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Several experimental studies have found that females have higher particle deposition in the airways than males. This has implications for the delivery of aerosolized therapeutics and for understanding sex differences in respiratory system response to environmental exposures. This study evaluates several factors that potentially contribute to sex differences in particle deposition, using scale-specific structure-function models of one-dimensional (1-D) ventilation distribution, particle transport, and deposition. The impact of gravity, inhalation flow rate, and dead space are evaluated in 12 structure-based models (7 females; 5 males). Females were found to have significantly higher total, bronchial, and alveolar deposition than males across a particle size range from 0.01 to 10 μm. Results suggest that higher deposition fraction in females is due to higher alveolar deposition for smaller particle sizes and higher bronchial deposition for larger particles. Females had higher alveolar deposition in the lower lobes and slightly lower particle concentration in the left upper lobe. Males were found to be more sensitive to changes due to gravity, showing greater reduction in bronchial deposition fraction. Males were also more sensitive to change in inhalation flow rate and to scaling of dead space due to the larger male baseline airway size. Predictions of sex differences in particle deposition—that are consistent with the literature—suggest that sex-based characteristics of lung and airway size interacting with particle size gives rise to differences in regional deposition. NEW & NOTEWORTHY: Sex differences in airway tract particle deposition are analyzed using computational models that account for scale-specific structure and function. We show that sex-related differences in lung and airway size can explain experimental observations of increased deposition fraction in females, with females tending toward enhanced fine particle deposition in the alveolar airways and enhanced bronchial deposition for larger particles. [ABSTRACT FROM AUTHOR]

Ground-level ozone (O3) is a potent air pollutant well recognized to acutely induce adverse respiratory symptoms and impairments in pulmonary function. However, it is unclear how the hyperpnea of exercise may modulate these effects, and the subsequent consequences on exercise performance. We tested the hypothesis that pulmonary function and exercise capability would be diminished, and symptom development would be increased during peak real-world levels of O3 exposure compared with room air. Twenty aerobically trained participants [13 M, 7 F; maximal O2 uptake (V̇ o 2max), 64.1 ± 7.0 mL·kg−1·min−1] completed a three-visit double-blinded, randomized crossover trial. Following a screening visit, participants were exposed to 170 ppb O3 or room air (<10 ppb O3) on separate visits during exercise trials, consisting of a 25-min moderate-intensity warmup, 30-min heavy-intensity bout, and a subsequent time-to-exhaustion (TTE) performance test. No differences in O2 uptake or ventilation were observed during submaximal exercise between conditions. During the TTE test, we observed significantly lower end-exercise O2 uptake (−3.2 ± 4.3%, P = 0.004), minute ventilation (−3.2 ± 6.5%, P = 0.043), tidal volume (−3.6 ± 5.1%, P = 0.008), and a trend toward lower exercise duration in O3 compared with room air (−10.8 ± 26.5%, P = 0.092). As decreases in O2 uptake and alterations in respiratory pattern were also present at matched time segments between conditions, a limitation of oxygen transport seems likely during maximal exercise. A more comprehensive understanding of the direct mechanisms that limit oxygen transport during exercise in high-pollutant concentrations is key for mitigating performance changes. NEW & NOTEWORTHY: We demonstrate that in highly trained endurance athletes, exposure to peak real-world levels of O3 air pollution (170 ppb) significantly diminishes O2 uptake along with corresponding changes in ventilation during maximal exercise. As no differences were observed during extended submaximal exercise, a combined effect of effective dose of pollution and exercise intensity on severity of responses seems likely. [ABSTRACT FROM AUTHOR]

Lung transplantation and lung volume reduction surgery have opened a new therapeutic era for patients with advanced emphysema. In addition to providing impressive clinical benefits, they have helped us better understand how the chest wall and respiratory muscles adapt to chronic hyperinflation. This article reviews the effects of these procedures on respiratory muscle and chest wall function. Inspiratory (including diaphragm) and expiratory muscle strength are often close to normal after unilateral and bilateral transplantation, although some patients have marked weakness. After bilateral transplantation for emphysema, graft volume is normal at full inflation but remains greater than normal at end expiration, which results from structural changes in the chest wall. In contrast, patients with unilateral transplantation have a reduction in graft volume at full inflation. The mediastinum is displaced toward the graft at end expiration, which reduces the surface area of the diaphragm on the transplanted side, and it moves toward the native lung during tidal and full inspiration and toward the graft during tidal and forced expiration. Lung volume reduction produces an increase in contractility, length and surface area of the diaphragm, and increases its contribution to tidal volume; at the same time, neural drive to the muscle and respiratory load are reduced, such that diaphragm neuromechanical coupling is improved. Diaphragm configuration and rib cage dimensions are only minimally affected by the procedure. Single-lung transplantation and lung volume reduction favorably impact on the disadvantageous size interaction by which the lungs are functionally restricted by the chest wall in emphysema. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease with no effective treatment that can reduce mortality or slow the disease progression. COPD is the third leading cause of global death and is characterized by airflow limitations due to chronic bronchitis and alveolar damage/emphysema. Chronic cigarette smoke (CS) exposure damages airway and alveolar epithelium and remains a major risk factor for the pathogenesis of COPD. We found that the expression of caveolin-1, a tumor suppressor protein; p53; and plasminogen activator inhibitor-1 (PAI-1), one of the downstream targets of p53, was markedly increased in airway epithelial cells (AECs) as well as in type II alveolar epithelial (AT2) cells from the lungs of patients with COPD or wild-type mice with CS-induced lung injury (CS-LI). Moreover, p53- and PAI-1-deficient mice resisted CS-LI. Furthermore, treatment of AECs, AT2 cells, or lung tissue slices from patients with COPD or mice with CS-LI with a seven amino acid caveolin-1 scaffolding domain peptide (CSP7) reduced mucus hypersecretion in AECs and improved AT2 cell viability. Notably, induction of PAI-1 expression via increased caveolin-1 and p53 contributed to mucous cell metaplasia and mucus hypersecretion in AECs, and reduced AT2 viability, due to increased senescence and apoptosis, which was abrogated by CSP7. In addition, treatment of wild-type mice having CS-LI with CSP7 by intraperitoneal injection or nebulization via airways attenuated mucus hypersecretion, alveolar injury, and significantly improved lung function. This study validates the potential therapeutic role of CSP7 for treating CS-LI and COPD. NEW & NOTEWORTHY: Chronic cigarette smoke (CS) exposure remains a major risk factor for the pathogenesis of COPD, a debilitating disease with no effective treatment. Increased caveolin-1 mediated induction of p53 and downstream plasminogen activator inhibitor-1 (PAI-1) expression contributes to CS-induced airway mucus hypersecretion and alveolar wall damage. This is reversed by caveolin-1 scaffolding domain peptide (CSP7) in preclinical models, suggesting the therapeutic potential of CSP7 for treating CS-induced lung injury (CS-LI) and COPD. [ABSTRACT FROM AUTHOR]

The lung is extremely sensitive to interstitial fluid balance, yet the role of pulmonary lymphatics in lung fluid homeostasis and its interaction with cardiovascular pressures is poorly understood. In health, there is a fine balance between fluid extravasated from the pulmonary capillaries into the interstitium and the return of fluid to the circulation via the lymphatic vessels. This balance is maintained by an extremely interdependent system governed by pressures in the fluids (air and blood) and tissue (interstitium), lung motion during breathing, and the permeability of the tissues. Chronic elevation in left atrial pressure (LAP) due to left heart disease increases the capillary blood pressure. The consequent fluid accumulation in the delicate lung tissue increases its weight, decreases its compliance, and impairs gas exchange. This interdependent system is difficult, if not impossible, to study experimentally. Computational modeling provides a unique perspective to analyze fluid movement in the cardiopulmonary vasculature in health and disease. We have developed an initial in silico model of pulmonary lymphatic function using an anatomically structured model to represent ventilation and perfusion and underlying biophysical laws governing fluid transfer at the interstitium. This novel model was tested against increased LAP and noncardiogenic effects (increased permeability). The model returned physiologically reasonable values for all applications, predicting pulmonary edema when LAP reached 25 mmHg and with increased permeability. [ABSTRACT FROM AUTHOR]

