Airway Retention Research Articles

Dynamics of pulmonary mucosal cytotoxic CD8 T-cells in people living with HIV under suppressive antiretroviral therapy

BackgroundDespite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their smoking status. Cytotoxic CD8 T-cells are likely implicated in this phenomenon and may act as a double-edged sword. While being essential in viral infection control, their hyperactivation can also contribute to lung mucosal tissue damage. The effects of HIV and smoking on pulmonary mucosal CD8 T-cell dynamics has been a neglected area of research, which we address herein.MethodsBronchoalveolar lavage (BAL) fluid were obtained from ART-treated PLWH (median duration of supressed viral load: 9 years; smokers: n = 14; non-smokers: n = 21) and HIV-uninfected controls (smokers: n = 11; non-smokers: n = 20) without any respiratory symptoms or active infection. Lymphocytes were isolated and CD8 T-cell subsets and homing markers were characterized by multiparametric flow cytometry.ResultsBoth smoking and HIV infection were independently associated with a significant increase in frequencies of total pulmonary mucosal CD8 T-cell. BAL CD8 T-cells were primarily CD69 + expressing CD103 and/or CD49a, at least one of the two granzymes (GzmA/GzmB), and little Perforin. Higher expression levels of CD103, CD69, and GzmB were observed in smokers versus non-smokers. The ex vivo phenotype of GzmA + and GzmB + cells revealed increased expression of CD103 and CXCR6 in smokers, while PLWH displayed elevated levels of CX3CR1 compared to controls.ConclusionSmoking and HIV could promote cytotoxic CD8 T-cell retention in small airways through different mechanisms. Smoking likely increases recruitment and retention of GzmB + CD8 Trm via CXCR6 and CD103. Heightened CX3CR1 expression could be associated with CD8 non-Trm recruitment from the periphery in PLWH.

Aesthetic and Functional Consequences of Spreader Graft without Suturing To the Upper Lateral Nasal Cartilage: A Randomized Double-Blinded Clinical Trial.

Considering the importance of the spreader graft technique in order to prevent collapse and airway retention and the importance of its effect on the dorsal aesthetic line and nasal width, in this study we compared the outcome of suturing spreader graft to septum _upper lateral cartilageas the classic technique to suturing spreader graft only to septum. This comparative observational study was conducted on 50 consecutive patients referred to Rhinoplasty Department in 15 khordad Hospital from 2019 - 2020 . The study participants were randomly assigned into two groups which scheduling the new spreader graft technique without suturing the upper lateral cartilage (n = 25) or the frequent spreader graft technique with suturing to both septum and upper lateral nasal cartilage (n = 25). The nasal obstruction degree, the status and health-related quality of life, patients' satisfaction, and subjective mental image of the nasal structure were the study endpoint. The patients were followed-up for six months. The two groups were matched for gender and age. Although all study endpoints significantly improved in both groups, but the six-month trend of the change in each parameter was different in the two groups with superior improvement in those who planned for spreader graft technique without suturing the upper lateral cartilage. In patients scheduling for selective rhinoplasty, new procedural technique including spreader graft without suturing to upper lateral cartilage can lead to more postoperative favorable outcome with regard to patients' satisfaction of the procedure, lack of obstructive symptoms, aesthetic feature, and health-related quality of life as compared to suturing to both septum and upper lateral cartilage.

Factors associated with artificial airway retention after skull base chordoma resection: A retrospective cohort study.

