Total Respiratory Tract Research Articles

The fate of an inhaled cigarette puff in the human respiratory tract

Objective Cigarette smoking can lead to a host of adverse health effects such as lung and heart disease. Increased lung cancer risk is associated with inhalation of carcinogens present in a puff of smoke. These carcinogenic compounds deposit in the lung at different sites and trigger a cascade of events leading to adverse outcomes. Understanding the site-specific deposition of various smoke constituents will inform the study of respiratory diseases from cigarette smoking. We previously developed a deposition model for inhalation of aerosol from electronic nicotine delivery systems. In this study, the model was modified to simulate inhalation of cigarette smoke consisting of soluble and insoluble tar, nicotine, and cigarette-specific constituents that are known or possible human carcinogens. Materials and Methods The deposition model was further modified to account for nicotine protonation and other cigarette-specific physics-based mechanisms that affect smoke deposition. Model predictions showed a total respiratory tract uptake in the lung for formaldehyde (99%), nicotine (80%), and benzo[a]pyrene (60%). Results The site of deposition and uptake depended primarily on the constituent’s saturation vapor pressure. High vapor pressure constituents such as formaldehyde were preferentially absorbed in the oral cavity and proximal lung regions, while low vapor pressure constituents such as benzo[a]pyrene were deposited in the deep lung regions. Model predictions of exhaled droplet size, droplet retention, nicotine retention, and uptake of aldehydes compared favorably with experimental data. Conclusion The deposition model can be integrated into exposure assessments and other studies that evaluate potential adverse health effects from cigarette smoking.

Fate of inhaled electronic nicotine delivery systems (ENDS) puff constituents in the human respiratory tract

Published research on the fate of a puff from electronic nicotine delivery systems (ENDS) in the lungs is limited; more information would better inform human exposure and potential adverse outcomes from ENDS use. An ENDS puff is a mixture of multiple constituents in droplet and vapor form, including propylene glycol, vegetable glycerin, nicotine, water, and flavor chemicals. Understanding the complexity of the puff aids in developing mechanistic models that can account for the physical, physiological, and thermodynamic processes of the puff while traveling and depositing in lung airways. Previously, we developed a mathematical model to predict deposition and uptake of ENDS constituents in the oral cavity. In this study, we formulated the model for lung airways to extend to the entire respiratory tract and made adjustments to mechanisms such as phase change and nicotine protonation to study effects on droplet pH and nicotine evaporation. We conducted model simulations for two representative inhalation profiles relevant to ENDS users: mouth-to-lung and direct-to-lung inhalation. Simulation results showed that vapor uptake during ENDS use was the primary mechanism of the overall tissue dose for higher vapor pressure constituents. Nicotine protonation was unaffected by the ratio of propylene glycol to vegetable glycerin but changes to vanillin molarity impacted droplet pH and free nicotine fraction. The largest uptake and deposition occurred in the deep lung, where constituents more efficiently reach the arterial blood. Predicted total respiratory tract retention of higher vapor pressure constituents such as nicotine, propylene glycol, and benzaldehyde were 94–95%, whereas retention of lower volatility constituents such as vegetable glycerin and vanillin was 82–83%. Results also indicated regional uptake differences for the constituents evaluated in the two inhalation scenarios. Predictions from the ENDS deposition model can be linked to physiologically based pharmacokinetic (PBPK) models to determine the fate of puff constituents such as nicotine in other tissues and organs of the body and provides further basis for evaluating flavor chemicals and puff constituents based on user-specific exposure characteristics as well as internal dose to inform risk assessment of ENDS.

Upper Respiratory Tract OC43 Infection Model for Investigating Airway Immune-Modifying Therapies.

Respiratory virus infections initiate and transmit from the upper respiratory tract (URT). Coronaviruses, including OC43, are a major cause of respiratory infection and disease. Failure to mount an effective antiviral immune response in the nasal mucosa increases the risk of severe disease and person-to-person transmission, highlighting the need for URT infection models to support the development of nasal treatments that improve coronavirus antiviral immunity. We aimed to determine if OC43 productively infected the mouse URT and would therefore be a suitable model to assess the efficacy and mechanism of action of nasal-targeting immune-modifying treatments. We administered OC43 via intranasal inoculation to wild-type Balb/c mice and assessed virus airway tropism (by comparing total respiratory tract vs. URT-only virus exposure) and characterized infection-induced immunity by quantifying specific antiviral cytokines and performing gene array assessment of immune genes. We then assessed the effect of immune-modulating therapies, including an immune-stimulating TLR2/6 agonist (INNA-X) and the immune-suppressing corticosteroid fluticasone propionate (FP). OC43 replicated in nasal respiratory epithelial cells, with peak viral RNA observed 2 days after infection. Prophylactic treatment with INNA-X accelerated expression of virus-induced IFN-λ and IFN-stimulated genes. In contrast, intranasal FP treatment increased nasal viral load by 2.4 fold and inhibited virus-induced IFN and IFN-stimulated gene expression. Prior INNA-X treatment reduced the immune-suppressive effect of FP. We demonstrate that the mouse nasal epithelium is permissive to OC43 infection and strengthen the evidence that TLR2 activation is a β-coronavirus innate immune determinant and therapeutic target.