Biomass fuels (wood) are commonly used indoors in underventilated environments for cooking in the developing world, but the impact on lung physiology is poorly understood. Quantitative computed tomography (qCT) can provide sensitive metrics to compare the lungs of women cooking with wood vs. liquified petroleum gas (LPG). We prospectively assessed (qCT and spirometry) 23 primary female cooks (18 biomass, 5 LPG) with no history of cardiopulmonary disease in Thanjavur, India. CT was obtained at coached total lung capacity (TLC) and residual volume (RV). qCT assessment included texture-derived ground glass opacity [GGO: Adaptive Multiple Feature Method (AMFM)], air-trapping (expiratory voxels ≤ -856HU) and image registration-based assessment [Disease Probability Measure (DPM)] of emphysema, functional small airways disease (%AirTrapDPM), and regional lung mechanics. In addition, within-kitchen exposure assessments included particulate matter <2.5 µm(PM2.5), black carbon, β-(1, 3)-D-glucan (surrogate for fungi), and endotoxin. Air-trapping went undetected at RV via the threshold-based measure (voxels ≤ -856HU), possibly due to density shifts in the presence of inflammation. However, DPM, utilizing image-matching, demonstrated significant air-trapping in biomass vs. LPG cooks (P = 0.049). A subset of biomass cooks (6/18), identified using k-means clustering, had markedly altered DPM-metrics: greater air-trapping (P < 0.001), lower TLC-RV volume change (P < 0.001), a lower mean anisotropic deformation index (ADI; P < 0.001), and elevated % GGO (P < 0.02). Across all subjects, a texture measure of bronchovascular bundles was correlated to the log-transformed β-(1, 3)-D-glucan concentration (P = 0.026, R = 0.46), and black carbon (P = 0.04, R = 0.44). This pilot study identified environmental links with qCT-based lung pathologies and a cluster of biomass cooks (33%) with significant small airways disease. NEW & NOTEWORTHY Quantitative computed tomography has identified a cluster of women (33%) cooking with biomass fuels (wood) with image-based markers of functional small airways disease and associated alterations in regional lung mechanics. Texture and image registration-based metrics of lung function may allow for early detection of potential inflammatory processes that may arise in response to inhaled biomass smoke, and help identify phenotypes of chronic lung disease prevalent in nonsmoking women in the developing world. [ABSTRACT FROM AUTHOR]

Dysanapsis, a mismatch between airway tree caliber and lung size, contributes to a large variation in lung function on spirometry in healthy subjects. However, it remains unclear whether other morphological features of the airway tree could be associated with the variation in lung function independent of dysanapsis. This study used lung cancer screening chest computed tomography (CT) and spirometry data from asymptomatic never smokers. Dysanapsis and the complexity of airway tree geometry were quantified on CT by measuring airway to lung ratio (ALR) and airway fractal dimension (AFD). Moreover, total airway count (TAC), ratio of airway luminal surface area to volume (SA/V), longitudinal tapering and irregularity of the radius of the internal lumen from the central to peripheral airways (Tapering index and Irregularity index) were quantified. In 431 asymptomatic never smokers without a history of lung diseases, lower ALR was associated with lower forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FEV1/FVC). The associations of ALR with AFD and TAC (r = 0.41 and 0.13) were weaker than the association between TAC and AFD (r = 0.64). In multivariable models adjusted for age, sex, height, and mean lung density, lower AFD and TAC were associated with lower FEV1 and FEV1/FVC independent of ALR, whereas SA/V and Tapering index were not. These results suggest that the smaller airway tree relative to a given lung size and the lower complexity of airway tree shape, including lower branch count, are independently associated with lower lung function in healthy subjects. [ABSTRACT FROM AUTHOR]

Dysanapsis, a mismatch between airway tree caliber and lung size, contributes to a large variation in lung function on spirometry in healthy subjects. However, it remains unclear whether other morphological features of the airway tree could be associated with the variation in lung function independent of dysanapsis. This study used lung cancer screening chest computed tomography (CT) and spirometry data from asymptomatic never smokers. Dysanapsis and the complexity of airway tree geometry were quantified on CT by measuring airway to lung ratio (ALR) and airway fractal dimension (AFD). Moreover, total airway count (TAC), ratio of airway luminal surface area to volume (SA/V), longitudinal tapering and irregularity of the radius of the internal lumen from the central to peripheral airways (Tapering index and Irregularity index) were quantified. In 431 asymptomatic never smokers without a history of lung diseases, lower ALR was associated with lower forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FEV1/FVC). The associations of ALR with AFD and TAC (r = 0.41 and 0.13) were weaker than the association between TAC and AFD (r = 0.64). In multivariable models adjusted for age, sex, height, and mean lung density, lower AFD and TAC were associated with lower FEV1 and FEV1/FVC independent of ALR, whereas SA/V and Tapering index were not. These results suggest that the smaller airway tree relative to a given lung size and the lower complexity of airway tree shape, including lower branch count, are independently associated with lower lung function in healthy subjects. [ABSTRACT FROM AUTHOR]

Collaborative teaching strategies such as peer instruction and conventional group work have previously been shown to enhance meaningful learning, but they have not previously been compared. In this present study, we compared the impact of solving quizzes with peer instruction and conventional group work on immediate learning in a laboratory exercise. A total of 186 second- year medical students were randomized to solve two quizzes by either a peer instruction strategy (n = 93) or conventional group work (n = 93) during a mandatory laboratory exercise on respiratory physiology, after which all students completed an individual test. There was no difference in total test scores between groups, but students randomized to peer instruction obtained the highest test scores in solving simple integrated questions. Conversely, students randomized to conventional group work provided the best evaluations of the overall assessment of the laboratory exercise. In conclusion, different collaborative teaching strategies implemented during a laboratory exercise appear to affect immediate learning and student satisfaction differently. [ABSTRACT FROM AUTHOR]

Micro-computed tomography (micro-CT) imaging is an emerging technology with many applications in small animals, for example, the study of pulmonary diseases, although clear guidelines and critical mass of evidence are still missing in the preclinical literature. The neonatal rabbit is a valuable model for studying pulmonary development. However, the longitudinal monitoring of lung function by micro-CT can be challenging. Distinctive datasets corresponding to the end-inspiration and end-expiration phases need to be generated and analyzed to derive lung-functional parameters. The quality of CT scans and the reliability of parameters obtained remain highly dependent on the anesthesia protocol used. Three different anesthetic protocols were tested. The combination of dexmedetomidine 0.25 mg/kg injected intraperitoneally followed by 1% isoflurane was found to facilitate CT imaging at 4 and 11 days after birth. Contrarily, isoflurane and ketamine-xylazine were found unsuitable and thus not investigated further. Total lung volumes significantly increased at day 11 compared with baseline in both respiratory phases, whereas lung tissue remained constant. As expected, functional residual capacity, air-to-tissue ratio, and minute ventilation were significantly increased at day 11 in each animal. Those parameters were correlated with inspiratory capacity, compliance, elastance, and resistance of both respiratory system and tissue component, as measured by flexiVent. Lung development was also evaluated by histomorphometric analyses. In conclusion, we have identified a safe and suitable anesthesia protocol for micro-CT imaging in neonatal rabbits. Moreover, the possibility to longitudinally measure lung function in the same subject dramatically reduced the intraexperimental variability. [ABSTRACT FROM AUTHOR]

We examined the relationship between the work of breathing (Wb) during exercise and in vivo measures of airway size in healthy females and males. We hypothesized that sex differences in airway luminal area would explain the larger resistive Wb during exercise in females. Healthy participants (n = 11 females and n = 11 males; 19-30 yr) completed a cycle exercise test to exhaustion where Wb was assessed using an esophageal balloon catheter. On a separate day, each participant underwent a bronchoscopy procedure for optical coherence tomography measures of seven airways. In vivo measures of luminal area were made for the fourth to eighth airway generations. A composite index of airway size was calculated as the sum of the luminal area for each generation, and the total area was calculated based on Weibel's model. We found that index of airway size (males: 37.4 ± 6.3 mm² vs. females: 27.5 ± 7.4 mm²) and airway area calculated based on Weibel's model (males: 2,274 ± 557 mm² vs. females: 1,594 ± 389 mm²) were significantly larger in males (both P = 0.003). When minute ventilation was greater than -60 L·min-1, the resistive Wb was higher in females. At the highest equivalent flow achieved by all subjects, resistance to inspired flow was larger in females and significantly associated with two measures of airway size in all subjects: index of airway size (r = 0.524, P = 0.012) and Weibel area (r = 0.525, P = 0.012). Our findings suggest that innate sex differences in luminal area result in a greater resistive Wb during exercise in females compared with males. [ABSTRACT FROM AUTHOR]

