways has specialized structures for respiratory defense. Glands secret mucus that may act as a barrier to particle penetration and participate in particle clearance. Intraepithelial irritant receptors aid in particle clearance through airway constriction and cough. The epithelium acts as a barrier to the penetration of inhaled material into the airway wall. Morphologic studies have identified the tight junctions adjoining respiratory epithelial cells as the principal barrier to passive solute translocation across the airway. New approaches have been used to study airway epithelial function. Use of excised canine trachea mounted in Ussing chambers has permitted quantitative estimates of probe molecule permeation, the correlation of permeability with bioelectric properties, and estimation of equivalent pore radii. Probe molecule diffusion across canine trachea [mean transmucosal electric potential difference (PD) = 33 mV, lumen negative] is directly related to conductance (2.9 mS/cm2) and is compatible with an equivalent pore radius of 7.5 nm. Direct measurement of tracheal PD in vivo (-29 mV) facilitates study of the genesis of the biopotential in intact animals. Measurement of the movement of HRP by radioimmunoassay has allowed correlation of the rate of probe flow across airway walls in vivo with ultrastructure. These approaches lend themselves to the study of pharmacologic and toxicologic effects on epithelial function. Antigen challenge, diethyl ether, and unfractionated cigarette smoke have been shown to increase epithelial permeability to HRP accompanied by ultrastructural evidence of tight junctional damage. Application of pharmacologic agents, e.g. amphotericin, ouabain, onto the respiratory epithelium induces similar changes in in vitro and in vivo PD. We conclude that techniques that have been used to measure permeability and transport in other epithelia may help elucidate modes of action of environmental agents on airways.

Air Pollutants↗
PubMed1980

The effect of cigarette smoke on the permeability of guinea pig airways.

The epithelium lining the conducting airways restricts the movement of inhaled foreign materials into the interstitial and circulatory space. In the present study, we have investigated the effects of graded doses of inhaled whole cigarette smoke on this function by measuring the rate of movement of horseradish peroxidase (HRP) from the airways lumen across the tracheal epithelium into blood, by assessing the penetration of HRP into tracheal epithelium using transmission electron microscopy, and by examining the morphology of tracheal epithelial tight junctions using the freeze-fracture technique. These studies showed that 5, 20, and 100 puffs of whole smoke increased penetration of HRP from the tracheal lumen into blood in a dose-dependent fashion. Transmission electron microscopy showed that HRP penetrated the tracheal epithelium only in the 100-puff exposure group while the freeze-fracture studies showed progressive disruption of epithelial tight junction beginning with a 100-puff exposure and becoming more extensive after the 200-puff exposure. We conclude that inhaled cigarette smoke damages the mucosal barrier and causes increased permeability to HRP by disrupting the intercellular tight junctions and that measuring the appearance of HRP in blood is more sensitive than electron microscopy in assessing this damage.

Airway Resistance↗
PubMed1979

The pathophysiology of asthma.

Because postmortem studies of humans provide little information on the initial pathophysiologic events in asthma, animal models have been developed. Recently the Ascaris-allergic rhesus monkey has provided an opportunity to examine the onset of pathophysiologic changes following challenge and to correlate them with airway structure. These studies have suggested that the initial interaction between antigen and mast cells may occur in the bronchial lumen or in the epithelium superficial to the tight junctions, where a small but significant percentage of airway mast cells exist. It also appears that this initial antigen-antibody interaction results in the release of mediators that both stimulate the rapidly adapting stretch receptors in the mucosa and alter the mucosal barrier so that proteins of large molecular weight can penetrate. The fact that antigen challenge results in hyperresponsiveness to a subsequent dose of inhaled histamine and increased systemic absorption of histamine suggests that the airway hyperresponsiveness could be related to increased penetration of histamine into the bronchial wall. These observations suggest that the initial event in an acute asthmatic attack is the release of mediators from superficial mast cells, and that this amplifies the allergic response by altering the mucosal permeability so that more antigen reaches the submucosal mast cells. This altered permeability may also help explain the hyperreactivity of the airways to nonspecific airway stimulants in persons with asthma.

Airway Resistance↗
PubMed1979

Relationship between airway hyperreactivity and hyperpermeability in Ascaris-sensitive monkeys.