BackgroundChordoma is a malignant bone and soft tissue tumor derived from embryonic notochord remnants, and skull base chordoma accounts for ~1/3 of all chordoma cases. Skull base chordoma is closely related to the brainstem and cranial nerves and has a high recurrence rate. The purpose of this study was to investigate the influence of the timing of tracheal extubation on perioperative pulmonary complications. We also aimed to explore predictors of postoperative artificial airway (AA) retention in patients with skull base chordoma.MethodsThis was a single-center, retrospective cohort study. The study population included all skull base chordoma patients undergoing surgical treatment between January 2019 and December 2021 at Beijing Tiantan Hospital. The primary outcome was the incidence of postoperative pulmonary complications. Several patient characteristics were evaluated for potential associations with AA retention.ResultsA total of 310 patients with skull base chordoma were enrolled. The frequency of AA retention after surgery for skull base chordoma was 30.97%. The incidence of postoperative pulmonary complications was much lower in those without AA retention (3.74 vs. 39.58%, P < 0.001). Factors with the highest point estimates for the odds of AA retention included body mass index, cranial nerve involvement, maximum tumor diameter, operative method, hemorrhage volume, operative duration and intraoperative mechanical ventilation duration.ConclusionsIn this retrospective cohort study, most of the factors associated with postoperative airway retention were closely related to the patient's tumor characteristics. These data demonstrate that respiratory management in patients with skull base chordoma remains an ongoing concern.

Comparison of brain nicotine uptake from electronic cigarettes and combustible cigarettes.

Brain accumulation rate and magnitude are critical for the acute reinforcing effects of nicotine. Despite electronic cigarettes' (E-cigs) appeal as substitutes for traditional combustible cigarettes (C-cigs), brain nicotine accumulation (BNA) from E-cigs has not been compared with that from C-cigs using a within-subjects design. BNA was directly assessed with 16 adult dual users (10 females) of E-cigs (e-liquid pH 9.4) and C-cigs, using 11C-nicotine and positron emission tomography (PET). Participants went through two 15-min head scanning sessions during which they inhaled a single puff of E-cig vapor or C-cig smoke containing 11C-nicotine in a randomized order. A full-body scan was also conducted at each session to measure total absorbed dose of 11C-nicotine. Mean maximum concentration (Cmax) and area under curve of BNA were 22.1% and 22.7% lower, respectively, following E-cig compared with C-cig inhalation. Meanwhile, T1/2 was 2.7 times longer following inhalation of E-cig vapor relative to C-cig smoke (all ps < 0.005). Whole-body imaging indicated greater nicotine retention in the respiratory tract from vapor versus smoke inhalation (p < 0.0001). Following vapor inhalation, nicotine retention in the respiratory tract was correlated with Cmax values of BNA (rs = -0.59, p < 0.02). Our results confirm that E-cigs with alkaline pH e-liquid can deliver nicotine rapidly to the brain, albeit less efficiently than C-cigs partly due to greater airway retention of nicotine. Since brain nicotine uptake mediates reinforcement, these results help elucidate actions of E-cigs in terms of abuse liability and effectiveness in substituting for combustible cigarettes.

Management of Pseudomonas aeruginosa infection in cystic fibrosis patients using inhaled antibiotics with a focus on nebulized liposomal amikacin.

Pseudomonas aeruginosa (PsA) is a highly prevalent bacterial organism recovered from the lungs of cystic fibrosis (CF) patients and chronic PsA infection is linked to progressive pulmonary function decline. The eradication and treatment of this organism from CF airways is particularly challenging to CF care providers. Aerosolized antibiotics that target PsA help to slow down growth, maintain lung function and reduce the frequency of pulmonary exacerbations. In this review, we discuss the currently available inhaled antibiotics for management of PsA lung infections in CF patients, with a focus on liposomal amikacin for inhalation (LAI). LAI is a unique formulation of amikacin under development that enhances drug delivery and retention in CF airways via drug incorporation into neutral liposomes. Factors such as once-daily dosing, mucus and biofilm penetration and potentially prolonged off-drug periods make LAI a potentially attractive option to manage chronic PsA lung infections in CF patients.

Theoretical models for the simulation of particle deposition and tracheobronchial clearance in lungs of patients with chronic bronchitis.

