Large Airways Research Articles

Bronchodilator Response Predicts Longitudinal Improvement in Small Airway Function in World Trade Center Dust Exposed Community Members.

The evolution of lung function, including assessment of small airways, was assessed in individuals enrolled in the World Trade Center Environmental Health Center (WTC-EHC). We hypothesized that a bronchodilator response at initial evaluation shown by spirometry or in small airways, as measured by forced oscillation technique (FOT), would be associated with improvement in large and small airway function over time. Standardized longitudinal assessment included pre and post bronchodilator (BD) spirometry (forced vital capacity, FVC; forced expiratory volume in 1 second, FEV1) and FOT (resistance at 5 Hz, R5; resistance at 5 minus 20 Hz, R5–20). Longitudinal changes were assessed using linear mixed-effects modelling with adjustment for potential confounders (median follow-up 2.86 years; 95% measurements within 4.9 years). Data demonstrated: (1) parallel improvement in airflow and volume measured by spirometry and small airway function (R5 and R5–20) measured by FOT; (2) the magnitude of longitudinal improvement was tightly linked to the initial BD response; and (3) longitudinal values for small airway function on FOT were similar to residual abnormality observed post BD at initial visit. These findings suggest presence of reversible and irreversible components of small airway injury that are identifiable at initial presentation. These results have implications for treatment of isolated small airway abnormalities that can be identified by non-invasive effort independent FOT particularly in symptomatic individuals with normal spirometry indices. This study underscores the need to study small airway function to understand physiologic changes over time following environmental and occupational lung injury.

Pulmonary Complications of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterized by the production of pathogenic autoantibodies and immune complexes and is responsible for significant morbidity and mortality through a wide range of clinical manifestations which can affect almost any organ. Pulmonary involvement is prevalent and seen in 50 to 70% of SLE patients and may even be the presenting feature in 4 to 5% of patients. By 10 years postdiagnosis, 12% will have accumulated an element of permanent lung damage. Pulmonary complications are broad and include pleural disease, interstitial lung disease (ILD), vasculitis, pulmonary embolism, pulmonary hypertension, large airway disease, shrinking lung syndrome, and infection. Conditions can range mostly from asymptomatic, for example, in mild cases of pleural effusion or obstructive airway disease, to life-threatening disease, for example, in acute lupus pneumonitis or diffuse alveolar hemorrhage. ILD and pulmonary hypertension are both frequently seen in other autoimmune rheumatic diseases such as systemic sclerosis; however, in SLE, they tend to be milder and have a comparatively favorable prognosis. Although collectively pulmonary involvement in SLE is common, the heterogeneity of SLE and rareness of individual complications make clinical trials difficult and treatment is usually based on case series reports and anecdotal experience with various immunosuppressive agents. Some of these immunosuppressive agents such as azathioprine, methotrexate, and cyclophosphamide have also been linked with drug-induced lung injury.

Inflammatory Cytokines IL‐13 or IL‐17/TNFα Do Not Alter the Low Paracellular Bicarbonate Permeability of Cystic Fibrosis Airway Epithelia

The airway‐surface liquid, the thin aqueous layer on the apical side of airway epithelia, maintains a pH that is more acidic than the serosal pH. For human large airways, this acidic pH is the balance of HCO3− secretion by the cystic fibrosis transmembrane conductance regulator (CFTR) and H+ secretion by the H+/K+ pump ATP12A, both transcellular mechanisms. Newborn humans with cystic fibrosis (CF) have an acidic airway‐surface liquid pH compared to non‐CF newborns. With time, the pH difference between CF and non‐CF individuals disappears. However, adult CF epithelia cultured at the air‐liquid interface are more acidic than non‐CF epithelia. We hypothesized that CF‐related inflammation in vivo is responsible for the age‐dependent airway alkalinization. Here, we tested the hypothesis that cytokines increase paracellular movement of HCO3− into the airway‐surface liquid. Dilution potentials observed for cultured CF airway indicate that paracellular transport favored cations (PCl/PNa = 0.7). The paracellular conductance and selectivity were unaffected by changing the pH from 7.4 to 6.0. HCO3− was less permeable than Cl− through the paracellular pathway (PHCO3/PNa = 0.35). Treating cultures with cytokines (IL‐13 or IL‐17 and TNFa), which increase the airway‐surface liquid pH, did not affect paracellular PHCO3/PNa. These data suggest that differences in transcellular pH transport are responsible for cytokine‐mediated ASL pH changes. Similar transcellular mechanisms may cause the longitudinal ASL pH changes observed for CF patients.Support or Funding InformationMJW is an Investigator of the Howard Hughes Medical InstituteCystic Fibrosis Foundation Research Development ProgramNIH HL091842This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impulse Oscillometry Discerns the Peripheral Airway Response to an Inhaled Bronchodilator between Obese and Nonobese Children