In four Ascaris-sensitive rhesus monkeys, we measured the fractional absorption of 3H-histamine (3HH) and airway response, as pulmonary resistance (R1), to standard histamine aerosols containing tracer amounts of 3HH for control runs (Run 1) and runs after Ascaris antigen challenge (Run 2). The mean rate of accumulation of radioactivity in the plasma volume as a function of delivered dose during histamine exposure (2 min) was fivefold greater for Run 2 (0.047% delivered dose/min) as compared with Run 1 (0.009% delivered dose/min). Whereas histamine inhalation led to insignificant (less than 25%) increases in R1 over control in Run 1. R1 increased by 247% over control after histamine inhalation in Run 2. Thus, both airway hyperpermeability and hyperreactivity to inhaled histamine were observed following specific antigen challenge in this animal model. These data are consistent with the hypothesis that airway mucosal hyperpermeability induced by an allergic reaction is one of the factors contributing to airway hyperreactivity by increasing flows of inhaled bronchoactive agents to effector sites in the airway wall.

Airway Resistance↗
PubMed1979

Pulmonary effects of acute and chronic antigen exposure of immunized guinea pigs.

Subdivisions of lung volume and pressure-volume (PV) curves of the lung and chest wall were measured in guinea pigs immunized to ovalbumin before and after acute (group 1) and chronic (group 2) antigen exposure. The histopathology produced in chronically exposed animals was also assessed. Animals were anesthetized with pentobarbital sodium and studied in a pressure-sensitive body plethysmograph, using a fluid-filled esophageal catheter to measure transpulmonary pressure (PL). Functional residual capacity (FRC) was determined by the Boyle's law technique; total lung capacity (TLC) was defined as the lung volume at a PL of 30 cmH20, and residual volume (RV) was defined as the lung volume at a transrespiratory pressure of -50 cmH2O. Acute antigen challenge of group 1 animals resulted in a decrease in TLC (22%), and increases in FRC (20%) and RV (110%), suggesting combined bronchoconstriction and alveolar duct constriction. Chronic antigen exposure of group 2 animals resulted in minimal changes in subdivisions of lung volume and PV curves, and produced a histological lesion resembling allergic alveolitis rather than asthma.

Aerosols↗
PubMed1979

Bronchial mucosal permeability.

The tracheobronchial epithelium has well-developed tight junctions which on a morphologic basis should be markedly resistant to penetration by protein molecules. Despite this, antigen inhalation in monkeys allergic to Ascaris suum results in the rapid onset of pulmonary physiologic changes. Recent studies in man and animals have shown that a substantial number of mast cells exist in the bronchial lumen and epithelium. We suggest that antigen-antibody interaction initially occurs on these superficial mast cells leading to mediator release and the stimulation of airway irritant receptors. Antigen challenge also results in increased epithelial permeability to protein in the Ascaris-allergic monkey, and from studies on guinea pigs we suggest that this is due to alterations in the tight junctions. Antigen challenge in the monkey also produces increased permeability to labeled histamine and hyperresponsiveness to low concentrations of histamine. We suggest that the apparent airway hyperreactivity to inhaled histamine seen after inhalation of ozone, and NO2, or after upper respiratory infections could be due to damage to epithelial tight junctions. The resultant increase in mucosal permeability would result in an increased amount of histamine reaching airway smooth muscle for a given inhaled concentration.

Airway Resistance↗
PubMed1978

Effect of histamine and methacholine on guinea pig tracheal permeability to HRP.

The effects of histamine, methacholine, and ether on the permeability of the respiratory mucosa to macromolecules were investigated employing a radioimmunoassay and histochemical techniques to monitor movement of horseradish peroxidase (HRP) from airway lumen to blood. We found that 0.08% of the dose of HRP instilled into guinea pig tracheas was present in the blood volume at 10 min, and plasma HRP levels increased at a rate of 0.0036% instilled dose/min thereafter. After inhalation challenge, significant increases in plasma rates of accumulation of HRP were recorded for the histamine, methacholine, and ether groups, whereas no change in rate was noted for the control (Tyrode's) group. Electron micrographs of tracheal sections showed HRP penetration into the intercellular spaces of the epithelium after histamine, methacoline, or ether exposure but no penetration in the Tyrode's group. We conclude that, like ether, histamine and methacholine increase tracheobronchial permeability and this effect is most likely mediated by a functional change in the epithelial tight junction.