Based upon theoretical models particle deposition and clearance in human respiratory systems affected by chronic bronchitis can be approximated reliably. As a consequence of those hypothetical results, optimal frame conditions (e.g., inhalation time and volume, particle properties) for inhalation therapies can be determined. Simulation of particle deposition was conducted by modelling a partly or fully obstructed tracheobronchial architecture. Bronchitis-induced reductions of the airway calibres were computed by application of specific scaling factors. Three different scenarios of chronic bronchitis were modelled. Brownian motion, inertial impaction, interception, and gravitational settling were assumed as main deposition forces influencing inhaled particular mass. Tracheobronchial clearance was approximated by application of generation-specific mucus velocities as well as the consideration of a slow bronchial clearance phase, whose half-time varied between 5 and 20 days. Under different breathing conditions (i.e., sitting and light-work breathing) deposition of submicron and µm-sized particles is significantly enhanced within the bronchial lung region, but also alveolar deposition becomes partly enhanced. By changing the inhalation conditions target sites of therapeutic aerosols may be reached with rather high accuracy. Based on the data of this modified models, particle retention in lung airways of patients suffering from chronic bronchitis may be noticeably prolonged, with 24-hour retention values being increased by up to 50%. As exhibited by the results, particle deposition behaviour in lungs affected by chronic bronchitis differs remarkably from that in healthy lungs. These theoretical finds are mostly supported by experimental data. Further, experimental and theoretical deposition results may be used for an estimation of the grade of disease. Tracheobronchial clearance reduces its efficiency with each progress of the disease which increases the probability of bacterial infections in the airways.

Pharmacokinetic Evaluation of Intranasally Administered Vinyl Polymer-Coated Lorazepam Microparticles in Rabbits

The intranasal (IN) administration of lorazepam is desirable in order to maximize speed of onset and minimise carry-over sedation; however, this benzodiazepine is prone to chemical hydrolysis and poor airway retention, and thus, innovative epithelial presentation is required. The aim of this study was to understand how the in situ self-assembly of a mucoretentive delivery system, formed by the dissolution of vinyl polymer-coated microparticles in the nasal mucosa, would influence lorazepam pharmacokinetics (PK). IN administration of the uncoated lorazepam powder (particle size, 6.7 ± 0.1μm) generated a biphasic PK profile, which was indicative of sequential intranasal and oral absorption (n = 6; dose, 5mg/kg). Coating the drug with the vinyl polymer, MP1 (9.9 ± 0.5μm with 38.8 ± 14.0%, w/w lorazepam) and MP2 (10.7 ± 0.1μm with 47.0 ± 1.0%, w/w lorazepam), allowed rapid systemic absorption (MP1, T (max) 14.2 ± 4.9min; MP2, T (max) 9.3 ± 3.8min) in rabbits and modified the PK profiles in a manner that suggested successful nasal retention. The poly(vinyl pyrrolidone)-rich MP2 system provided the best comparative bioavailability, it prolonged the early-phase nasal drug absorption and minimised drug mucociliary clearance, which correlated well with the intermolecular hydrogen-bond-driven vinyl polymer interactions observed in vitro.

Rétention dans les voies aériennes des particules nanométriques de l’aérosol de la fumée de cigarette au cours du tabagisme passif

Second hand cigarette smoke consists predominantly of nanoparticles (with two dimensions less than 100 nanometres). The aim of this study was to examine the aerosol of cigarette smoke suspended in the air of a smoking room, its disappearance over the course of time, and its retention in the airways of passive smokers, as these processes remain poorly characterised.A smoking machine produced cigarette smoke in a room. A low pressure electrostatic impactor with 13 plates, measured the size distribution and the concentration of the smallest particle sizes in the room air. Healthy adult volunteers (n=14) inhaled and exhaled this air through a nasal mask, allowing calculation of the retention of nanometric particles.The tobacco smoke aerosol was composed of 75% of nanometric particles. The half-life of these particles in the air was 18min. After 2h, 3% of the tobacco smoke particles remained suspended in the air. In passive smokers, the measured airway retention was on average 20%.This work shows that 75% of second hand cigarette smoke aerosol is made up of nanoparticles. When non-smokers inhale this passively, 20% of the particles are retained in their respiratory tract.

