Factors modulating the interindividual variability of airway responsiveness to histamine. The influence of H1 and H2 receptors.
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Adult↗
Biomedical subjects
M C Michoud
Publications and source records attributed to M C Michoud.
Comparison of steady state pulmonary diffusing capacity estimates for O2 and CO in dogs.
In view of the fact that the inhomogeneity effects on pulmonary diffusing capacity (DL) estimates are quite different for O2 and for CO, simultaneous determinations of steady-state DLCO and DLO2 were attempted and compared. To this end, pulmonary gas exchange was measured in 17 anesthetized and artificially ventilated dogs, in hypoxia with and without carbon monoxide in inspired gas (FIO2 = 0.12, FICO = 0.0009 to 0.0016). The diffusing capacity estimates were computed by two conventional procedures, the first (Dapp) taking into account the mean alveolar partial pressures and the second (DVDA) the ideal alveolar partial pressures. It was found that the presence of COHb in blood, inevitable in the steady-state DLCO procedure, leads to a marked underestimation of DLO2; therefore DLCO values could only be adequately compared to DLO2 values obtained in the absence of CO from inspired gas. These DLO2 were 18.5 and 33.4 mumol . min-1 . Torr-1 . kg-1 for the mean DappO2 and DVDAO2, respectively, whereas the DLCO values obtained after 15 to 25 min CO inspiration were 30.0 and 83.4 mumol . min-1 . Torr-1 . kg-1 for the mean DappCO and the mean DVDACO, respectively. The salient feature is that with both procedures the mean value of DLCO estimate is higher than the corresponding DLO2 estimate. This finding suggests that in anesthetized, artificially ventilated dogs DappO2 and DVDACO estimates obtained by steady-state procedures in hypoxia are largely influenced by inhomogeneity effects and of limited value for assessment of the diffusing properties of the lung. DappCO and DVDAO2 are also affected by inhomogeneities but to a lesser degree.
Animals↗
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↗
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↗
The number and distribution of mast cells in monkey lungs.
We estimated the number of mast cells in monkey lungs by both quantitative histologic examination and measurement of total lung histamine, and showed that monkey lungs contain between 10(7) and 10(8) mast cells, with approximately 83% of these being located in conducting airways, and 17% in the parenchyma. The number of mast cells found in each airway generation increased from approximately 60,000 in the trachea to 8 million in the terminal bronchioles. In airways from different generations the number of mast cells superficial to the basement membrane in the epithelium and lumen (EMC) was compared to the number of mast cells found in the submucosa between basement membrane and cartilage and to the number of those found outside the cartilage. The number of EMC varied between animals and ranged from 0-0.4% of the total number of mast cells in the trachea, to 0-27% of the total in the terminal bronchioles. On the average, EMC accounted for 12% of the total number of mast cells in conducting airways, where we calculate that there is approximately one EMC for every 100,000 epithelial cells. Eosinophils were distributed in close relation to mast cells in the mucosa and submucosa, but were rare outside the cartilage. We conclude that the number of mast cells increases from central to peripheral airways and that this may account for the marked peripheral airway response observed after antigen challenge.
Animals↗
Airway sensitivity to slow-reacting substance of anaphylaxis, histamine, and antigen in Ascaris sensitive monkeys.
The effects of Ascaris suum antigen, histamine, and slow-reacting substance of anaphylaxis (SRS-A) on the respiratory system were compared in 3 anesthetized rhesus monkeys. The agents were administered by instillation into the trachea, and the animals were studied in a volume displacement body plethysmograph. Two of the animals showed skin and bronchial sensitivity to Ascaris suum antigen and responded to it with increased pulmonary resistance and decreased dynamic compliance. A similar response was seen in all 3 animals after instillation of histamine, but SRS-A at 2 concentrations produced a predominant effect of decreased dynamic compliance with lesser alterations in pulmonary resistance. The effects of SRS-A were slow in onset and prolonged, as compared to the abrupt and short-lived effects of Ascaris suum antigen and histamine. The predominant effect of SRS-A on dynamic compliance suggests a more peripheral site of action of this mediator. In 5 monkeys allergic to Ascaris, no SRS-A could be detected in the blood at one and 5 min after antigen challenge, using the bioassay techniques.
Administration, Topical↗
Static lung mechanics of intact and excised rhesus monkey lungs and lobes.