Three-dimensional imaging is essential to evaluate local abnormalities and understand structure-function relationships in an organ. However, quantifiable and interpretable methods to localize abnormalities remain unestablished. Visual assessments are prone to bias, machine learning methods depend on training images, and the underlying decision principle is usually difficult to interpret. Here, we developed a homological approach to mathematically define emphysema and fibrosis in the lungs on computed tomography (CT). With the use of persistent homology, the density of homological features, including connected components, tunnels, and voids, was extracted from the volumetric CT scans of lung diseases. A pair of CT values at which each homological feature appeared (birth) and disappeared (death) was computed by sweeping the threshold levels from higher to lower CT values. Consequently, fibrosis and emphysema were defined as voxels with dense voids having a longer lifetime (birthdeath difference) and voxels with dense connected components having a lower birth, respectively. In an independent dataset including subjects with idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and combined pulmonary fibrosis and emphysema (CPFE), the proposed definition enabled accurate segmentation with comparable quality to deep learning in terms of Dice coefficients. Persistent homology-defined fibrosis was closely associated with physiological abnormalities such as impaired diffusion capacity and long-term mortality in subjects with IPF and CPFE, and persistent homology-defined emphysema was associated with impaired diffusion capacity in subjects with COPD. The present persistent homology-based evaluation of structural abnormalities could help explore the clinical and physiological impacts of structural changes and morphological mechanisms of disease progression. [ABSTRACT FROM AUTHOR]

We investigated whether dual bronchodilator therapy (glycopyrrolate/formoterol fumarate; GFF; Bevespi Aerosphere) would increase exercise tolerance during a high-intensity constant work rate exercise test (CWRET) and the relative contributions of dead space ventilation (VD/VT) and dynamic hyperinflation (change in inspiratory capacity) to exercise limitation in chronic obstructive pulmonary disease (COPD). In all, 48 patients with COPD (62.9 ± 7.6 yrs; 33 male; GOLD spirometry stage 1/2/3/4, n = 2/35/11/0) performed a randomized, double blind, placebo (PL) controlled, two-period crossover, single-center trial. Gas exchange and inspiratory capacity (IC) were assessed during cycle ergometry at 80% incremental exercise peak work rate. Transcutaneous PCO2 (TcPCO2) measurement was used for VD/VT estimation. Baseline postalbuterol forced expiratory volume in 1 s (FEV1) was 1.86 ± 0.58 L (63.6% ± 13.9 predicted). GFF increased FEV1 by 0.18 ± 0.21 L relative to placebo (PL; P < 0.001). CWRET endurance time was greater after GFF vs. PL (383 ± 184 s vs. 328 ± 115 s; difference 55 ± 125 s; P = 0.013; confidence interval: 20-90 s), a 17% increase. IC on GFF was above placebo IC at all time points and fell less with GFF vs. PL (P ≤ 0.0001). Isotime tidal volume (1.54 ± 0.50 vs. 1.47 ± 0.45 L; P = 0.022) and ventilation (52.9 ± 19.9 vs. 51.0 ± 18.9 L/min; P = 0.011) were greater, and respiratory rate was unchanged (34.9 ± 9.2 vs. 35.1 ± 8.0 br/min, P = 0.865). Isotime VD/VT did not differ between groups (GFF 0.28 ± 0.08 vs. PL 0.27 ± 0.09; P = 0.926). GFF increased exercise tolerance in patients with COPD, and the increase was accompanied by attenuated dynamic hyperinflation without altering VD/VT. NEW & NOTEWORTHY This study was a randomized clinical trial (NCT03081156) that collected detailed physiology data to investigate the effect of dual bronchodilator therapy on exercise tolerance in COPD, and additionally to determine the relative contributions of changes in dead space ventilation (VD/VT) and dynamic hyperinflation to alterations in exercise limitation. We utilized a unique noninvasive method to assess VD/VT (transcutaneous carbon dioxide, TcPCO2) and found that dual bronchodilators yielded a moderate improvement in exercise tolerance. Importantly, attenuation of dynamic hyperinflation rather than change in dead space ventilation was the most important contributor to exercise tolerance improvement. [ABSTRACT FROM AUTHOR]

Bronchial thermoplasty (BT) is a treatment for moderate-to-severe asthma, which generally improves quality-of-life scores but not conventional measures of lung function. Newer methodologies have begun to demonstrate the underlying physiological changes and elucidate the mechanism of action. We postulated that systematic, computed tomography (CT)-based assessment of the response of individual airways to BT is feasible, and our aim was to determine the distribution of these responses and the relationship with airway size. Twenty patients meeting the European Respiratory Society/American Thoracic Society (ERS/ATS) definition of severe asthma underwent BT and assessment including CT, Asthma Control Questionnaire (ACQ), and spirometry. Treatment was structured so that the left and right lungs are treated sequentially with a midtreatment assessment providing an internal control. Pairs of CT scans were analyzed using a new semiautomatic processing algorithm that matched individual segmented airways for quantitative comparison. Cross-sectional airway lumen area from matched airway pairs in treated lungs increased on average by 6.4% after BT (P < 0.02) but showed no change in the untreated lung. Matched airway length was also unchanged. Breakdown by airway size showed amplified response in more distal airways, with the smallest quintile of measured airways dilating by 13.2% (P < 0.001). ACQ improved from 3.5 ± 0.9 to 1.9 ± 1.2 (P < 0.001). These data show that the response to BT in individual airways can be assessed by CT and that dilation is heterogeneous and predominant in distal compared with proximal airways. A CT-based approach may further our understanding of the physiological changes in BT and aid in the development of refined and personalized versions of the therapy. NEW & NOTEWORTHY CT scanning was used to evaluate the response of individual airways in patients undergoing bronchial thermoplasty. Airways dilated after treatment by 6.4% on average with substantial heterogeneity and a greater response in the most distal airways measured. [ABSTRACT FROM AUTHOR]

Smoking-induced ventilation heterogeneity measured at the mouth via established washout indices [lung clearance index (LCI) and alveolar mixing efficiency (AME)] potentially results from unequal expansion, which can be quantified by computer tomography (CT), and structural changes down to the lung periphery, characterized by CT parametric response mapping indices [percentage of lung affected by functional small airway disease (PRMfSAD) and emphysema (PRMEmph)]. By combining CT imaging and nitrogen (N2) washout tests in smokers, we specifically examined the roles of unequal lung expansion and peripheral structure. We first extracted three-dimensional maps of local lung expansion from registered inspiratory/expiratory CT images in 50 smokers (GOLD 0-IV) to compute for each smoker the theoretical N2 washout concentration curve solely attributable to unequal local expansion. By a head-on comparison with washout N2 concentrations measured at the mouth in the same smokers supine, we observed that 1) LCI increased from 4.8 ± 0.2 (SD) to 6.6 ± 0.8 (SD) due to unequal lung expansion alone and further increased to 9.0 ± 1.5 (SD) independent of local expansion and 2) AME decreased (from 100% by definition) to 95 ± 2 (SD)% due to unequal expansion alone and further decreased to 75 ± 7(SD)% independent of local expansion. In a multiple regression between the washout indices and CT-derived PRMfSAD and PRMEmph, LCI was related to PRMfSAD (r = +0.58; P < 0.001), whereas AME was related to both PRMfSAD (rpartial = −0.44; P = 0.002) and PRMEmph (rpartial = −0.31; P = 0.033), in line with AME being dominated by alterations in peripheral structure. We conclude that smokers showing an increased LCI without corresponding AME decrease are predominantly affected by unequal lung expansion, whereas an AME decrease with a commensurate LCI increase indicates a smoking-induced alteration of peripheral structure. NEW & NOTEWORTHY A head-on comparison between imaging and multiple breath washout in supine smokers shows that computer tomography-measured unequal local lung expansion accounts for 50% or less of smoking-induced increase in ventilation heterogeneity. The contributions from unequal lung expansion and peripheral structure to the two main washout indices also explain their respective association with parametric response mapping indices. [ABSTRACT FROM AUTHOR]