Differences in Endogenous Esterification and Retention in the Rat Trachea between Budesonide and Ciclesonide Active Metabolite

The airway retention of inhaled glucocorticosteroids (GCs) depends largely on their lipophilicity. Inhaled budesonide (BUD) becomes highly lipophilic reversibly by the formation of esters acting as a reservoir of active BUD. Ciclesonide (CIC) was also reported to form esters after hydrolysis to active metabolite (CIC-AM). We have investigated lipophilicity and airway retention of BUD, CIC/CIC-AM, fluticasone propionate (FP), and mometasone furoate (MF), and compared esterification of BUD and CIC-AM and its contribution to GC airway retention. Rat tracheas were preincubated with the esterification inhibitor cyclandelate or vehicle. A (3)H-GC ( approximately 10(-7) M: BUD, CIC, CIC-AM, FP, MF) was added for 20 min. After incubation, one half of the trachea was used for analysis of GC uptake and the other to analyze GC release during 3 h in drug-free medium. GC species in trachea halves were analyzed by radiochromatography. At 20 min, the uptake of BUD was similar to that of CIC/CIC-AM; however, the BUD-ester pool was 9-fold greater (p < 0.01). BUD overall retention in trachea at 3 h was greater than that of other GCs (p < 0.01), and the BUD-ester pool was 3-fold greater than the CIC-AM-ester pool (p < 0.01). Cyclandelate decreased the initial BUD- and CIC-AM-ester pools (p < 0.01), and reduced the overall retention of BUD at 3 h (p < 0.01) but not of CIC-AM. Thus, BUD becomes esterified in the airways more promptly and to a greater extent than CIC-AM, and BUD esterification prolongs BUD airway retention. In contrast, airway retention of CIC-AM and CIC seems to be determined mainly by their lipophilicity, similar to FP and MF, which are not esterified.

Bronchoscopic assessment of airway retention time of aerosolized xylitol

BackgroundHuman airway surface liquid (ASL) has abundant antimicrobial peptides whose potency increases as the salt concentration decreases. Xylitol is a 5-carbon sugar that has the ability to lower ASL salt concentration, potentially enhancing innate immunity. Xylitol was detected for 8 hours in the ASL after application in airway epithelium in vitro. We tested the airway retention time of aerosolized iso-osmotic xylitol in healthy volunteers.MethodsAfter a screening spirometry, volunteers received 10 ml of nebulized 5% xylitol. Bronchoscopy was done at 20 minutes (n = 6), 90 minutes (n = 6), and 3 hours (n = 5) after nebulization and ASL was collected using microsampling probes, followed by bronchoalveolar lavage (BAL). Xylitol concentration was measured by nuclear magnetic resonance spectroscopy and corrected for dilution using urea concentration.ResultsAll subjects tolerated nebulization and bronchoscopy well. Mean ASL volume recovered from the probes was 49 ± 23 μl. The mean ASL xylitol concentration at 20, 90, and 180 minutes was 1.6 ± 1.9 μg/μl, 0.6 ± 0.6 μg/μl, and 0.1 ± 0.1 μg/μl, respectively. Corresponding BAL concentration corrected for dilution was consistently lower at all time points. The terminal half-life of aerosolized xylitol obtained by the probes was 45 minutes with a mean residence time of 65 minutes in ASL. Corresponding BAL values were 36 and 50 minutes, respectively.ConclusionAfter a single dose nebulization, xylitol was detected in ASL for 3 hours, which was shorter than our in vitro measurement. The microsampling probe performed superior to BAL when sampling bronchial ASL.

