Regional airflow obstruction after bronchoconstriction and subsequent bronchodilation in subjects without pulmonary disease

Some subjects with asthma have ventilation defects that are resistant to bronchodilator therapy, and it is thought that these resistant defects may be due to ongoing inflammation or chronic airway remodeling. However, it is unclear whether regional obstruction due to bronchospasm alone persists after bronchodilator therapy. To investigate this, six young, healthy subjects, in whom inflammation and remodeling were assumed to be absent, were bronchoconstricted with a PC20 [the concentration of methacholine that elicits a 20% drop in forced expiratory volume in 1 s (FEV1)] dose of methacholine and subsequently bronchodilated with a standard dose of albuterol on three separate occasions. Specific ventilation imaging, a proton MRI technique, was used to spatially map specific ventilation across 80% of each subject’s right lung in each condition. The ratio between regional specific ventilation at baseline and after intervention was used to classify areas that had constricted. After albuterol rescue from methacholine bronchoconstriction, 12% (SD 9) of the lung was classified as constricted. Of the 12% of lung units that were classified as constricted after albuterol, approximately half [7% (SD 7)] had constricted after methacholine and failed to recover, whereas half [6% (SD 4)] had remained open after methacholine but became constricted after albuterol. The incomplete regional recovery was not reflected in the subjects’ FEV1 measurements, which did not decrease from baseline ( P = 0.97), nor was it detectable as an increase in specific ventilation heterogeneity ( P = 0.78). NEW & NOTEWORTHY In normal subjects bronchoconstricted with methacholine and subsequently treated with albuterol, not all regions of the healthy lung returned to their prebronchoconstricted specific ventilation after albuterol, despite full recovery of integrative lung indexes (forced expiratory volume in 1 s and specific ventilation heterogeneity). The regions that remained bronchoconstricted following albuterol were those with the highest specific ventilation at baseline, which suggests that they may have received the highest methacholine dose.

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Persistent airflow obstruction in inner-city children with asthma

Allergy and Asthma Proceedings ◽

10.2500/aap.2021.42.210043 ◽

2021 ◽

Vol 42 (4) ◽

pp. 310-316

Author(s):

Kenny Y. Kwong ◽

Yang Z. Lu ◽

Emilio Jauregui ◽

Lyne Scott

Keyword(s):

Lung Function ◽

Inner City ◽

Airway Remodeling ◽

Airflow Obstruction ◽

Later Life ◽

Forced Expiratory Volume ◽

Initial Visit ◽

Asthma Care ◽

Increased Risk ◽

Children With Asthma

Background: Airway remodeling has been shown to be persistent in patients with asthma despite treatment with controller medications. Patients with early airflow obstruction may continue to experience poor lung function despite treatment. Objectives: To determine whether early airflow obstruction in inner-city children with asthma persists despite guideline-based asthma care. Methods: In a retrospective study that used a cohort of inner-city children with asthma treated by using an asthma-specific disease management system, the patients were stratified into “low” or “high” lung function groups at the time of the initial visit (high, forced expiratory volume in the first second of expiration [FEV1] % predicted and FEV1/forced vital capacity [FVC] ≥ 80%; and low, FEV1% predicted and FEV1/FVC < 80%). These patients then received National Heart, Lung, and Blood Institute guideline‐based asthma treatment at regular follow-up intervals with spirometry performed at these visits as part of regular care. FEV1% predicted and FEV1/FVC were followed up for up to 10 years for both the high and low cohorts. Results: Over 10 years, the patients initially in the “high” group maintained FEV1% predicted and FEV1/FVC at values similar to the initial visit (94 to 96% and 87 to 89%, respectively), whereas those in the low group had only slight increases of FEV1% predicted and FEV1/FVC over the same time (77 to 82% and 78 to 82%, respectively). Low FEV1% predicted and FEV1/FVC at the time of the first visit was significantly associated with an increased risk of low values of these lung functions over the next 3‐5 years despite treatment. African American ethnicity and male gender were also associated with lower lung function over time. Conclusion: Early airflow obstruction in inner city children asthma is associated with poor lung function in later life despite guideline-based asthma care. Current asthma therapy may not affect pathways and leads to airway remodeling in children with asthma.