Structural changes to airway morphology, such as increased bronchial wall thickness (BWT) and airway wall area, are cardinal features of chronic obstructive pulmonary disease (COPD). Ferrets are a recently established animal model uniquely exhibiting similar clinical and pathological characteristics of COPD as humans, including chronic bronchitis. Our objective was to develop a microcomputed tomography (-CT) method for evaluating structural changes to the airways in ferrets and assess whether the effects of smoking induce changes consistent with chronic bronchitis in humans. Ferrets were exposed to mainstream cigarette smoke or air control twice daily for 6 mo. μCT was conducted in vivo at 6 mo; a longitudinal cohort was imaged monthly. Manual measurements of BWT, luminal diameter (LD), and BWT-to-LD ratio (BWT/LD) were conducted and confirmed by a semiautomated algorithm. The square root of bronchial wall area (-WA) versus luminal perimeter was determined on an individual ferret basis. Smoke-exposed ferrets reproducibly demonstrated 34% increased BWT (P < 0.001) along with increased LD and BWT/LD versus air controls. Regression indicated that the effect of smoking on BWT persisted despite controlling for covariates. Semiautomated measurements replicated findings. ✓WA for the theoretical median airway luminal perimeter of 4 mm (Pi4) was elevated 4.4% in smoke-exposed ferrets (P = 0.015). Increased BWT and Pi4 developed steadily over time. &#956'CT-based airway measurements in ferrets are feasible and reproducible. Smokeexposed ferrets develop increased BWT and Pi4, changes similar to humans with chronic bronchitis. μCT can be used as a significant translational platform to measure dynamic airway morphological changes. [ABSTRACT FROM AUTHOR]

Parametric response mapping (PRM) is a computed tomography (CT)-based method to phenotype patients with chronic obstructive pulmonary disease (COPD). It is capable of differentiating emphysema-related air trapping with nonemphysematous air trapping (small airway disease), which helps to identify the extent and localization of the disease. Most studies evaluating the gene expression in smokers and COPD patients related this to spirometric measurements, but none have investigated the relationship with CT-based measurements of lung structure. The current study aimed to examine gene expression profiles of brushed bronchial epithelial cells in association with the PRM-defined CT-based measurements of emphysema (PRMEmph) and small airway disease (PRMfSAD). Using the Top Institute Pharma (TIP) study cohort (COPD = 12 and asymptomatic smokers = 32), we identified a gene expression signature of bronchial brushings, which was associated with PRMEmph in the lungs. One hundred thirty-three genes were identified to be associated with PRMEmph. Among the most significantly associated genes, CXCL11 is a potent chemokine involved with CD8+ T cell activation during inflammation in COPD, indicating that it may play an essential role in the development of emphysema. The PRMEmph signature was then replicated in two independent data sets. Pathway analysis showed that the PRMEmph signature is associated with proinflammatory and notch signaling pathways. Together these findings indicate that airway epithelium may play a role in the development of emphysema and/or may act as a biomarker for the presence of emphysema. In contrast, its role in relation to functional small airways disease is less clear. [ABSTRACT FROM AUTHOR]

Alcohol breath test (ABT) measurements are sensitive to the volume of the exhaled breath. Although a minimum breath volume is required for a legally acceptable sample, any additional increase in the volume of exhaled air increases the measurement of breath alcohol concentration (BrAC). Using a sample of 115 ABTs collected by police agencies for evidentiary purposes, we studied the influence of exhaled air volume on the measurement of BrAC. The 115 ABTs were performed on 30 different Alcotest 9510s. Each of the tests included paired, time series measurements of exhaled breath flow rates and breath alcohol content. The exhalation flow rates and exhalation times were used to create exhalation volume-BrAC plots. On average, exhaled air volumes were ~50% of the subjects' age-, height-, race-, and sex-predicted vital capacities (VC). More than 80% of the samples had exhaled air volumes ranging between 30 and 70% of the subject's predicted VC. Breath volumes for duplicate breath samples were similar. For all breath samples, BrAC increased with exhalation volume, an expected behavior for any very high blood solubility compound such as alcohol. Beyond the legally accepted minimum expiratory volume, BrAC increased, on average, at a rate of 9.2 ± 2.8%/liter air exhaled. As a result, a person who exhales just beyond the minimum volume will have a lower BrAC compared with a person who exhales a full VC. Exhaled volume materially impacts the measurement of an ABT. NEW & NOTEWORTHY Subjects who provide breath samples for evidentiary alcohol breath tests exhale, on average, about half of their predicted vital capacity. Because breath alcohol concentration increases with greater exhaled air volume, subjects who exhale more than average volume will have a greater breath alcohol concentration, whereas subjects who exhale less than average volume will have a lesser breath alcohol concentration. A quantification of air volume impact on breath alcohol concentration is provided. [ABSTRACT FROM AUTHOR]

Air trapping due to airway closure has been associated with unstable asthma. In addition to airway closure that occurs at lower lung volumes during slow expiration, there may be further closure during a forced expiration because of airway compression. The purpose of this study was to define a reference range from a nonasthmatic population and investigate the characteristics of compressive air trapping in asthma. Spirometry and plethysmography were performed in 117 nonasthmatic subjects (ages 18-87 yr) and 153 asthma subjects (ages 12-72 yr). Air trapping was assessed as residual lung volume and the ratio of forced expiratory vital capacity (FVC) to slow inspiratory vital capacity (iVC) (FVC/iVC). There were no significant age or sex effects on the FVC/iVC ratio in the nonasthmatic subjects, and a fifth percentile lower limit of normal (LLN) of 0.93 was computed. An FVC/iVC ratio less than LLN defined compressive air trapping. Asthma subjects exhibited an age-related decline in the FVC/iVC ratio of 0.0027 per year (P ± 0.0001) in a mixed effects model, with additional decreases associated with severe asthma and male sex. FVC/iVC ratios± LLN were infrequent in subjects ±30 yr but evident in most asthma subjects =50 yr. Lung residual volumes followed similar patterns of greater elevations in subjects with severe asthma, older age, and male sex. Compressive air trapping occurs frequently in older asthmatics, appearing to be a feature of the natural history of asthma that is greater in severe asthma and men. This component of premature airway closure affects spirometric assessment of airway function and may contribute to asthma symptoms during physical exertion. [ABSTRACT FROM AUTHOR]

To longitudinally monitor progressive fibrosis in the transforming growth factor-α (TGF-α) transgenic mouse model of lung fibrosis, we used retrospective self-gating ultrashort echo time (UTE) magnetic resonance imaging (MRI) to image mouse lung at baseline and after 4 and 8 wk of fibrosis initiation via doxycycline administration. Only bitransgenic mice were used in this study and divided into two cohorts: six mice were fed doxycycline food to induce lung fibrosis (referred to as Dox cohort), and five other mice were fed normal food (referred to as control cohort). Lung mechanics, histology, and hydroxyproline were assessed after the final MRI. A linear mixed-effects model was used to analyze MRI-derived longitudinal lung-function parameters. Tidal volume decreased at a rate of −0.016 ± 0.002 ml/week [χ2(1) = 16.48, P < 0.001] for Dox cohort and increased at a rate of 0.010 ± 0.003 ml/week [χ2(1) = 6.37, P = 0.01] for control cohort. Minute ventilation decreased at a rate of −1.71 ± 0.26 ml·min-1·wk-1 [χ2(1) = 14.04, P < 0.001] for Dox cohort but did not change significantly over time for control cohort. High-density lung volume percentage increased at a rate of 3.9 ± 0.7%/wk for Dox cohort [χ2(1) = 11.47, P < 0.001] but did not change significantly over time for control cohort. MRI-derived lung structure and function parameters were strongly correlated with pleural thickness, hydroxyproline content, lung compliance, airway resistance, and airway elastance. We conclude that self-gating UTE MRI could be used to longitudinally monitor lung fibrosis in the TGF-α transgenic mouse model. NEW & NOTEWORTHY Self-gating UTE MRI was used to monitor morphology and physiology in lung fibrosis in a transforming growth factor-α transgenic mouse model. Tidal volume was shown for the first time to correlate strongly with conventional metrics of fibrosis such as hydroxyproline and pleural thickness. [ABSTRACT FROM AUTHOR]

The accurate representation of the human airway anatomy is crucial for understanding and modeling the structure-function relationship in both healthy and diseased lungs. The present knowledge in this area is based on morphometric studies of excised lung casts, partially complemented by in vivo studies in which computed tomography (CT) was used on a small number of subjects. In the present study, we analyzed CT scans of a cohort of healthy subjects and obtained comprehensive morphometric information down to the seventh generation of bronchial branching, including airway diameter, length, branching angle, and rotation angle. Although some of the geometric parameters (such as the child-to-parent branch diameter ratio) are found to be in line with accepted values, for others (such as the branch length-to-diameter ratio) our findings challenge the common assumptions. We also evaluated several metrics of self-similarity, including the fractal dimension of the airway tree. Additionally, we used phase-contrast magnetic resonance imaging (MRI) to obtain the volumetric flow field in the three-dimensional-printed airway model of one of the subjects during steady inhalation. This is used to relate structural and functional parameters and, in particular, to close the power-law relationship between branch flow rate and diameter. The diameter exponent is found to be significantly lower than in the usually assumed Poiseuille regime, which we attribute to the strong secondary (i.e., transverse) velocity component. The strength of the secondary velocity with respect to the axial component exceeds the levels found in idealized airway models and persists within the first seven generations. NEW & NOTEWORTHY We performed a comprehensive computed tomography-based study of the conductive airway morphology in normal human subjects, including branch diameter, length, and mutual angles. We found significant departure from classic homothetic relationships. We also carried out MRI measurements of the three-dimensional inspiratory flow in an anatomy-based model and directly assessed structure-function relationships that have so far been assumed. We found that strong secondary flows (i.e., transverse velocity components) persist through the first seven generations of bronchial branching. [ABSTRACT FROM AUTHOR]