IntroductionImpulse oscillometry (iOS) is a useful tool to distinguish between central and peripheral airway resistance. For example, iOS has shown that peripheral airway resistance is greater in children with versus those without obesity, despite no difference in FEV1. Considering the added peripheral airway resistance in children with obesity, we sought to determine if iOS can detect potential differences in the peripheral airway response to an inhaled bronchodilator (BD) between children with and those without obesity.MethodsTwenty‐four children with and eleven without obesity, ages 8–12yrs, completed iOS and spirometry testing before and 15mins after the administration of four puffs of an inhaled BD (Ventolin®, 90μg). A mixed models ANOVA (group by pre‐to‐post‐BD) was used to determine differences in FEV1, plethysmographic airway resistance (Raw) and specific Raw (sRaw), and iOS parameters associated with airway resistance. These parameters include resistance at 5 Hz, 10 Hz (R5 and R10: total airway resistance), 20 Hz (R20: large airway resistance), and the difference between R5 and R20 (R5–20: peripheral airway resistance). Reactance at 5 Hz (X5: total airway elastic recoil) and the area under the reactance‐frequency curve (AX: index of small airway patency) were also measured using iOS.ResultsThere was no difference in FEV1 (% pred) or FEV1/FVC between groups and none of our participants showed a positive BD response based on the conventional method of a ≥12% increase in FEV1. Compared with children without obesity, children with obesity presented a greater baseline R5 (7.28 ± 1.20 vs. 5.42 ± 1.44 cmH2O·L−1·s−1; p=0.001), R10 (6.04 ± 1.12 vs. 4.58 ± 1.07 cmH2O·L−1·s−1; p=0.002), R20 (4.76 ± 0.95 vs. 3.94 ± 0.79 cmH2O·L−1·s−1; p=0.025), R5–20 (2.52 ± 0.64 vs. 1.49 ± 0.75 cmH2O·L−1·s−1; p<0.001), and AX (7.65 ± 5.59 vs. 3.75 ± 1.97 cmH2O·L−1; p=0.008), with no difference in X5 (−1.19 ± 0.77 vs. −1.19 ± 0.33 cmH2O·L−1; p=0.667). A group by pre‐to‐post‐BD interaction was found for R5 (p=0.033) and R10 (p=0.024). Both R5 and R10 decreased to a greater extent with BD in children with obesity versus children without obesity (R5: −20.8 ± 9.5% vs. −12.8 ± 15.2%; R10: −21.6 ± 8.6% vs. −14.5 ± 13.1%). In all children (n=35), Raw, sRaw, and all iOS parameters, except for X5, decreased with the BD (p<0.05).ConclusionIn addition to greater central and peripheral airway resistance in children with obesity, iOS also detected a greater peripheral airway response to a BD in children with obesity. Although no established criteria exist for children ages 8–12yrs, the American Thoracic Society defines an airway response in preschool children as a 20–40% decrease in R5 and a 15–30% decrease in R10. Based on these criteria, our finding that R5 and R10 dropped by 20.8% and 21.6% in children with obesity indicates potential peripheral airway hyperresponsiveness in children with obesity. However, further research is warranted to establish the meaning of, or normal criteria for, peripheral airway responsiveness in prepubescent children.Support or Funding InformationNIH R01 HL136643, Texas Health Presbyterian Hospital Dallas, King Charitable Foundation Trust, and Dr. Pepper Snapple.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Gene signatures common to allograft rejection are associated with lymphocytic bronchitis.