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Effect of deep inspiration avoidance on ventilation heterogeneity and airway responsiveness in healthy adults

Journal of Applied Physiology ◽

10.1152/japplphysiol.00855.2010 ◽

2011 ◽

Vol 110 (5) ◽

pp. 1400-1405 ◽

Cited By ~ 10

Author(s):

David G. Chapman ◽

Norbert Berend ◽

Gregory G. King ◽

Cheryl M. Salome

Keyword(s):

Healthy Subjects ◽

Forced Expiratory Volume ◽

Airway Responsiveness ◽

Deep Inspiration ◽

Airway Closure ◽

Airway Narrowing ◽

Before And After ◽

Ventilation Heterogeneity ◽

Peripheral Airway ◽

Diffusion Convection

The mechanisms by which deep inspiration (DI) avoidance increases airway responsiveness in healthy subjects are not known. DI avoidance does not alter respiratory mechanics directly; however, computational modeling has predicted that DI avoidance would increase baseline ventilation heterogeneity. The aim was to determine if DI avoidance increased baseline ventilation heterogeneity and whether this correlated with the increase in airway responsiveness. Twelve healthy subjects had ventilation heterogeneity measured by multiple-breath nitrogen washout (MBNW) before and after 20 min of DI avoidance. This was followed by another 20-min period of DI avoidance before the inhalation of a single methacholine dose. The protocol was repeated on a separate day with the addition of five DIs at the end of each of the two periods of DI avoidance. Baseline ventilation heterogeneity in convection-dependent and diffusion-convection-dependent airways was calculated from MBNW. The response to methacholine was measured by the percent fall in forced expiratory volume in 1 s/forced vital capacity (FVC) (airway narrowing) and percent fall in FVC (airway closure). DI avoidance increased baseline diffusion-convection-dependent airways ( P = 0.02) but did not affect convection-dependent airways ( P = 0.9). DI avoidance increased both airway closure ( P = 0.002) and airway narrowing ( P = 0.02) during bronchial challenge. The increase in diffusion-convection-dependent airways due to DI avoidance did not correlate with the increase in either airway narrowing ( rs = 0.14) or airway closure ( rs = 0.12). These findings suggest that DI avoidance increases diffusion-convection-dependent ventilation heterogeneity that is not associated with the increase in airway responsiveness. We speculate that DI avoidance reduces surfactant release, which increases peripheral ventilation heterogeneity and also predisposes to peripheral airway closure.

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Reassessment of the interruption technique for measuring flow resistance in humans

Journal of Applied Physiology ◽

10.1152/jappl.1989.67.3.933 ◽

1989 ◽

Vol 67 (3) ◽

pp. 933-937 ◽

Cited By ~ 32

Author(s):

G. Liistro ◽

D. Stanescu ◽

D. Rodenstein ◽

C. Veriter

Keyword(s):