Small airways represent the key factor of chronic obstructive pulmonary disease (COPD) pathophysiology. The effect of different classes of bronchodilators on small airways is still poorly understood and difficult to assess. Hence the acute effects of tiotropium (18 µg) and indacaterol (150 µg) on closing volume (CV) and ventilation inhomogeneity were investigated and compared in 51 stable patients (aged 70 ± 7 yr, mean ± SD; 82% men) with moderate to very severe COPD. Patients underwent body plethysmography, arterial blood gas analysis, tidal expiratory flow limitation (EFL), dyspnea assessment, and simultaneous recording of single-breath N2 test and transpulmonary pressure-volume curve (PL-V), before and 1 h after drug administration. The effects produced by indacaterol on each variable did not differ from those caused by tiotropium, independent of the severity of disease, assessed according to the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) scale and the presence of EFL. Bronchodilators significantly decreased the slope of phase III and CV (-5 ± 4 and -2.5 ± 2.1%, respectively, both P < 0.001), with an increase in both slope and height of phase IV and of the anatomical dead space. Arterial oxygen pressure and saturation significantly improved (3 ± 3 mmHg and 2 ± 2%, respectively, both P < 0.001); their changes negatively correlated with those of phase III slope (r = -0.659 and r = -0.454, respectively, both P < 0.01). The vital capacity (VC) increased substantially, but the PL-V/VC curve above CV was unaffected. In conclusion, bronchodilators reduce the heterogeneity of peripheral airway mechanical properties and the extent of their closure, with minor effects on critical closing pressure. This should lessen the risk of small-airway damage and positively affect gas exchange. NEW & NOTEWORTHY This is the first study investigating in stable chronic obstructive pulmonary disease patients the acute effects of two long-acting bronchodilators, a β-agonist and a muscarinic antagonist, on peripheral airways using simultaneous lung pressure-volume curve and single-breath N2 test. By lessening airway mechanical property heterogeneity, both drugs similarly reduced ventilation inhomogeneity and extent of small-airway closure, as indicated by the decrease of phase III slope, increased oxygen saturation, and fall of closing volume, often below expiratory reserve volume. [ABSTRACT FROM AUTHOR]

The hypothesis that the small conducting airways were the major site of obstruction to airflow in normal lungs was introduced by Rohrer in 1915 and prevailed until Weibel introduced a quantitative method of studying lung anatomy in 1963. Green repeated Rohrer's calculations using Weibels new data in 1965 and found that the smaller conducting airways offered very little resistance to airflow. This conflict was resolved by seminal experiments conducted by Macklem and Mead in 1967, which confirmed that a small proportion of the total lower airways resistance is attributable to small airways<2mmin diameter. Shortly thereafter, Hogg, Macklem, and Thurlbeck used this technique to show that small airways become the major site of obstruction in lungs affected by emphysema. These and other observations led Mead to write a seminal editorial in 1970 that postulated the small airways are a silent zone within normal lungs where disease can accumulate over many years without being noticed. This review provides a progress report since the 1970s on methods for detecting chronic obstructive pulmonary disease, the structural nature of small airways' disease, and the cellular and molecular mechanisms that are thought to underlie its pathogenesis. [ABSTRACT FROM AUTHOR]

The alcohol breath test is reviewed with a focus on gas exchange factors affecting its accuracy. The basis of the alcohol breath test is the assumption that alveolar air reaches the mouth during exhalation with no change in alcohol concentration. Recent investigations have shown that alcohol concentration is altered during its transit to the mouth. The exhaled alcohol concentration is modified by interaction with the mucosa of the pulmonary airways. Exhaled alcohol concentration is not an accurate indicator of alveolar alcohol concentration. Measuring alcohol concentration in the breath is very different Downloaded from process than measuring a blood level from air equilibrated with a blood sample. Airway exchange of alcohol leads to a bias against certain individuals depending on the anatomic and physiologic characteristics. Methodological modifications are proposed to improve the accuracy of the alcohol breath test to become fair to all. [ABSTRACT FROM AUTHOR]

Aeroatelectasis has developed in aircrew flying routine peacetime flights on the latest generation high-performance aircraft, when undergoing excessive oxygen supply. To single out the effects of hyperoxia and hypergravity on lung tissue compression, and on ventilation and perfusion, eight subjects were studied before and after 1 h 15 min exposure to +1 to +3.5 Gz in a human centrifuge. They performed the protocol three times, breathing air, 44.5% O2, or 100% O2 and underwent functional and topographical imaging of the whole lung by ultrasound and single-photon emission computed tomography combined with computed tomography (SPECT/CT). Ultrasound lung comets (ULC) and atelectasis both increased after exposure. The number of ULC was <1 pre protocol (i.e., normal lung) and larger post 100% O2 (22 ± 3, mean ± SD) than in all other conditions (P < 0.001). Post 44.5% O2 differed from air (P < 0.05). Seven subjects showed low- to mediumgrade atelectasis post 100% O2. There was an effect on grade of gas mixture and hypergravity, with interaction (P < 0.001, respectively); 100% O2, 44.5% O2, and air differed from each other (P < 0.05). SPECT ventilation and perfusion were always normal. Ultrasound concurred with CT in showing normal lung in the upper third and ULC/atelectasis in posterior and inferior areas, not for other localizations. In conclusion, hyperoxia and hypergravity are independent risk factors of reversible atelectasis formation. Ultrasound is a useful screening tool. Together with electrical impedance tomography measurements (reported separately), these findings show that zones with decreased ventilation prone to transient airway closure are present above atelectatic areas. [ABSTRACT FROM AUTHOR]

One of the most effective ways of engaging students of physiology and medicine is through laboratory demonstrations and case studies that combine 1) the use of equipment, 2) problem solving, 3) visual representations, and 4) manipulation and interpretation of data. Depending on the measurements made and the type of test, laboratory demonstrations have the added benefit of being able to show multiple organ system integration. Many research techniques can also serve as effective demonstrations of integrative human physiology. The "Duffin" hyperoxic rebreathing test is often used in research settings as a test of central respiratory chemosensitivity and cerebrovascular reactivity to CO2. We aimed to demonstrate the utility of the hyperoxic rebreathing test for both respiratory and cerebrovascular responses to increases in CO2 and illustrate the integration of the respiratory and cerebrovascular systems. In the present article, methods such as spirometry, respiratory gas analysis, and transcranial Doppler ultrasound are described, and raw data traces can be adopted for discussion in a tutorial setting. If educators have these instruments available, instructions on how to carry out the test are provided so students can collect their own data. In either case, data analysis and quantification are discussed, including principles of linear regression, calculation of slope, the coefficient of determination (R2), and differences between plotting absolute versus normalized data. Using the hyperoxic rebreathing test as a demonstration of the complex interaction and integration between the respiratory and cerebrovascular systems provides senior undergraduate, graduate, and medical students with an advanced understanding of the integrative nature of human physiology. [ABSTRACT FROM AUTHOR]

This study aims to assess regional ventilation, nonlinearity, and hysteresis of human lungs during dynamic breathing via image registration of four-dimensional computed tomography (4D-CT) scans. Six healthy adult humans were studied by spiral multidetector-row CT during controlled tidal breathing as well as during total lung capacity and functional residual capacity breath holds. Static images were utilized to contrast static vs. dynamic (deep vs. tidal) breathing. A rolling-seal piston system was employed to maintain consistent tidal breathing during 4D-CT spiral image acquisition, providing required between-breath consistency for physiologically meaningful reconstructed respiratory motion. Registration- derived variables including local air volume and anisotropic deformation index (ADI, an indicator of preferential deformation in response to local force) were employed to assess regional ventilation and lung deformation. Lobar distributions of air volume change during tidal breathing were correlated with those of deep breathing (R2 ≈ 0.84). Small discrepancies between tidal and deep breathing were shown to be likely due to different distributions of air volume change in the left and the right lungs. We also demonstrated an asymmetric characteristic of flow rate between inhalation and exhalation. With ADI, we were able to quantify nonlinearity and hysteresis of lung deformation that can only be captured in dynamic images. Nonlinearity quantified by ADI is greater during inhalation, and it is stronger in the lower lobes (P < 0.05). Lung hysteresis estimated by the difference of ADI between inhalation and exhalation is more significant in the right lungs than that in the left lungs. [ABSTRACT FROM AUTHOR]