Pulmonary Retention of Particulate Matter is Associated with Airway Inflammation in Allergic Rats Exposed to Air Pollution in Urban Detroit

A collaborative research study was conducted in order to improve our understanding of the source-to-receptor pathway for ambient fine particulate matter (aerodynamic diameter ≤ 2.5 μ m; PM2.5) and subsequently to investigate the identity and sources of toxic components in PM2.5 responsible for adverse health effects in allergic humans. This research used a Harvard fine particle concentrator to expose Brown Norway rats, with and without ovalbumin-induced allergic airway disease, to concentrated air particles (CAPs) generated from ambient air in an urban Detroit community where the pediatric asthma rate was three times higher than the national average. Rats were exposed to CAPs during the exposure periods in July (mean = 676 μg/m3) and September (313 μg/m3) of 2000. Twenty-four hours after exposures lung lobes were either lavaged with saline to determine cellularity and protein in bronchoalveolar lavage fluid (BALF), or removed for analysis by inductively coupled plasma–mass spectrometry (ICP-MS) to detect ambient PM2.5-derived trace element retention. PM2.5 trace elements of anthropogenic origin, lanthanum (La), vanadium (V), manganese (Mn), and sulfur (S), were recovered from the lung tissues of CAPs-exposed rats. Recovery of those pulmonary anthropogenic particles was further increased in rats with allergic airways. In addition, eosinophils and protein in BALF were increased only in allergic animals exposed to CAPs. These results demonstrate preferential retention in allergic airways of air particulates derived from identified local combustion sources after a short-term exposure. Our findings suggest that the enhancement of allergic airway responses by exposure to PM2.5 is mediated in part by increased pulmonary deposition and localization of potentially toxic elements in urban air.

Airway retention of materials of different solubility following local intrabronchial deposition in dogs.

We used a gamma camera to monitor the retention and clearance of radiolabeled human serum albumin (HSA), a water-soluble material with molecular weight of 66,000 Daltons, and radiolabeled sulfur colloid (SC), an insoluble submicron (0.22 microm) particle, following localized deposition in a 4-5-mm bronchus in each of five dogs. The average retention time of HSA was significantly greater than that of SC both in the deposition site (23.3 +/- 2.3 vs. 18.2 +/- 2.9 min respectively, p < 0.05) and in the clearance pathway (26.5 +/- 2.0 vs. 22.0 +/- 1.4 min, respectively, p < 0.05). The mean percent retention at the deposition site at 60 minutes post-deposition also was significantly greater for HSA than for SC (33.5 +/- 10.1 vs. 11.6 +/- 4.7%, respectively, p < 0.05). The percentage of HSA which had cleared to the level of the cuffed endotracheal tube was significantly less than that of SC (18.0 +/- 6.7 vs. 35.8 +/- 3.5%, respectively, p < 0.05) at 60 min post-deposition. These findings indicate that a low-permeating water-soluble material such as HSA deposited on the surface of an airway remains in contact with the sensitive airway epithelium to a greater extent than does a solid insoluble particle. Based on our results, we speculate that the slower clearance of HSA compared to SC was likely due to diffusion of a greater portion of the HSA into the periciliary sol layer which may be transported less efficiently than the mucus layer during mucociliary clearance. Additionally, some degree of uptake of HSA by bronchial epithelium may have contributed to its increased retention.

Bronchial edema alters (99m)Tc-DTPA clearance from the airway surface in sheep.

Airway wall edema, prominent in inflammatory airways disease, may alter barrier properties at the airway air-liquid interface such that normal absorption of soluble substances into the airway circulation is altered. We studied the effects of bradykinin-induced airway wall edema on the clearance of the soluble tracer technetium-99m-labeled diethylenetriamine pentaacetic acid ((99m)Tc-DTPA) from subcarinal airways in sheep (n = 8). (99m)Tc-DTPA (6-10 microl) was delivered by a microspray nozzle inserted through a bronchoscope to a fourth-generation bronchus both before and 1 h after bradykinin (20 ml; 10(-6) M) had been infused through a cannulated and perfused bronchial artery. Airway retention (by scintigraphy) and blood levels of radiolabel were monitored for 30 min after the local deposition of (99m)Tc-DTPA. During control conditions, 85-90% of the tracer cleared from the deposition site within 30 min. The maximum blood level during that time was 17% of the total delivered tracer. However, 1 h after bradykinin infusion, there was significant retention of the marker at the deposition site with clearance within 30 min reduced to 63-70% and decreased blood levels of radiolabel (8%; both P < 0.05). These results demonstrate that moderate airway wall edema alters blood uptake and removal of soluble substances delivered to the subcarinal airways. We suggest that the interplay between vascular and mucociliary clearance routes will impact the resident time for clearance of soluble air toxins and/or therapeutic agents from the epithelial surface.