Lung Disease ◽

Healthy Subjects ◽

Obstructive Lung Disease ◽

Airflow Obstruction ◽

Forced Expiratory Volume ◽

Whole Body ◽

Quiet Breathing ◽

Flow Interruption ◽

Whole Body Plethysmography ◽

Closed Airway

We have previously produced evidence that, in patients with obstructive lung disease, compliance of extrathoracic airways is responsible for lack of mouth-to-alveolar pressure equilibration during respiratory efforts against a closed airway. The flow interruption method for measuring respiratory resistance (Rint) is potentially faced with the same problems. We reassessed the merits of the interruption technique by rendering the extrathoracic airways more rigid and by using a rapid shutter. We measured airway resistance (Raw) with whole body plethysmography during panting (at 2 Hz) and Rint during quiet breathing. Rint and Raw were expressed as specific airway (sGaw) and interruptive conductance (sGint), respectively. In nine healthy subjects (cheeks supported), sGint (0.140 +/- 0.050 s-1.cmH2O-1) was lower (P less than 0.02) than sGaw (0.182 +/- 0.043 s-1.cmH2O-1). By contrast, in 12 patients with severe obstructive lung disease (forced expiratory volume in 1 s/vital capacity = 41.0 +/- 19.8%), sGint (0.058 +/- 0.012 s-1.cmH2O-1) was higher (P less than 0.05) than sGaw (0.047 +/- 0.007 s-1.cmH2O-1), when the cheeks were supported. When the mouth floor was also supported, average values of sGaw (0.048 +/- 0.008 s-1.cmH2O-1) and sGint (0.049 +/- 0.014 s-1.cmH2O-1) became similar. In conclusion, we confirm previous findings in healthy subjects of higher values of Rint, with respect to Raw, probably because of differences in glottis opening between quiet breathing and panting. In airflow obstruction, supporting both the cheeks and the mouth floor decreased sGint, which became similar to sGaw.

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Methacholine versus histamine: paradoxical response of spirometry and ventilation distribution

Journal of Applied Physiology ◽

10.1152/jappl.2001.91.6.2587 ◽

2001 ◽

Vol 91 (6) ◽

pp. 2587-2594 ◽

Cited By ~ 11

Author(s):

Sylvia Verbanck ◽

Daniël Schuermans ◽

Marc Noppen ◽

Walter Vincken ◽

Manuel Paiva

Keyword(s):

Dose Group ◽

Normal Subjects ◽

Forced Expiratory Volume ◽

Double Dose ◽

Ventilation Distribution ◽

Paradoxical Response ◽

Airway Narrowing ◽

Equal Dose ◽

Ventilation Heterogeneity ◽

Group A

We investigated the differential effect of histamine and methacholine on spirometry and ventilation distribution (where indexes S cond and S acin represent conductive and acinar ventilation heterogeneity; Verbanck S, Schuermans D, Van Muylem A, Noppen M, Paiva M, and Vincken W. J Appl Physiol 83: 1807–1816, 1997). Thirty normal subjects were challenged with cumulative doses of 6.52 μmol histamine and, on a separate day, with either 6.67 μmol methacholine (equal-dose group; n = 15) or 13.3 μmol methacholine (double-dose group; n = 15). Largest average forced expiratory volume in 1 s (FEV1) decreases or S cond increases obtained in either group were −9% and +286%, respectively; S acin remained unaffected at all times. In the equal-dose group, a smaller FEV1 decline ( P= 0.002) after methacholine was paralleled by a smaller S cond increase ( P = 0.041) than with histamine. However, in the double-dose group, methacholine maintained a smaller FEV1 decline ( P = 0.009) while inducing a larger S cond increase ( P = 0.006) than did histamine. The differential action of histamine and methacholine is confined to the conductive airways, where histamine likely causes the greatest overall airway narrowing and methacholine induces the largest parallel heterogeneity in airway narrowing, probably at the level of the large and small conductive airways, respectively. The observed ventilation heterogeneities predict a risk for dissociation between ventilation-perfusion mismatch and spirometry, particularly after methacholine challenge.

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Breathing during exercise in subjects with mild-to-moderate airflow obstruction: effects of physical training

Journal of Applied Physiology ◽

10.1152/jappl.1999.87.5.1697 ◽

1999 ◽

Vol 87 (5) ◽

pp. 1697-1704 ◽

Cited By ~ 25

Author(s):

Riccardo Pellegrino ◽

Carlo Villosio ◽

Ugo Milanese ◽

Giuseppe Garelli ◽

Joseph R. Rodarte ◽

...