The physiology of breath holding is complex, and voluntary breath-hold duration is affected by many factors, including practice, psychology, respiratory chemoreflexes, and lung stretch. In this activity, we outline a number of simple laboratory activities or classroom demonstrations that illustrate the complexity of the integrative physiology behind breath-hold duration. These activities require minimal equipment and are easily adapted to small-group demonstrations or a larger-group inquiry format where students can design a protocol and collect and analyze data from their classmates. Specifically, breath-hold duration is measured during a number of maneuvers, including after end expiration, end inspiration, voluntary prior hyperventilation, and inspired hyperoxia. Further activities illustrate the potential contribution of chemoreflexes through rebreathing and repeated rebreathing after a maximum breath hold. The outcome measures resulting from each intervention are easily visualized and plotted and can comprise a comprehensive data set to illustrate and discuss complex and integrated cardiorespiratory physiology. [ABSTRACT FROM AUTHOR]

Cessation of blood flow represents a physical event that is sensed by the pulmonary endothelium leading to a signaling cascade that has been termed "mechanotransduction." This paradigm has clinical relevance for conditions such as pulmonary embolism, lung bypass surgery, and organ procurement and storage during lung transplantation. On the basis of our findings with stop of flow, we postulate that normal blood flow is "sensed" by the endothelium by virtue of its location at the interface of the blood and vessel wall and that this signal is necessary to maintain the endothelial cell membrane potential. Stop of flow is sensed by a "mechanosome" consisting of PECAM-VEGF receptor-VE cadherin that is located in the endothelial cell caveolae. Activation of the mechanosome results in endothelial cell membrane depolarization that in turn leads to activation of NADPH oxidase (NOX2) to generate reactive oxygen species (ROS). Endothelial depolarization additionally results in opening of T-type voltage-gated Ca2+channels, increased intracellular Ca2+, and activation of nitric oxide (NO) synthase with resultant generation of NO. Increased NO causes vasodilatation whereas ROS provide a signal for neovascularization; however, with lung transplantation overproduction of ROS and NO can cause oxidative injury and/or activation of proteins that drive inflammation and cell death. Understanding the key events in the mechanosignaling cascade has important lessons for the design of strategies or interventions that may reduce injury during storage of donor lungs with the goal to increase the availability of lungs suitable for donation and thus improving access to lung transplantation. [ABSTRACT FROM AUTHOR]

Hyperpolarized 3He MRI previously revealed spatially persistent ventilation defects in healthy, older compared with healthy, younger never-smokers. To understand better the physiological consequences and potential relevance of 3He MRI ventilation defects, we evaluated 3He-MRI ventilation-defect percent (VDP) and the effect of deep inspiration (DI) and salbutamol on VDP in older never-smokers. To identify the potential determinants of ventilation defects in these subjects, we evaluated dyspnea, pulmonary function, and cardiopulmonary exercise test (CPET) measurements, as well as occupational and second-hand smoke exposure. Fifty-two never-smokers (71 ± 6 yr) with no history of chronic respiratory disease were evaluated. During a single visit, pulmonary function tests, CPET, and 3He MRI were performed and the Burden of Obstructive Lung Disease questionnaire administered. For eight of 52 subjects, there was spirometry evidence of airflow limitation (Global Initiative for Chronic Obstructive Lung Disease-Unclassified, I, and II), and occupational exposure was reported in 13 of 52 subjects. In 13 of 52 (25%) subjects, there were no ventilation defects and in 39 of 52 (75%) subjects, ventilation defects were observed. For those subjects with ventilation defects, six of 39 showed a VDP response to DI/salbutamol. Ventilation heterogeneity and VDP were significantly greater, and forced expiratory volume in 1 s (FEV1)/forced vital capacity was significantly lower (P < 0.05) for subjects with ventilation defects with a response to DI/salbutamol than subjects with ventilation defects without a response to DI/salbutamol and subjects without ventilation defects. In a step-wise, forward multivariate model, FEV1, inspiratory capacity, and airway resistance significantly predicted VDP (R2 = 0.45, P < 0.001). In conclusion, most never-smokers had normal spirometry and peripheral ventilation defects not reversed by DI/salbutamol; such ventilation defects were likely related to irreversible airway narrowing/ collapse but not to dyspnea and decreased exercise capacity. [ABSTRACT FROM AUTHOR]

Maintenance of upright posture involves complex neuromotor processes that include control of thoracic and abdominal pressures. Control of airflow by glottal structures is a primary determinant of thoracic pressure and may have a role in control of postural stability. This study aimed to investigate the effect of modulation of airway control on upright postural stability during postural perturbations. Standing balance was gently perturbed in the sagittal plane during 7 breathing/voicing tasks that ranged from completely closed (breath-hold), to partially opened (voicing) or completely open (sigh) glottal conditions in 11 healthy adults. Dependent measures were peak amplitude of displacement of the thorax and center of pressure (CoP). When the glottis was completely open during sigh, thoracic displacement in response to the perturbation was greater than in all other conditions, regardless of direction of perturbation (post hoc, all P < 0.002). The absolute amplitude of CoP displacement was greater with backward perturbation (main effect, Direction P = 0.001) and was greater at both extremes of glottal modulation (glottis closed and completely open) than when the glottis was partially opened during counting out loud (post hoc, all P < 0.04). These results show that airway modulation affects postural control during upright perturbations. The thorax was more stable when the glottis was engaged than when it was required to remain open, whereas control of CoP displacement appeared more optimal during the natural dynamic mid-range airway modulation of voicing. These data suggest that glottal control influences balance, and that glottal control strategies may be an important consideration for patients with breathing and/or balance disorders. [ABSTRACT FROM AUTHOR]

Some pilots flying modern high-performance fighter aircraft develop "hypoxia-like" incidents characterized by short periods of confusion and cognitive impairment. The problem is serious and recently led to the grounding of a fleet of aircraft. Extensive discussions of the incidents have taken place but some people believe that there is inadequate data to determine the cause. There is a tremendous disconnect between what is known about the function of the aircraft and the function of the pilot. This paper describes a plan for measuring the inspired and expired PO2 and PCO2 in the pilot's mask, the inspiratory flow rate, and pressure in the mask. A critically important requirement is that the interference with the function of the pilot is minimal. Although extensive physiological measurements were previously made on pilots in ground-based experiments such as rapid decompression in an altitude chamber and increased acceleration on a centrifuge, in-flight measurements of gas exchange have not been possible until now primarily because of the lack of suitable equipment. The present paper shows how the recent availability of small, rapidly responding oxygen and carbon dioxide analyzers make sophisticated in-flight measurements feasible. The added information has the potential of greatly improving our knowledge of pilot physiology, which could lead to an explanation for the incidents. [ABSTRACT FROM AUTHOR]

Excessive apoptosis and prolonged inflammation of alveolar cells are associated with the pathogenesis of pulmonary emphysema. We aimed to determine whether CD40 affects alveolar epithelial cells and endothelial cells, with regard to evoking apoptosis and inflammation. Mice were repeatedly treated with agonistic-anti CD40 antibody (Ab), with or without agonistic-anti Fas Ab, and evaluated for apoptosis and inflammation in lungs. Human pulmonary microvascular endothelial cells and alveolar epithelial cells were treated with agonistic anti- CD40 Ab and/or anti-Fas Ab to see their direct effect on apoptosis and secretion of proinflammatory molecules in vitro. Furthermore, plasma soluble CD40 ligand (sCD40L) level was evaluated in patients with chronic obstructive pulmonary disease (COPD). In mice, inhaling agonistic anti-CD40 Ab induced moderate alveolar enlargement. CD40 stimulation, in combination with anti-Fas Ab, induced significant emphysematous changes and increased alveolar cell apoptosis. CD40 stimulation also enhanced IFN-γ-mediated emphysematous changes, not via apoptosis induction, but via inflammation with lymphocyte accumulation. In vitro, Fas-mediated apoptosis was enhanced by CD40 stimulation and IFN-γ in endothelial cells and by CD40 stimulation in epithelial cells. CD40 stimulation induced secretion of CCR5 ligands in endothelial cells, enhanced with IFN-γ. Plasma sCD40L levels were significantly increased in patients with COPD, inversely correlating to the percentage of forced expiratory volume in 1 s and positively correlating to low attenuation area score by CT scan, regardless of smoking history. Collectively CD40 plays a contributing role in the development of pulmonary emphysema by sensitizing Fas-mediated apoptosis in alveolar cells and increasing the secretion of proinflammatory chemokines. [ABSTRACT FROM AUTHOR]