Lymphocytic bronchitis (LB) precedes chronic lung allograft dysfunction. The relationships of LB (classified here as Endobronchial or E-grade rejection) to small airway (A- and B-grade) pathologies are unclear. We hypothesized that gene signatures common to allograft rejection would be present in LB. We studied LB in two partially overlapping lung transplant recipient cohorts: Cohort 1 included large airway brushes (6 LB cases and 18 post-transplant referents). Differential expression using DESeq2 was used for pathway analysis and to define an LB-associated metagene. In Cohort 2, eight biopsies for each pathology subtype were matched with pathology-free biopsies from the same subject (totaling 48 samples from 24 subjects). These biopsies were analyzed by multiplexed digital counting of immune transcripts. Metagene score differences were compared by paired t tests. Compared to referents in Cohort 1, LB demonstrated upregulation of allograft rejection pathways, and upregulated genes in these cases characterized an LB-associated metagene. We observed statistically increased expression in Cohort 2 for this LB-associated metagene and four other established allograft rejection metagenes in rejection vs paired non-rejection biopsies for both E-grade and A-grade subtypes, but not B-grade pathology. Gene expression-based categorization of allograft rejection may prove useful in monitoring lung allograft health.

A case report of primary anaplastic large cell lymphoma arising from the trachea

Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin’s lymphoma. Its presentation as an isolated primary lesion in the airway is extremely rare and not often considered in the differential diagnosis of airway lesions. Thus, it is important to be aware of its presenting manifestations, imaging features and treatment complications. Here, we report a case of pathologically confirmed tracheal-based ALCL. We especially focus on presenting the salient imaging features of this entity and the associated clinical and pathological findings of this rare large airway disease.

Small airway dysfunction may be an indicator of early asthma: findings from high-resolution CT

BackgroundIncreasing attention is now focused on the role of the small airways in asthma. Patients with small airway asthma typically have a preserved forced expiratory volume in 1 second, with disproportionate small airway dysfunction. ObjectiveThe aim of this study was to determine whether there are structural changes in the large airways in patients with small airway asthma. MethodsNine patients with small airway asthma and 20 healthy controls underwent high-resolution computed tomography (HRCT) scan. The apicoposterior segmental bronchus in the left upper lobe (LB1+2) and the posterior basal segmental bronchus in the left lower lobe (LB10) were identified on HRCT images. The luminal area (LA), wall area (WA), and wall area percentage (WA%) of each bronchus were measured from the 2nd (lobar) to the 6th generation and compared between the patients with small airway asthma and the healthy controls. ResultsThe WA% of the 6th generation in the patients with small airway asthma was higher than that in the healthy controls; the difference was statistically significant (LB1 + 2, P = .040; LB10, P = .033). ConclusionStructural changes in the large airways of patients with small airway asthma may represent an early stage of asthma.

Risk factors of ventilator-induced lung injury: mechanical power as surrogate of energy dissipation

Soon after physicians began to artificially ventilate patients with respiratory insufficiency due to poliomyelitis (1) and intensive care units developed, risks of mechanical ventilation—namely ventilator-induced lung injury (VILI)—became evident (2). The recognition of this iatrogenic, and potentially lethal, syndrome led to a slow change in the goal of mechanical ventilation for respiratory failure: from maintaining near-normal gas exchange, with use of large tidal volumes and high airway pressures (3), to avoiding additional lung damage—the so-called “lung protective” ventilation (4). The last 60 years of preclinical and clinical research in the field focused on identifying the single ventilator variable most responsible for VILI, with no conclusive answer.

Reconstruction of Large Airways Following Main Bronchial Rapture a Year after Blunt Trauma

We present the case of a 19-year-old boy with a history of breathlessness and blunt chest trauma one year ago. Figure 1 show CT scan of patient. Figure 2: show bronchoscopic of patient. Figure 3 and 4 show intra operative view and Fig 5 show CXR of patient after surgery

High‐flow nasal therapy – modelling the mechanism

High‐flow nasal therapy – modelling the mechanism

Inspiratory muscle activation via ventral lower thoracic high-frequency spinal cord stimulation.