Keyword(s):

Tidal Volume ◽

Physical Training ◽

Airflow Obstruction ◽

Normal Subjects ◽

Cycle Ergometer ◽

Forced Expiratory Volume ◽

Training Period ◽

Breathing Frequency ◽

Work Intensity ◽

Expiratory Flow

In this study we explored the effects of physical training on the response of the respiratory system to exercise. Eight subjects with irreversible mild-to-moderate airflow obstruction [forced expiratory volume in 1 s of 85 ± 14 (SD) % of predicted and ratio of forced expiratory volume in 1 s to forced vital capacity of 68 ± 5%] and six normal subjects with similar anthropometric characteristics underwent a 2-mo physical training period on a cycle ergometer three times a week for 31 min at an intensity of ∼80% of maximum heart rate. At this work intensity, tidal expiratory flow exceeded maximal flow at control functional residual capacity [FRC; expiratory flow limitation (EFL)] in the obstructed but not in the normal subjects. An incremental maximum exercise test was performed on a cycle ergometer before and after training. Training improved exercise capacity in all subjects, as documented by a significant increase in maximum work rate in both groups ( P < 0.001). In the obstructed subjects at the same level of ventilation at high workloads, FRC was greater after than before training, and this was associated with an increase in breathing frequency and a tendency to decrease tidal volume. In contrast, in the normal subjects at the same level of ventilation at high workloads, FRC was lower after than before training, so that tidal volume increased and breathing frequency decreased. These findings suggest that adaptation to breathing under EFL conditions does not occur during exercise in humans, in that obstructed subjects tend to increase FRC during exercise after experiencing EFL during a 2-mo strenuous physical training period.

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Does increased baseline ventilation heterogeneity following chest wall strapping predispose to airway hyperresponsiveness?

Journal of Applied Physiology ◽

10.1152/japplphysiol.01582.2011 ◽

2012 ◽

Vol 113 (1) ◽

pp. 25-30 ◽

Cited By ~ 9

Author(s):

David G. Chapman ◽

Norbert Berend ◽

Karla R. Horlyck ◽

Gregory G. King ◽

Cheryl M. Salome

Keyword(s):

Chest Wall ◽

Airway Hyperresponsiveness ◽

Healthy Subjects ◽

Forced Expiratory Volume ◽

Airway Responsiveness ◽

High Dose ◽

Ventilation Heterogeneity ◽

Similar Disease ◽

Residual Capacity ◽

Diffusion Convection

Baseline ventilation heterogeneity is associated with airway hyperresponsiveness (AHR) in asthma; however, it is unknown whether increased baseline ventilation heterogeneity leads to AHR or both are independent effects of similar disease pathophysiology. Reducing functional residual capacity (FRC) in healthy subjects increases baseline ventilation heterogeneity and airway responsiveness, but the relationship between the two is unclear. The aim was to determine whether an increase in baseline ventilation heterogeneity due to a reduction in FRC correlated with the increase in response to methacholine. In 13 healthy male subjects, ventilation heterogeneity was measured by multiple-breath N2 washout before a cumulative high-dose (0.79–200 μmol) methacholine challenge. On a separate day, the protocol was performed with chest wall strapping (CWS) to reduce FRC. Indexes of ventilation heterogeneity in the convection-dependent (Scond) and diffusion-convection-dependent (Sacin) airways were calculated from the multiple-breath N2 washout. CWS decreased FRC by 15.6 ± 2.7% ( P < 0.0001). CWS increased the percent fall in forced expiratory volume in 1 s during bronchial challenge ( P = 0.006), and the magnitude of this effect was independently determined by the effect of CWS on Sacin and FRC ( radj2 = 0.55, P = 0.02). This suggests that changes in baseline ventilation heterogeneity in healthy subjects are sufficient to increase airway responsiveness, independent of the presence of disease pathology.

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Effect of airways constriction on exhaled nitric oxide

Journal of Applied Physiology ◽

10.1152/japplphysiol.01019.2007 ◽

2008 ◽

Vol 104 (4) ◽

pp. 925-930 ◽

Cited By ~ 30

Author(s):

Sylvia Verbanck ◽

Yannick Kerckx ◽

Daniel Schuermans ◽

Walter Vincken ◽

Manuel Paiva ◽

...