Subdivisions of lung volume and pressure-volume (PV) curves of the lung and chest wall (CW) were measured in 12 rhesus monkeys (Macacca mulatta) under pentobarbital anesthesia. In addition, volumes and PV curves were obtained on the excised lungs and lobes of 12 cynomolgus monkeys (M. fasicularis). Boyle's law was used to determine functional residual capacity (FRC) in the intact animals and water displacement to determine minimal volume (MV) in the excised lungs. Total lung capacity (TLC = lung volume at a transpulmonary pressure of 30 cmH2O) was similar in vivo and in vitro (90 + 83 ml/kg) but residual volume (RV = volume at airway pressure of -50 cmH2O) and MV differed markedly (16.5 + 5.9 ml/kg). In the intact animals a very stiff CW appeared to determine RV, whereas airway closure determined MV in excised lungs. PV curves of upper and lower lobes were not different when expressed as %TLC but when expressed as milliliters of gas per gram of lung, the upper lobes contained significantly more gas per unit weight.
Animals↗
Airway responses to histamine and methocholine in Ascaris suum-allergic rhesus monkeys.
We performed dose-response curves to inhaled histamine (H) and methacholine (MC) in a group of eight rhesus monkeys, with and without natural allergy to Ascaris suum antigen (AA). The animals were anesthetized with pentobarbital sodium, 25 mg/kg im and studied in a volume-displacement body plethysmograph. The dose of H or MC producing a 50% increase in pulmonary resistance (RL) was used to determine sensitivity to these agents and the increase in RL at a given dose was employed as a measure of reactivity. Sensitivity and reactivity to H and MC were then compared with AA responsiveness. A wide range of responses was observed but allergic animals were not more sensitive or reactive to H or MC than nonallergic animals. In addition, we studied the changes in breathing pattern that occurred during the inhalation of AA, H, and MC in four AA-sensitive animals. AA and H produced rapid shallow breathing within 30 s of starting inhalation, but MC, despite causing an equal degree of bronchoconstriction, did not produce alterations in breathing pattern.
Aerosols↗
Effect of indomethacin and atropine in experimental asthma in conscious guinea pigs.
Pulmonary mechanics were measured in unanesthetized guinea pigs sensitized to horseradish peroxidase (HRP) before and during two aerosolized challenges of this antigen. During the first challenge the pulmonary resistance increased in all animals. Prior to second challenge the animals received either atropine (0.2 mg/kg) or indomethacin (10 mg/kg) intraperitoneally. We found that during the second challenge the indomethacin group had an increase in pulmonary resistance slightly greater or similar to that during the first exposure to the antigen, while the animals treated with atropine had a significantly diminished response (P less than 0.05). In five guinea pigs sensitized to HRP but challenged with a nonspecific aerosal made up of rabbit albumin, we found that pulmonary resistance increased in some animals and that this increase could be partially blocked by atropine. These results show that indomethacin has no effect on this model of allergic airways disease. They also confirm the importance of the vagus nerves in allergic bronchoconstriction and in addition show that nonspecific hyperirritability can be induced in some animals by immunization.
Aerosols↗
Effect of atrial natriuretic peptide on bronchial tone in anesthetized rabbits.
The effect of atrial natriuretic peptide (ANP) on histamine-induced bronchoconstriction was studied in vivo (in normoxic and in hypoxic rabbits) and in vitro. Thirty-two anesthetized rabbits, spontaneously breathing room air or 10% O2, received infusions of ANP (20, 40, or 80 ng/min/kg normoxia; 20 ng/min/kg hypoxia) or the vehicle for 100 min. After 75 min of ANP infusion, bronchoconstriction was induced inhaling histamine; respiratory resistance (Rrs) was measured prior to and until 20 min posthistamine. The results show that the histamine-induced increase in Rrs was significantly reduced by ANP 80 ng/kg/min in normoxia, and by ANP 20 ng/kg/min in hypoxia. In vitro, ANP had no effect on tracheal and bronchial smooth muscle precontracted with histamine or acetylcholine. These results show that ANP can decrease a histamine-induced bronchoconstriction in vivo but not in vitro, suggesting an indirect mechanism of action.
Airway Resistance↗
The effect of dopamine on tracheal smooth muscle.
Dose-response curves to dopamine were obtained on guinea-pig, dog and human tracheal smooth muscle. Dopamine produced a relaxation of the guinea-pig tracheal chain, and this relaxation was completely blocked by propranolol. The potency of dopamine as a beta-agonist was 1/10 000 that of isoprenaline, 1/250 that of adrenaline and 1/50 that of noradrenaline. In human and dog tracheal smooth muscle, dopamine induced a contraction which could be entirely abolished by alpha-adrenoceptor antagonists. As an alpha-agonist, the potency of dopamine was 1/20 that of adrenaline and noradrenaline. Our data also show that a dopamine induced contraction is greatly potentiated if the smooth muscle specimen has been previously slightly contracted with histamine. We conclude that there are few, if any, specific dopaminergic receptors in the airways. Dopamine acts on both alpha- and beta-adrenoceptors, but in humans and dogs, its effect is predominantly on alpha-adrenoceptors.
Animals↗
A comparison of pulmonary function tests used for bronchial challenges.
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Adult↗