The role of the bronchial vasculature in soluble particle clearance.

Although a role for the airway circulation in the clearance of inhaled particles is generally assumed, there is little information to confirm its importance. We studied the effects of decreased bronchial blood flow on the uptake of the soluble tracer technetium=99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) from subcarinal airways in sheep (n = 7). The bronchial artery was cannulated and perfused with autologous blood at a control flow (0.6 mL/min/kg) or when the perfusion pump was stopped (no flow). (99m)Tc-DTPA (6-10 microL) was delivered by a microspray nozzle inserted through a bronchoscope to a fourth-generation bronchus both during control blood flow conditions and no-flow conditions. Airway retention (by scintigraphy) and blood uptake were monitored for 30 min after the local deposition of (99m(Tc-DTPA. During control flow conditions, 30 min after the delivery of the radiolabel, 21% of the tracer remained at the deposition site. Of the total delivered tracer, maximum blood uptake was 18% (n) = 3). When bronchial perfusion was stopped, airway retention 30 min after deposition increased to 43%, and maximum blood uptake decreased to 7% of the total delivered tracer. Although mucociliary clearance was not directly measured, radiolabel tracer was observed to move progressively from the deposition site up to larger airways and contributed to the overall removal of tracer from the site of deposition during both flow conditions. However, these results demonstrate that decreased bronchial perfusion increases airway retention by limiting vascular uptake of the soluble tracer. These results emphasize the importance of normal perfusion of the airway vasculature for uptake of therapeutic agents delivered specifically to the conducting airways.

Interdependence of bronchial circulation and clearance of 99mTc-DTPA from the airway surface.

The extent to which the systemic vasculature is involved in soluble-particle uptake in the conducting airways has not been studied extensively. In anesthetized, ventilated sheep, 6-10 microl of technetium-99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) was delivered through a microspray nozzle to a fourth-generation airway. Perfusion of the cannulated bronchial artery was varied between control flow (0.6 ml x min(-1) x kg(-1)), high flow (1.8 ml x min(-1) x kg(-1)) or no flow (the infusion pump was stopped). Airway retention of the radioactive tracer was monitored using gamma camera imaging, and venous blood was sampled. During control perfusion, tracer retention at the site of deposition at 30 min averaged 20 +/- 6% (n = 7). With no flow, retention was significantly elevated to 32 +/- 8% (P = 0.03). In another group of sheep (n = 5) with a control retention of 13 +/- 4%, high flow resulted in an increase in tracer (25 +/- 4%; P = 0.04). Maximum blood uptake of tracer was calculated by estimating circulating blood volume and averaged 16% of total activity during control flow. Only during high-flow conditions was 99mTc-DTPA in the blood decreased (10%; P = 0.04). Most of the tracer was cleared by mucociliary clearance as visualized by imaging. This component was substantially decreased during no flow. The results demonstrate that both decreased and increased airway perfusion limit removal of soluble tracer applied to the conducting airways.