Restriction of total lung capacity (TLC) is found in some obese subjects, but the mechanism is unclear. Two hypotheses are as follows: 1) increased abdominal volume prevents full descent of the diaphragm; and 2) increased intrathoracic fat reduces space for full lung expansion. We have measured total intrathoracic volume at full inflation using magnetic resonance imaging (MRI) in 14 asymptimatic obese men [mean age 52 yr, body mass index (BMI) 35-45 kg/m²] and 7 control men (mean age 50 yr, BMI 22-27 kg/m²). MRI volumes were compared with gas volumes at TLC. All measurements were made with subjects supine. Obese men had smaller functional residual capacity (FRC) and FRC-to-TLC ratio than control men. There was a 12% predicted difference in mean TLC between obese (84% predicted) and control men (96% predicted). In contrast, differences in total intrathoracic volume (MRI) at full inflation were only 4% predicted TLC (obese 116% predicted TLC, control 120% predicted TLC), because mediastinal volume was larger in obese than in control [heart and major vessels (obese 1.10 liter, control 0.87 liter, P = 0.016) and intrathoracic fat (obese 0.68 liter, control 0.23 liter, P < 0.0001)]. As a consequence of increased mediastinal volume, intrathoracic volume at FRC in obese men was considerably larger than indicated by the gas volume at FRC. The difference in gas volume at TLC between the six obese men with restriction. TLC < 80% predicted (OR), and the eight obese men with TLC > 80% predicted (ON) was 26% predicted TLC. Mediastinal volume was similar in OR (1.84 liter) and ON (1.73 liter), but total intrathoracic volume was 19% predicted TLC smaller in OR than in ON. We conclude that the major factor restricting TLC in some obese men was reduced thoracic expansion at full inflation. [ABSTRACT FROM AUTHOR]

Peribronchial edema has been proposed as a mechanism enhancing airway responses to constrictor stimuli. Acute exposure to altitude in nonacclimatized lowlanders leads to subclinical interstitial pulmonary edema that lasts for several days after ascent, as suggested by changes in lung mechanics. We, therefore, investigated whether changes in lung mechanics consistent with fluid accumulation at high altitude within the lungs are associated with changes in airway responses to methacholine or exercise. Fourteen healthy subjects were studied at 4,559 and at 120 m above sea level. At high altitude, both static and dynamic lung compliances and respiratory reactance at 5 Hz significantly decreased, suggestive of interstitial pulmonary edema. Resting minute ventilation significantly increased by ∼30%. Compared with sea level, inhalation of methacholine at high altitude caused a similar reduction of partial forced expiratory flow but less reduction of maximal forced expiratory flow, less increments of pulmonary resistance and respiratory resistance at 5 Hz, and similar effects of deep breath on pulmonary and respiratory resistance. During maximal incremental exercise at high altitude, partial forced expiratory flow gradually increased with the increase in minute ventilation similarly to sea level but both achieved higher values at peak exercise. In conclusion, airway responsiveness to methacholine at high altitude is well preserved despite the occurrence of interstitial pulmonary edema. We suggest that this may be the result of the increase in resting minute ventilation opposing the effects and/or the development of airway smooth muscle force, reduced gas density, and well preserved airwayto-parenchyma interdependence. [ABSTRACT FROM AUTHOR]

We sought to determine the relationship between lung size and airway size in men and women of varying stature. We also asked if men and women matched for lung size would still have differences in airway size and if so where along the pulmonary airway tree would these differences exist. We used computed tomography to measure airway luminal areas of the large and central airways. We determined airway luminal areas in men (n = 25) and women (n = 25) who were matched for age, body mass index, smoking history, and pulmonary function and in a separate set of men (n = 10) and women (n = 11) who were matched for lung size. Men had greater values for the larger airways and many of the central airways. When male and female subjects were pooled there were significant associations between lung size and airway size. Within the male and female groups the magnitudes of these associations were decreased or nonsignificant. In males and females matched for lung size women had significantly smaller airway luminal areas. The larger conducting airways in females are significantly smaller than those of males even after controlling for lung size. [ABSTRACT FROM AUTHOR]

In advanced cirrhosis, decreased lung transfer for carbon monoxide (TLCO) and increased alveolar-arterial oxygen tension difference (PA-aO2 ⩾15 mmHg while breathing ambient air) are frequently detected. Pulmonary membrane diffusion capacity for CO (DmCO) and pulmonary capillary blood volume (Vcap) can be derived from the simultaneous measurement of TLCO and lung transfer for nitric oxide (TLNO). Measurements of single-breath TLNO and TLCO were performed in 49 cirrhotic patients with advanced liver cirrhosis and in 35 healthy controls to derive Vcap, DmCO, and TLNO:TLCO ratio. Twenty-five patients had increased PA-aO2, of whom 11 had hepatopulmonary syndrome (HPS). Compared with controls, non-HPS patients with normal PA-aO2 had a significant ∼10% decrease in TLCO, DmCO, and Vcap but similar TLNO:TLCO ratios. Compared with non-HPS patients with normal PA-aO2, non-HPS patients with increased PA-aO2 had lower Vcap and higher TLNO:TLCO ratio but similar DmCO. HPS patients had lower Vcap and higher TLNO:TLCO ratios than both subgroups of non-HPS patients. In cirrhotic patients, TLNO: TLCO ratios correlated positively, and TLCO (percentage of the predicted value) and Vcap (percentage of the predicted value) correlated negatively with PA-aO2 (r² = 0.25, P = 0.0003, r² = 0.48, P < 0.0001 and r² = 0.57, P < 0.0001, respectively). We concluded that, in cirrhotic patients, lower TLCO and increased PA-aO2 are associated with lower Vcap. In addition, high TLNO:TLCO ratios in patients with increased PA-aO2 suggest a decreased thickness of the capillary blood layer in these patients. [ABSTRACT FROM AUTHOR]

This is a brief overview of physiological reactions, limitations, and pathophysiological mechanisms associated with human breath-hold diving. Breath-hold duration and ability to withstand compression at depth are the two main challenges that have been overcome to an amazing degree as evidenced by the current world records in breath-hold duration at 10:12 mm and depth of 214 m. The quest for even further performance enhancements continues among competitive breath-hold divers, even if absolute physiological limits are being approached as indicated by findings of pulmonary edema and alveolar hemorrhage postdive. However, a remarkable, and so far poorly understood, variation in individual disposition for such problems exists. Mortality connected with breath-hold diving is primarily concentrated to less well-trained recreational divers and competitive spearfishermen who fall victim to hypoxia. Particularly vulnerable are probably also individuals with preexisting cardiac problems and possibly, essentially healthy divers who may have suffered severe alternobaric vertigo as a complication to inadequate pressure equilibration of the middle ears. The specific topics discussed include the diving response and its expression by the cardiovascular system, which exhibits hypertension, bradycardia, oxygen conservation, arrhythmias, and contraction of the spleen. The respiratory system is challenged by compression of the lungs with barotrauma of descent, intrapulmonary hemorrhage, edema, and the effects of glossopharyngeal insufflation and exsufflation. Various mechanisms associated with hypoxia and loss of consciousness are discussed, including hyperventilation, ascent blackout, fasting, and excessive postexercise O2 consumption. The potential for high nitrogen pressure in the lungs to cause decompression sickness and N2 narcosis is also illuminated. [ABSTRACT FROM AUTHOR]

In this report, a brief history of the Valsalva (Valsalva-Weber) maneuver is outlined, followed by an explanation on the use of this approach for the evaluation of cardiac autonomic function based on underlying heart rate changes. The most important methodological and interpretative aspects of the Valsalva-Weber maneuver are critically updated, and some guidelines are established for simple application of the maneuver in a teaching or research laboratory setting. These include the hemodynamic and cardiac autonomic mechanisms involved, technical aspects such as the intensity and duration of the expiratory straining, frequency of maneuver sessions, training and posture of the individuals tested, different time- and grade change-dependent indexes of heart interval variation, and clinical application of the maneuver. [ABSTRACT FROM AUTHOR]