Keyword(s):

Nitric Oxide ◽

Vital Capacity ◽

Normal Subjects ◽

Forced Expiratory Volume ◽

Exhaled Nitric Oxide ◽

Lung Model ◽

Airway Constriction ◽

Exhaled No ◽

Ventilation Heterogeneity ◽

Mechanical Factors

While airway constriction has been shown to affect exhaled nitric oxide (NO), the mechanisms and location of constricted airways most likely to affect exhaled NO remain obscure. We studied the effects of histamine-induced airway constriction and ventilation heterogeneity on exhaled NO at 50 ml/s (FeNO,50) and combined this with model simulations of FeNO,50 changes due to constriction of airways at various depths of the lung model. In 20 normal subjects, histamine induced a 26 ± 15(SD)% FeNO,50 decrease, a 9 ± 6% forced expiratory volume in 1 s (FEV1) decrease, a 19 ± 9% mean forced midexpiratory flow between 25% and 75% forced vital capacity (FEF25–75) decrease, and a 94 ± 119% increase in conductive ventilation heterogeneity. There was a significant correlation of FeNO,50 decrease with FEF25–75 decrease ( P = 0.006) but not with FEV1 decrease or with increased ventilation heterogeneity. Simulations confirmed the negligible effect of ventilation heterogeneity on FeNO,50 and showed that the histamine-induced FeNO,50 decrease was due to constriction, with associated reduction in NO flux, of airways located proximal to generation 15. The model also indicated that the most marked effect of airways constriction on FeNO,50 is situated in generations 10–15 and that airway constriction beyond generation 15 markedly increases FeNO,50 due to interference with the NO backdiffusion effect. These mechanical factors should be considered when interpreting exhaled NO in lung disease.

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Responses of Platelets to Strains of Streptococcus sanguis: Findings in Healthy Subjects, Bernard-Soulier, Glanzmann’s, and Collagen-Unresponsive Patients

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651098 ◽

1987 ◽

Vol 57 (02) ◽

pp. 222-225 ◽

Cited By ~ 19

Author(s):

A H Soberay ◽

M C Herzberg ◽

J D Rudney ◽

H K Nieuwenhuis ◽

J J Sixma ◽

...

Keyword(s):

Platelet Aggregation ◽

Healthy Subjects ◽

Normal Subjects ◽

Membrane Glycoprotein ◽

Response Mechanism ◽

Platelet Response ◽

Induce Platelet Aggregation ◽

Streptococcus Sanguis ◽

Lag Times ◽

Bernard Soulier Syndrome

SummaryThe ability of endocarditis and dental strains of Streptococcus sanguis to induce platelet aggregation in plasma (PRP) from normal subjects were examined and compared to responses of PRP with known platelet membrane glycoprotein (GP) and response defects. S. sanguis strains differed in their ability to induce normal PRPs to aggregate. Strains that induced PRP aggregation in more than 60% of donors were significantly faster agonists (mean lag times to onset of aggregation less than 6 min) than those strains inducing response in PRPs of fewer than 60% of donors.Platelets from patients with Bernard-Soulier syndrome aggregated in response to strains of S. sanguis. In contrast, platelets from patients with Glanzmann’s thrombasthenia and from a patient with a specific defect in response to collagen were unresponsive to S. sanguis. These observations show that GPIb and V are not essential, but GPIIb-IIIa and GPIa are important in the platelet response mechanism to S. sanguis. Indeed, the data suggests that the platelet interaction mechanisms of S. sanguis and collagen may be similar.