PROLONGED AIRWAY RETENTION OF INSOLUBLE PARTICLES IN CYSTIC FIBROSIS VERSUS PRIMARY CILIARY DYSKINESIA

Patients with cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) have been shown to have impaired large airway clearance of radiolabelled particles as measured by external gamma camera scanning up to 6 hours post deposition. Recent studies suggest that 24-hour retention of particles may reflect some airway retention in addition to alveolar retention. In a retrospective study, we analyzed the relationship between the deposition pattern and 24-hour retention (Ret24 hr) of technetium 99 radiolabelled iron oxide (99Tc-Fe2O3) particles in 20 patients with CF, 12 patients with PCD, and 17 normal subjects. By gamma camera analysis, initial aerosol deposition was analyzed in terms of central peripheral (C/P) activity within the lungs. Gamma camera scanning was performed immediately following deposition and again at 24 hours to assess residual retention (Ret24hr) as a percent of initial deposition. C/P analysis was also performed on the 24-hour scan (C/P24). For all subjects, initial deposition pattern (C/P) was inversely related to lung function (forced expiratory volume in 1 second \\[FEV1]%pred vs. C/P, r =-.54). Ret24hr was also inversely related to initial deposition pattern for all subjects (Ret24hr vs. C/P ratio, r=-.42). Analysis of covariance showed that for a given C/P ratio, CF patients had significantly greater Ret24hr compared to normal subjects (9.8 +/- 2.8\\[SE]%). In addition, the CF patients had similar C/P24 as the normal subjects (1.35 +/- 0.40\\[SD] vs. 1.10 +/- 0.39, respectively). These results suggest that small airway clearance is compromised in CF patients compared to normal subjects. On the other hand, PCD patients had C/P24 similar to their initial deposition C/P ratios (2.78 +/- 1.72 vs. 2.45 +/- 0.87, respectively), significantly greater than 1.0, and significantly greater than CF or normal subjects, suggesting that PCD patients have prolonged particle retention associated with their large bronchial airways.

Anatomic localization of 24- and 96-h particle retention in canine airways.

Long-term retention of particles in airways is controversial. However, precise anatomic localization of the particles is not possible in people. In this study the anatomic location of retained particles after shallow bolus inhalation was determined in anesthetized, ventilated beagle dogs. Fifty 30-cm(3) boluses containing monodisperse 2.5-micron polystyrene particles (PSL) were delivered to a shallow lung depth of 81-129 cm(3). At 96 h before euthanasia, red fluorescent PSL were used; at 24 h, green fluorescent PSL and (99m)Tc-labeled PSL were used. Clearance of (99m)Tc-PSL was measured during the next 24 h. Sites of particle retention were determined in systematic, volume-weighted random samples of microwave-fixed lung tissue. Precise particle localization and distribution was analyzed by using gamma counting, conventional fluorescence microscopy, and confocal microscopy. Within 24 h after shallow bolus inhalation, 50-95% of the deposited (99m)Tc-PSL were cleared, but the remaining fraction was cleared slowly in all dogs, similar to previous human results. The three-dimensional deposition patterns showed particles across the entire cross-sectional plane of the lungs at the level of the carina. In these locations, 33 +/- 9.9% of the retained particles were found in small, nonrespiratory airways (0.3- to 1-mm diameter) and 49 +/- 10% of the particles in alveoli; the remaining fraction was found in larger airways. After 96 h, a similar pattern was found. These findings suggest that long-term retention in airways is at the bronchiolar level.

A CD18/ICAM-1-dependent pathway mediates eosinophil adhesion to human bronchial epithelial cells.

Eosinophil adhesion to airway epithelium is believed to facilitate eosinophil accumulation and retention in asthmatic airways. Monoclonal antibodies (mAb) against intercellular adhesion molecule-1 (ICAM-1) and its CD18 leukocyte integrin ligands have been shown to inhibit airway eosinophilia in animal models of asthma, although the role of this pathway in eosinophil-epithelial adhesion is not fully understood. To investigate the role in vitro of CD18 and ICAM-1, we measured adhesion of fluorescently labeled human eosinophils to normal human bronchial epithelial cell (NHBEC) monolayers pretreated for 24 h with culture medium (low constitutive ICAM-1) or tumor necrosis factor-alpha (TNF-alpha; 1 ng/ml) and interferon-gamma (IFN-gamma) (10 ng/ml; increased ICAM-1). Stimulation of eosinophils with C5a (10(-7) M) increased adhesion measured at 30 min to unactivated NHBEC from 11.4 +/- 0.7 to 15.5 +/- 0.4% (n = 4), and this increase was CD18/ICAM-1-independent, whereas phorbolmyristate acetate (PMA) (10(-8) M)-induced adhesion (20.7 +/- 1.7%) was abolished by anti-CD18 and reduced by anti-ICAM-1. In contrast, C5a- and PMA-induced adhesion to TNF-alpha/IFN-gamma-activated NHBEC (increased from 11.1 +/- 1.3% to 21.9 +/- 1.0% and 27.6 +/- 1.9%, respectively) was CD18- and ICAM-1-dependent. Eotaxin, but not regulated on activation normal T cells expressed and secreted, macrophage inflammatory protein-1, formyl methionyl leucyl phenylalanine, leukotriene B4 or platelet-activating factor, also induced CD18/ICAM-1-dependent adhesion to activated NHBEC. In the absence of added chemoattractants, eosinophil adhesion to NHBEC increased with time and, at 120 min, was significantly greater (P < 0.01) to activated NHBEC (37.3 +/- 2.4%, n = 5) than to unactivated monolayers (24.3 +/- 1.9%); mAb against CD18 or ICAM-1 abolished increased, but not basal, adhesion. These results suggest that CD18/ICAM-1 mediated eosinophil adhesion to activated NHBEC but that adhesion to resting NHBEC was largely independent of this pathway.