In animals, high-frequency spinal cord stimulation (HF-SCS) applied on the ventral epidural surface at the T2 level results in negative airway pressure generation consistent with inspiratory muscle activation. In the present study, in anesthetized dogs, we found that ventral HF-SCS (500 Hz) applied at all thoracic levels resulted in negative airway pressure generation. In the region of the lower thoracic spinal cord, negative airway pressure generation was most pronounced at the T9 level. At this level, airway pressure generation was monitored: 1) during ventral HF-SCS over a wide range of stimulus amplitudes (0.5-15 mA) and frequencies (50-1,000 Hz) and 2) following spinal sections at C8 (to assess potential diaphragm activation) and subsequently at T6 (to assess potential intercostal muscle activation). The application of low stimulus currents between 1 and 2 mA and high stimulus frequencies (>300 Hz) resulted in the development of large negative airway pressure generation. Stimulation with 1 mA, 500 Hz resulted in a highest negative airway pressure generation of 47 ± 2 cmH2O. Increasing stimulus current was associated with progressive reductions in the magnitude of negative airway pressure generation. HF-SCS (500 Hz) with 15 mA resulted in a negative airway pressure generation of 7 ± 3 cmH2O. C8 section markedly reduced negative airway pressure generation, and subsequent T6 section resulted in positive airway pressure generation after HF-SCS. Our results indicate the existence of pathways with connections to both the phrenic and inspiratory intercostal motoneuron pools in the ventral part of the lower thoracic spinal cord. We speculate that the circuits mediating the previously described excitatory intercostal-to-phrenic reflex mediate the observed responses. NEW & NOTEWORTHY This study suggests that, in contrast to dorsal high-frequency spinal cord stimulation at the T9 spinal level, which results in positive pressure generation, ventral high-frequency spinal cord stimulation at the same spinal level results in large negative airway pressure generation with low stimulus currents. This method, therefore, may provide an alternative method to restore ventilation in ventilator-dependent spinal cord-injured patients.

Big Choanae, Larger Face: Scaling Patterns Between Cranial Airways in Modern Humans and African Apes and Their Significance in Middle and Late Pleistocene Hominin Facial Evolution

This study aimed to understand the ontogenetic and allometric relationships in scaling between the anterior and posterior openings of the cranial airways and facial size, in order to shed light on the mechanisms that might underlie the evolution of a large face and large airways in Middle Pleistocene hominins and Neandertals. Sizes were calculated from 3D landmarks measured on the facial skeleton and airway structures of 403 skulls from two ontogenetic series of H. sapiens and P. troglodytes, an adult sample of gorillas and 11 Middle Pleistocene hominins and Neandertals. RMA regression models were used to compare the patterns in scaling between the anterior and posterior airways in relation to overall facial size. Our results show that the size of the anterior airways correlates more positively with facial size than the size of the posterior airways. This ontogenetic mechanism could explain the large faces and noses in the Neandertal lineage despite the adverse effects of such a phenotype for respiratory air-conditioning in cold climates. A large facial size could be a developmentally constrained consequence of generating airways large enough to provide the necessary oxygen for high energy demand in this large-brained and heavy-bodied hominin lineage.

CT-based anatomical features of large airway and heart volume in dogs of different body size

Differences in the prevalence and clinical signs of cardiopulmonary diseases in dogs of different body sizes have been reported. It was hypothesized that the anatomical features of the heart and large airways varies by body size in dogs and might influence clinical manifestations of cardiopulmonary disease. The purpose of this study was to compare various anatomical features of the thoracic organs (heart, trachea, etc.) in dogs according to body size using computed tomography (CT) images.Dogs without clinically significant heart and lung disease (n=226) that underwent CT were divided into three groups on the basis of bodyweight: small (<7kg), medium (7–20kg), and large (>20kg). The following parameters were calculated from CT images using OsiriX and compared among groups: relative heart volume (heart volume/thoracic volume), relative distance from mainstem bronchi to vertebra (distance from mainstem bronchi to vertebra/heart length), longitudinal/transverse diameter ratio of trachea, and angle of bronchus. Small dogs had larger hearts relative to their thorax, a shorter distance from the heart to the vertebra, and laterally-elongated oval-shaped tracheas, compared to medium and/or large dogs. These differences in anatomical features according to body size may potentially contribute to different clinical manifestations when the heart is enlarged.