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EFFECTS OF INCREASING DOSES OF PYROGLUTAMYL-HISTIDYL-PROLINE AMIDE ON SERUM THYROTROPHIN LEVELS IN NORMAL SUBJECTS

Acta Endocrinologica ◽

10.1530/acta.0.0700196 ◽

1972 ◽

Vol 70 (1) ◽

pp. 196-208 ◽

Cited By ~ 12

Author(s):

Bengt Karlberg ◽

Sven Almqvist

Keyword(s):

Normal Saline ◽

Standard Dose ◽

Normal Subjects ◽

Response Curves ◽

Clinical Observations ◽

Trh Stimulation ◽

Stimulation Tests ◽

Serial Measurements ◽

Serum Tsh ◽

Stimulation Of

ABSTRACT The effects of the administration of normal saline in four normal subjects and the single iv injections of synthetic pyroglutamyl-histidyl-proline amide (TRH) in doses of 6.25, 12.5, 25, 50, 100, 200 and 400 μg in 12 healthy subjects were evaluated by clinical observations and serial measurements from −10 to + 360 minutes of serum TSH, PBI, STH, cholesterol, glucose and insulin. Normal saline and TRH 6.25 μg iv did not change the serum TSH level. The minimum iv dose of TRH increasing serum TSH within 10 minutes was 12.5 μg. Nine of 12 subjects gave maximal increases of serum TSH after TRH 100 μg and all after 200 and 400 μg. The time for the peak response varied with the dose from 15 to 60 minutes. The dose-response curves, average and individual, were complex and not linear. This was interpreted as a varying degree of stimulation of both pituitary synthesis and release of TSH by TRH. PBI changes were measured at 2 h and 6 h. Minimum dose for a significant increase of PBI was 12.5 μg and 6.25 μg of TRH for the respective times. No change in basal STH-levels occurred in 53 of 65 TRH-stimulation tests. Nine of the 12 changes in serum STH occurred in four subjects with varying basal STH-levels. No changes were found in serum cholesterol, glucose or insulin. Our results show that 50 μg of TRH can be used as a standard dose for the single iv stimulation of pituitary release of TSH. TRH stimulated both TSH and STH release in 18% of our tests.

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Ventilation Heterogeneity in Asthma and COPD: The Value of the Poorly Communicating Fraction as the Ratio of Total Lung Capacity to Alveolar Volume

Respiration ◽

10.1159/000513954 ◽

2021 ◽

pp. 1-7

Author(s):

Roberta Pisi ◽

Marina Aiello ◽

Luigino Calzetta ◽

Annalisa Frizzelli ◽

Veronica Alfieri ◽

...

Keyword(s):

Total Lung Capacity ◽

Airflow Obstruction ◽

Diffusing Capacity ◽

Body Plethysmography ◽

Alveolar Volume ◽

Asthmatic Patients ◽

Lung Capacity ◽

Copd Patients ◽

Ventilation Heterogeneity ◽

Patient Groups

Background: The ventilation heterogeneity (VH) is reliably assessed by the multiple-breath nitrogen washout (MBNW), which provides indices of conductive (Scond) and acinar (Sacin) VH as well as the lung clearance index (LCI), an index of global VH. VH can be alternatively measured by the poorly communicating fraction (PCF), that is, the ratio of total lung capacity by body plethysmography to alveolar volume from the single-breath lung diffusing capacity measurement. Objectives: Our objective was to assess VH by PCF and MBNW in patients with asthma and with COPD and to compare PCF and MBNW parameters in both patient groups. Method: We studied 35 asthmatic patients and 45 patients with COPD. Each patient performed spirometry, body plethysmography, diffusing capacity, and MBNW test. Results: Compared to COPD patients, asthmatics showed a significantly lesser degree of airflow obstruction and lung hyperinflation. In asthmatic patients, both PCF and LCI and Sacin values were significantly lower than the corresponding ones of COPD patients. In addition, in both patient groups, PCF showed a positive correlation with LCI (p < 0.05) and Sacin (p < 0.05), but not with Scond. Lastly, COPD patients with PCF >30% were highly likely to have a value ≥2 of the mMRC dyspnea scale. Conclusions: These results showed that PCF, a readily measure derived from routine pulmonary function testing, can provide a comprehensive measure of both global and acinar VH in asthma and in COPD patients and can be considered as a comparable tool to the well-established MBNW technique.

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