Aerosols↗
PubMed1977

Airway mucosal permeability in the Ascaris suum-sensitive rhesus monkey.

The permeability of the airways to technetium 99m-labeled albumin was measured in Ascaris suum-sensitive rhesus monkeys. All 8 animals were skin-sensitive to Ascaris suum (AA) antigen, 4 being respiratory responders (R) and 4 nonresponders (NR) to aerosolized antigen. In the absence of antigen challenge there were no differences in the accumulation in the blood of radioactive material from the tracheobranchial tree between the R and NR animals. After a five-minute challenge with aerosolized AA, there was a threefold increase in the rate of accumulation of radioactive material in the blood over control for the R group with no effect noted in the NR group. Gel filtration data indicated that the radioactivity in the blood most likely represented low molecular weight albumin fragments, resulting from spontaneous degradation of Tc-albumin, that crossed the mucosa and partially bound to circulating albumin. It is concluded that hyperpermeability of the airway mucosa probably is not a factor that contributes to the selective responsiveness of the R group to aerosolized antigen, and that airway permeability is increased consequent to the allergic reaction mediating acute bronchoconstriction.

Aerosols↗
PubMedDate not supplied

Pharmacokinetics of amiloride after inhalation and oral administration in adolescents and adults with cystic fibrosis.

STUDY OBJECTIVE: To compare the pharmacokinetics and systemic exposure of nebulized and oral amiloride in adolescents and adults with mild to moderate cystic fibrosis (CF). DESIGN: Open-label, randomized, two-way crossover, single-dose pharmacokinetic study. SETTING: University hospital clinical research unit. PATIENTS: Nine adolescents and 10 adults with mild to moderate CF (forced expiratory volume in 1 sec > or = 50% predicted, Brasfield score > or = 15). INTERVENTIONS: Patients received amiloride solution orally (10 mg of amiloride 1-mg/ml solution) and by inhalation [4.5 ml amiloride of 1-mg/ml solution in 12% saline (approximately 3.8 mmol/L) by DeVilbiss 646 nebulizer] during two study phases separated by a 7- to 28-day washout period. Serial blood and urine samples were collected for 48 and 72 hours, respectively. MEASUREMENTS AND MAIN RESULTS: After oral dosing, the mean +/- SD maximum peak concentration (Cmax) was 20.6 +/- 10.0 ng/ml at 3.2 +/- 1.2 hours in adults and 21.7 +/- 4.88 at 2.9 +/- 0.6 hours in the adolescents. Mean area under the concentration-time curve (AUC) from time zero to infinity hours was 275 +/- 115 and 254 +/- 60 ng.hr/ml in the adult and adolescent groups; half-life was 16.0 +/- 0.7 and 13.4 +/- 1.4 hours, respectively. After nebulization, 14 of 19 subjects exhibited two concentration peaks (Cmax1 and Cmax2) with mean values of 1.57 +/- 1.67 ng/ml at 0.5 +/- 0.2 hours and 1.37 +/- 1.21 ng/ml at 4.0 +/- 1.0 hours for adults, and 1.49 +/- 0.99 ng/ml at 0.5 +/- 0.1 hours and 1.52 +/- 0.81 ng/ml at 3.3 +/- 0.5 hours for adolescents. Estimated mean +/- SD dose nebulized was 1.91 +/- 0.66 and 2.28 +/- 0.30 mg in the adult and adolescent groups, respectively. Mean +/- SD AUC from time zero to the last measurable plasma amiloride concentration after inhalation was 14.4 +/- 17.6 and 15.4 +/- 10.1 ng.hr/ml in the adults and adolescents. No significant adverse events occurred during the study. Pharmacokinetic parameters were not statistically different between the adolescent and adult groups by route of administration. However significant differences in peak amiloride concentration, AUC, and urinary amiloride excretion were evident when comparing oral versus inhalation administration within each group. CONCLUSIONS: Mean amiloride plasma concentration peaks and AUC after inhalation were significantly lower than after oral dosing. In addition, the second amiloride plasma concentration peak may be due to oral ingestion of the nebulized amiloride, whereas the earlier Cmax1 after inhalation may be due to pulmonary absorption of amiloride. These results suggest that single-dose amiloride inhalation in patients with mild to moderate CF results in minimal systemic exposure compared with oral dosing, and that drug disposition is similar in adolescents and adults with CF.

Administration, Inhalation↗