Associations of AMP and adenosine induced dyspnea sensation to large and small airways dysfunction in asthma

BackgroundBronchial provocation is often used to confirm asthma. Dyspnea sensation, however, associates poorly with the evoked drop in FEV1. Provocation tests only use the large airways parameter FEV1, although dyspnea is associated with both large- and small airways dysfunction. Aim of this study was to explore if adenosine 5′-monophosphate (AMP) and adenosine evoke an equal dyspnea sensation and if dyspnea associates better with large or small airways dysfunction.MethodsWe targeted large airways with AMP and small airways with dry powder adenosine in 59 asthmatic (ex)-smokers with ≥5 packyears, 14 ± 7 days apart. All subjects performed spirometry, impulse oscillometry (IOS), and Borg dyspnea score. In 36 subjects multiple breath nitrogen washout (MBNW) was additionally performed. We analyzed the association of the change (Δ) in Borg score with the change in large and small airways parameters, using univariate and multivariate linear regression analyses. MBNW was analyzed separately.ResultsProvocation with AMP and adenosine evoked similar levels of dyspnea. ΔFEV1 was not significantly associated with ΔBorg after either AMP or adenosine provocation, in both univariate and multivariate analyses. In multivariate linear regression, a decrease in FEF25–75 during adenosine provocation was independently associated with an increase in Borg. In the multivariate analyses for AMP provocation, no significant associations were found between ΔBorg and any large or small airways parameters.ConclusionAMP and adenosine induce equally severe dyspnea sensations. Our results suggest that dyspnea induced with dry powder adenosine is related to small airways involvement, while neither large nor small airways dysfunction was associated with AMP-induced dyspnea.Trail registrationNCT01741285 at www.clinicaltrials.gov, first registered Dec 4th, 2012.

Lebensbedrohliches Hautemphysem nach banalem Stoß gegen den Hals

After aminor blow to the neck from the handlebars of a bike, a5-year-old boy developed amassive subcutaneous emphysema with respiratory distress. Orotracheal intubation was performed. A computed tomography (CT) scan of the neck and thorax showed a pneumomediastinum and abilateral pneumothorax. No injury to the large airways was identified. The patient was stabilized by insertion of chest tubes and controlled ventilation. The endoscopic examination of the trachea revealed atear of the pars membranacea, which was successfully treated conservatively. The specific features of the injury and the airway management are discussed based on a review of the current literature.

A Guinea Pig Model of Airway Smooth Muscle Hyperreactivity Induced by Chronic Allergic Lung Inflammation: Contribution of Epithelium and Oxidative Stress.

Asthma is a heterogeneous disease of the airways characterized by chronic inflammation associated with bronchial and smooth muscle hyperresponsiveness. Currently, different murine models for the study of asthma show poor bronchial hyperresponsiveness due to a scarcity of smooth muscle and large airways, resulting in a failure to reproduce smooth muscle hyperreactivity. Thus, we aimed to standardize a guinea pig model of chronic allergic lung inflammation mimicking airway smooth muscle hyperreactivity observed in asthmatics (Asth). Animals were randomly divided into a control group (Ctrl), which received saline (0.9% NaCl), and the Asth group, subjected to in vivo sensitization with ovalbumin (OVA) nebulization. Morphological analysis was performed by hematoxylin-eosin staining. Bronchial hyperresponsiveness was evaluated by nebulization time in the fifth, sixth, and seventh inhalations (NT5-7) and tracheal isometric contractions were assessed by force transducer. Total antioxidant capacity was measured by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and protein expression by Western blot. Histologically, the Asth group developed peribronchial cellular infiltrate, epithelial hyperplasia and smooth muscle thickening. After the fourth nebulization, the Asth group developed bronchial hyperreactivity. The trachea from the Asth group contracted after in vitro stimulation with OVA, differing from the Ctrl group, which showed no response. Additionally, airway smooth muscle hyperreactivity to carbachol and histamine was observed in the Asth group only in intact epithelium preparations, but not to KCl, and this effect was associated with an augmented production of reactive oxygen species. Moreover, lung inflammation impaired the relaxant potency of isoproterenol only in intact epithelium preparations, without interfering with nifedipine, and it was found to be produced by transforming growth factor-β negative modulation of β adrenergic receptors and, furthermore, big-conductance Ca2+-sensitive K+ channels. These effects were also associated with increased levels of phosphatidylinositol 3-kinases but not extracellular signal-regulated kinases 1/2 or phosphorylation, and augmented α-actin content as well, explaining the increased smooth muscle mass. Furthermore, pulmonary antioxidant capacity was impaired in the Asth group. Therefore, we developed a standardized and easy-to-use, reproducible guinea pig model of lung inflammation that mimics airway smooth muscle hypercontractility, facilitating the investigation of the mechanisms of bronchial hyperresponsiveness in asthma and new therapeutic alternatives.