Ventilation-perfusion changes after right-sided pulmonary contusion (PC) in swine were investigated by means of the multiple inert gas elimination technique (MIGET). Anesthetized swine (injury, n = 8; control, n = 6) sustained a right-chest PC by a captive-bolt apparatus. This was followed by a 12-ml/kg hemorrhage, resuscitation, and reinfusion of shed blood. MIGET and thoracic computed tomography (CT) were performed before and 6 h after injury. Three-dimensional CT scan reconstruction enabled determination of the combined fractional volume of poorly aerated and non-aerated lung tissue (VOL), and the mean gray-scale density (MGSD). Six hours after PC in injured animals, Pao2 decreased from 234.9 ± 5.1 to 113.9 ± 13.0 mmHg. Shunt (Qs) increased (2.7 ± 0.4 to 12.3 ± 2.2%) at the expense of blood flow to normal ventilation/perfusion compartments (97.1 ± 0.4 to 87.4 ± 2.2%). Dead space ventilation (VD/VT) increased (58.7 ± 1.7% to 67.2 ± 1.2%). MGSD increased (-696.7 ± 6.1 to -565.0 ± 24.3 Hounsfield units), as did VOL (4.3 ± 0.5 to 33.5 ± 3.2%). Multivariate linear regression of MGSD, VOL, VD/VT, and Qs vs. PaO2 retained VOL and Qs (r2 = .835) as independent covariates of PaO2. An increase in Qs characterizes lung failure 6 h after pulmonary contusion; Qs and VOL correlate independently with PaO2. [ABSTRACT FROM AUTHOR]

The apparent diffusion coefficients (ADCs) of hyperpolarized ³He and 129Xe gases were measured in the lungs of rabbits with elastase-induced emphysema and correlated against the mean chord length from lung histology. In vivo measurements were performed at baseline and 2, 4, 6, and 8 wk after instillation of elastase (mild and moderate emphyserna groups) or saline (control group). ADCs were determined from acquisitions that used two b values. To investigate the effect of b value on the results, b-value pairs of 0 and 1.6 s/cm² and 0 and 410 s/cm² were used for ³He, and b-value pairs of 0 and 5.0 s/cm² and 0 and 10.0 s/cm² were used for 129Xe. At 8 wk after instillation, the rabbits were euthanized. and the lungs were analyzed histologically and morphometrically. ADCs for the rabbits in the control group did not change significantly from baseline to week 8, whereas ADGs for the rabbits in the emphysema groups increased significantly (P < 0.05) for all gas and b-value combinations except 129Xe with the b-value pair of 0 and 5.0 s/cm². The largest percent change in mean ADC from baseline to week 8 (15.3%) occurred with ³He and the b-value pair of 0 and 1.6 s/cm² for rabbits in the moderate emphysema group. ADCs (all b values) were strongly correlated (r = 0.62-0.80, P < 0.001) with mean chord lengths from histology. These results further support the ability of diffusion-weighted MRI with hyperpolarized gases to detect regional and global structural changes of emphysema within the lung. [ABSTRACT FROM AUTHOR]

The effects of supine posture on airway responses to inhaled methacholine and deep inspiration (DI) were studied in seven male volunteers. On a control day, subjects were in a seated position during both methacholine inhalation and lung function measurements. On a second occasion, the whole procedure was repeated with the subjects lying supine for the entire duration of the study. On a third occasion, methacholine was inhaled from the seated position and measurements were taken in a supine position. Finally, on a fourth occasion, methacholine was inhaled from the supine position and measurements were taken in the seated position. Going from sitting to supine position, the functional residual capacity decreased by ∼1 liter in all subjects. When lung function measurements (pulmonary resistance, dynamic elastance, residual volume, and maximal flows) were taken in supine position, the response to methacholine was greater than at control, and this was associated with a greater dyspnea and a faster recovery of dynamic elastance after DI. By contrast, when methacholine was inhaled in supine position but measurements were taken in sitting position, the response to methacholine was similar to control day. These findings document the potential of the decrease in the operational lung volumes in eliciting or sustaining airflow obstruction in nocturnal asthma. It is speculated that the exaggerated response to methacholine in the supine posture may variably contribute to airway smooth muscle adaptation to short length, airway wall edema, and faster airway renarrowing after a large inflation. [ABSTRACT FROM AUTHOR]

We examined the effects of chest wall strapping (CWS) on the response to inhaled methacholine (MCh) and the effects of deep inspiration (DI). Eight subjects were studied on 1 day with MCh inhaled without CWS (CTRL), 1 day with MCh inhaled during CWS (CWSon/on), and 1 day with MCh inhaled during temporary removal of CWS (CWSoff/on), On the CWSon/on day, MCh caused greater increases in pulmonary resistance, upstream resistance, dynamic elastance, residual volume, and greater decreases in maximal expiratory flow than on the CTRL day. On the CWSoff/on day, the changes in these parameters with MCh were not different from the CTRL day. Six of the subjects were again studied using the same protocol on CTRL and CWSon/on days, except that, on a third day, MCh was given after applying the CWS, but the measurements before and after the inhalation were made without CWS (CWSon/off). The latter sequence was associated with more severe airflow obstruction than during CTRL, but less than with CWSon/on. The bronchodilator effects of a DI were blunted when CWS was applied during measurements (CWSon/on and CWSoff/on) but not after it was removed (CWSon/off). We conclude that CWS is capable of increasing airway responsiveness only when it is applied during the inhalation of the constrictor agent. We speculate that breathing at low lung volumes induced by CWS enhances airway narrowing because the airway smooth muscle is adapted at a length at which the contractile apparatus is able to generate a force greater than normal. [ABSTRACT FROM AUTHOR]

Thixotropy conditioning of inspiratory muscles consisting of maximal inspiratory effort performed at an inflated lung volume is followed by an increase in end-expiratory position of the rib cage in normal human subjects. When performed at a deflated lung volume, conditioning is followed by a reduction in end-expiratory position. The present study was performed to determine whether changes in end-expiratory chest wall and lung volumes occur after thixotropy conditioning. We first examined the acute effects of conditioning on chest wall volume during subsequent five-breath cycles using respiratory inductive plethysmography (n = 8). End-expiratory chest wall volume increased after conditioning at an inflated lung volume (P < 0.05), which was attained mainly by rib cage movements. Conditioning at a deflated lung volume was followed by reductions in end-expiratory chest wall volume, which was explained by rib cage and abdominal volume changes (P < 0.05). End-expiratory esophageal pressure decreased and increased after conditioning at inflated and deflated lung volumes, respectively (n = 3). These changes in end-expiratory volumes and esophageal pressure were greatest for the first breath after conditioning. We also found that an increase in spirometrically determined inspiratory capacity (n = 13) was maintained for 3 min after conditioning at a deflated lung volume, and a decrease for 1 min after conditioning at an inflated lung volume. Helium-dilution end-expiratory lung volume increased and decreased after conditioning at inflated and deflated lung volumes, respectively (both P < 0.05; n = 11). These results suggest that thixotropy conditioning changes end- expiratory volume of the chest wall and lung in normal human subjects. [ABSTRACT FROM AUTHOR]

To avoid limitations associated with the use of single-breath and rebreathe methods for assessing the lung diffusing capacity for carbon monoxide (DLCO) during exercise, we developed an open-circuit technique. This method does not require rebreathing or alterations in breathing pattern and can be performed with little cognition on the part of the patient. To determine how this technique compared with the traditional rebreathe (DLCO,RB) method, we performed both the open-circuit (DLCO,OC) and the DLCO,RB methods at rest and during exercise (25, 50, and 75% of peak work) in 11 healthy subjects [mean age = 34 yr (SD 11)]. Both DLCO,OC and DLCO,RB increased linearly with cardiac output and external work. There was a good correlation between DLCO,OC and DLCO,RB for rest and exercise (mean of individual r² = 0.88, overall r² = 0.69, slope = 0.97). DLCO,OC and DLCO, RB were similar at rest and during exercise [e.g., rest = 27.2 (SD 5.8) vs. 29.3 (SD 5.2), and 75% peak work = 44.0 (SD 7.0) vs. 41.2 ml·min-1·mmHg-1 (SD 6.7) for DLCO,OC vs. DLCO,RB]. The coefficient of variation for repeat measurements of DLCO,OC was 7.9% at rest and averaged 3.9% during exercise. These data suggest that the DLCO,OC method is a reproducible, well-tolerated alternative for determining DLCO, particularly during exercise. The method is linearly associated with cardiac output, suggesting increased alveolar-capillary recruitment, and values were similar to the traditional rebreathe method. [ABSTRACT FROM AUTHOR]