Bronchial airway deposition and retention of particles in inhaled boluses: effect of anatomic dead space

The fractional deposition of particles in boluses delivered to shallow lung depths and their subsequent retention in the airways may depend on the relative volume and size of an individual's airways. To evaluate the effect of variable anatomic dead space (ADS) on aerosol bolus delivery we had healthy subjects inhale radiolabeled, monodisperse aerosol (99mTc-iron oxide, 3.5 micron mean mondispersed aerosol diameter) boluses (40 ml) to a volumetric front depth of 70 ml into the lung at a lung volume of 70% total lung capacity end inhalation. By using filter techniques, aerosol photometry, and gamma camera analysis, we estimated the fraction of the inhaled boluses deposited in intrathoracic airways (IDF). ADS by single-breath N2 washout was also measured from 70% total lung capacity. Results showed that among all subjects IDF was variable (range = 0.04-0.43, coefficient of variation = 0.54) and increased with decreasing ADS (r = -0.76, P = 0.001, n = 16). We found significantly greater deposition in the left (L) vs. right (R) lungs; mean L/R (ratio of deposition in L lung to R lung, normalized to ratio of L-to-R lung volume) was 1.58 +/- 0.42 (SD; P < 0.001 for comparison with 1.0). Retention of deposited particles at 2 h was independent of ADS or IDF. There was significant retention of particles at 24 h postdeposition (0.27 +/- 0.05) and slow clearance of these particles continued through 48 h postdeposition. Finally, analysis of central-to-peripheral ratios of initial deposition and 24-h-retention gamma-camera images suggest significant retention of insoluble particles in large bronchial airways at 24 h postdeposition (i.e., 24 h central-to-peripheral ratio = 1.40 +/- 0. 44 and 1.82 +/- 0.54 in the R and L lung, respectively; P < 0.02 for comparison with 1.0). These data may prove useful for 1) designing aerosol delivery techniques to target bronchial airways and 2) understanding airway retention of inhaled particles.

Implications of airway retention for radiation doses from inhaled radionuclides.

A slow phase of bronchial and bronchiolar clearance ('airway retention') has been included in the revised dosimetric model for the human respiratory tract recently adopted by the International Commission on Radiological Protection (ICRP), based primarily on the results of the bolus clearance experiments conducted by Stahlhofen et al. The treatment of airway retention in the new ICRP model is described. An analysis was carried out of the sensitivity of the equivalent lung dose, and the effective dose, to assumptions made in the new model about the extent of airway retention. It was shown that inclusion of airway retention of material deposited in the bronchial tree does have a significant effect on both end-points (of the order of 10-50%) for a wide range of radionuclides. In some cases, notably moderately soluble forms of long-lived alpha-emitters, its inclusion increases these doses by up to a factor of three, so that it makes the dominant contribution to the calculated dose. The model assumes that material in transit through the bronchial tree, having initially deposited in the alveolar region, is not subject to airway retention. Including retention of this material would typically increase doses by a further factor similar to that resulting from the airway retention of the bronchial deposit.