Patient-specific targeted bronchial thermoplasty: predictions of improved outcomes with structure-guided treatment.

Bronchial thermoplasty is a recent treatment for asthma in which ablative thermal energy is delivered to specific large airways according to clinical guidelines. Therefore, current practice is effectively "blind," as it is not informed by patient-specific data. The present study seeks to establish whether a patient-specific approach based on structural or functional patient data can improve outcomes and/or reduce the number of procedures required for clinical efficacy. We employed a combination of extensive human lung specimens and novel computational methods to predict bronchial thermoplasty outcomes guided by structural or functional data compared with current clinical practice. Response to bronchial thermoplasty was determined from changes in airway responses to strong bronchoconstrictor simulations and flow heterogeneity after one or three simulated thermoplasty procedures. Structure-guided treatment showed significant improvement over current unguided clinical practice, with a single session of structure-guided treatment producing improvements comparable with three sessions of unguided treatment. In comparison, function-guided treatment did not produce a significant improvement over current practice. Structure-guided targeting of bronchial thermoplasty is a promising avenue for improving therapy and reinforces the need for advanced imaging technologies. The functional imaging-guided approach is predicted to be less effective presently, and we make recommendations on how this approach could be improved. NEW & NOTEWORTHY Bronchial thermoplasty is a recent treatment for asthma in which thermal energy is delivered via bronchoscope to specific airways in an effort to directly target airway smooth muscle. Current practice involves the treatment of a standard set of airways, unguided by patient-specific data. We consider the potential for guided treatments, either by functional or structural data from the lung, and show that treatment guided by structural data has the potential to improve clinical practice.

Disparate diagnostic accuracy of lung function tests as predictors of poor asthma control in children

Rationale: In practice, asthma control is assessed according to symptom burden and office spirometry. However, spirometry poorly tests peripheral lung function, which may be abnormal in asthma. Impluse oscillometry (IOS) and multiple-breath washout (MBW) are novel methods which measure reactance (X5) and ventilation heterogeneity (VH) in the peripheral lung, but how well these tests reflect asthma control is poorly understood. Objective: To compare the diagnostic accuracy of tests of large airways caliber (FEV1, FEV1/FVC, R20), peripheral zone properties (X5, VH), and airways inflammation (FeNO) as predictors of poor control in asthmatic children (44 poorly controlled/10 controlled). Methods: 54 children enriched in severe asthma completed a symptom-based control scale (ACT/cACT) and lung function tests after overnight bronchodilator withhold. The accuracy of each variable to predict poor control was ranked by area under the receiver operating characteristic (ROC) curve, sensitivity and specificity. Results: Among measures of large airways caliber, the FEV1% had the highest ROC curve area, with low sensitivity but perfect specificity. Among measures of peripheral lung function, X5 and VH in the conducting zone had fair curve areas with higher sensitivity but lower specificity compared to the FEV1%. VH in the acinar zone and FeNO both had poor accuracy. Conclusion: Tests of large airway and peripheral zone lung function performed disparately as predictors of poor control in a sample of children enriched in severe asthma. Further studies in a larger sample with more diverse phenotypic features are necessary to validate this preliminary conclusion.

Reply to LTE, "Role of 18F-FDG PET/CT in Cardiac Sarcoid Detection and Therapy Monitoring: Addition to the Expert Consensus".

293 Introduction: Mucociliary Clearance (MCC) is an innate respiratory host defense mechanism that removes inhaled and aspirated particles and pathogens from the airways. Defects in MCC contribute to many airway diseases such as primary ciliary dyskinesia, asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and cystic fibrosis. MCC has been visualized using inhaled aerosols containing insoluble Tc-99m labeled colloids with either planar scintigraphy or SPECT. However, the low temporal and spatial resolution of single photon imaging in this application makes it difficult to investigate the mechanisms of MCC defects in airways disease or to determine the efficacy of therapeutics. An imaging modality with higher temporal and spatial resolution, such as PET, will allow for quantitative measurement of MCC and opportunities to evaluate the efficacy of newer therapeutics. Objectives: The objective of the study was to develop a method to visualize and quantify MCC in pulmonary pathophysiology using PET imaging. Pre-clinical imaging was performed using a porcine model. Methods: [18F]-fluoride labeled alumina nanoparticles were obtained by adding aqueous [18F]-fluoride to γ-alumina nanoparticles (<50 nm). The suspension was incubated at room temperature with continuous shaking (20 min) followed by centrifugation (10 min). The unbound [18F]-fluoride was separated from the pellet, and the pellet was then washed with water, re-suspended, shaken (5 min) and centrifuged (5 min). The washing step was repeated two times, and the [18F]-fluoride alumina nanoparticles were formulated in saline. We used newborn piglets for this study. In one experiment, we targeted small distal airways by generating aerosols of [18F]-fluoride alumina nanoparticles in saline with mass median aerodynamic diameter (MMAD) of ~0.31 µm. We used 14 mCi with effective delivery of ~ 1 mCi into the airways. In another experiment, we targeted large proximal airways by generating aerosols of [18F]-fluoride alumina nanoparticles in saline with MMAD of ~10 µm. We delivered 1 mCi directly into the airways. An endotracheal tube was needed for the delivery of the aerosolized [18F]-fluoride alumina nanoparticles. Immediately after delivery of the aerosolized nanoparticles, the endotracheal tube was removed. The piglet breathed spontaneously throughout the study and maintained its own airway humidification. We obtained PET scans in list mode for a period of 60 minutes, along with a CT scan for attenuation correction. Decay- and attenuation-corrected data was binned into 30-second frames and the binned static images were used to assess MCC over time. Results: [18F]-fluoride alumina nanoparticles were obtained with radiochemical yields 95 ± 3% in < 70 minutes. Repeated washing of [18F]-labeled alumina nanoparticles with water and incubation in saline failed to release any significant [18F]-fluoride over 2-hour period. We achieved a diffuse and homogeneous delivery of the radiotracer regardless of whether a nebulizer or microsprayer was used. As predicted, the fine particles generated with the nebulizer deposited in distal airways. In contrast, the larger particles generated with a microsprayer deposited in proximal airways. With time, the radiotracer cleared out of the airways. Most of the clearance happened in the first few minutes of the study. Conclusions: A simple and highly efficient synthesis of [18F]-labeled alumina nanoparticles was developed and the [18F]-labeled alumina nanoparticles show good in vitro stability. The [18F]-labeled alumina nanoparticles were successfully delivered to pig airways via nebulizer or micro-sprayer. Varying the size of the droplets affected the deposition of the radioactivity within the airways. MCC clearance was observed using PET, with most of the clearance occurring within the first few minutes of radiotracer administration.

Small airway hyperresponsiveness in COPD: relationship between structure and function in lung slices.

The direct relationship between pulmonary structural changes and airway hyperresponsiveness (AHR) in chronic obstructive pulmonary disease (COPD) is unclear. We investigated AHR in relation to airway and parenchymal structural changes in a guinea pig model of COPD and in COPD patients. Precision-cut lung slices (PCLS) were prepared from guinea pigs challenged with lipopolysaccharide or saline two times weekly for 12 wk. Peripheral PCLS were obtained from patients with mild to moderate COPD and non-COPD controls. AHR to methacholine was measured in large and small airways using video-assisted microscopy. Airway smooth muscle mass and alveolar airspace size were determined in the same slices. A mathematical model was used to identify potential changes in biomechanical properties underlying AHR. In guinea pigs, lipopolysaccharide increased the sensitivity of large (>150 μm) airways toward methacholine by 4.4-fold and the maximal constriction of small airways (<150 μm) by 1.5-fold. Similarly increased small airway responsiveness was found in COPD patients. In both lipopolysaccharide-challenged guinea pigs and patients, airway smooth muscle mass was unaltered, whereas increased alveolar airspace correlated with small airway hyperresponsiveness in guinea pigs. Fitting the parameters of the model indicated that COPD weakens matrix mechanical properties and enhances stiffness differences between the airway and the parenchyma, in both species. In conclusion, this study demonstrates small airway hyperresponsiveness in PCLS from COPD patients. These changes may be related to reduced parenchymal retraction forces and biomechanical changes in the airway wall. PCLS from lipopolysaccharide-exposed guinea pigs may be useful to study mechanisms of small airway hyperresponsiveness in COPD.