Assessment of personal deposited dose of bioaerosols and particles in a wastewater treatment plant facility

The daily deposited dose of bioaerosols and particle mass or number in the human respiratory tract using an exposure dose model (ExDoM2) was quantified in the present study. The dose was calculated for the extrathoracic (ET), tracheobronchial (TB), and alveolar-interstitial (AI) regions of the human respiratory tract. The calculations were performed for viable, cultivable airborne heterotrophic bacteria, mesophilic fast-growing fungi, and total coliforms at a municipal wastewater treatment plant (WWTP) located at a suburban area at a Mediterranean site. The human dose was determined using data from two locations at the WWTP which correspond to two different wastewater treatment stages (aerated grit chamber (indoor) and primary settling tanks (outdoor)) and one outdoor location at the urban background site. In addition, the model simulations were performed for two exposure periods (March to April and May to June 2008). Higher daily deposited dose in the total human respiratory tract was observed for heterotrophic bacteria at the aerated grit chamber, whereas lower values of heterotrophic bacteria were observed at the primary settling tanks. These findings were associated with the corresponding stage of wastewater treatment activities and may be valuable information for determining future dose–response relationships. In addition, higher daily deposited dose was determined in the ET region for the three categories of bioaerosols. Regarding PM10 and PN1, the higher daily deposited dose received by a worker at the aerated grit chamber. Finally, the hazard quotients were estimated and the results showed that the non-carcinogenic effects can be ignored for bioaerosols and PM10 except for workers present at aerated grit chamber. Regarding PM2.5, the non-carcinogenic effects are of concern and cannot be ignored for all cases.

Association between ambient temperature and cause-specific respiratory outpatient visits: A case-crossover design with a distributed lag nonlinear model in Lanzhou, China

Little is known about the association between air temperature and causes-specific respiratory diseases (RD), especially in northwest China. A time-stratified case crossover design with a distributed lag nonlinear model (DLNM) was conducted to assess the nonlinear and delayed effects of temperature on total and cause-specific outpatient visits, with analyses stratified by gender and age. The cumulative effects of temperature were irregular M-shaped curves for total and upper respiratory tract infection (URTI), with inverted U-shaped curve for pneumonia, bronchitis and chronic obstructive pulmonary disease (COPD). Positive cold and heat effects were observed for URTI, pneumonia, bronchitis and COPD, bronchitis was most vulnerable to cold but pneumonia was more affected to heat. Heat effects were immediate whereas cold effects were delayed and lasted longer. The magnitude of temperature effects varies greatly by age, gender, and disease. Notably, the cold effect was greater for children aged 0–14 than that of other age groups. This study suggested that both cold and hot temperatures exposure could increase all-cause and cause-specific respiratory outpatient visits in Lanzhou, China. The harmful effect and duration of cold were greater than that of heat, and children aged 0–14 were more sensitive to cold. Protection against extreme temperatures should be strengthened.

Lung function and self-rated symptoms in healthy volunteers after exposure to hydrotreated vegetable oil (HVO) exhaust with and without particles

BackgroundDiesel engine exhaust causes adverse health effects. Meanwhile, the impact of renewable diesel exhaust, such as hydrotreated vegetable oil (HVO), on human health is less known. Nineteen healthy volunteers were exposed to HVO exhaust for 3 h in a chamber with a double-blind, randomized setup. Exposure scenarios comprised of HVO exhaust from two modern non-road vehicles with 1) no aftertreatment system (‘HVOPM+NOx’ PM1: 93 µg m−3, EC: 54 µg m−3, NO: 3.4 ppm, NO2: 0.6 ppm), 2) an aftertreatment system containing a diesel oxidation catalyst and a diesel particulate filter (‘HVONOx’ PM1: ~ 1 µg m−3, NO: 2.0 ppm, NO2: 0.7 ppm) and 3) filtered air (FA) as control. The exposure concentrations were in line with current EU occupational exposure limits (OELs) of NO, NO2, formaldehyde, polycyclic aromatic hydrocarbons (PAHs), and the future OEL (2023) of elemental carbon (EC). The effect on nasal patency, pulmonary function, and self-rated symptoms were assessed. Calculated predicted lung deposition of HVO exhaust particles was compared to data from an earlier diesel exhaust study.ResultsThe average total respiratory tract deposition of PM1 during HVOPM+NOx was 27 µg h−1. The estimated deposition fraction of HVO PM1 was 40–50% higher compared to diesel exhaust PM1 from an older vehicle (earlier study), due to smaller particle sizes of the HVOPM+NOx exhaust. Compared to FA, exposure to HVOPM+NOx and HVONOx caused higher incidence of self-reported symptoms (78%, 63%, respectively, vs. 28% for FA, p < 0.03). Especially, exposure to HVOPM+NOx showed 40–50% higher eye and throat irritation symptoms. Compared to FA, a decrement in nasal patency was found for the HVONOx exposures (− 18.1, 95% CI: − 27.3 to − 8.8 L min−1, p < 0.001), and for the HVOPM+NOx (− 7.4 (− 15.6 to 0.8) L min−1, p = 0.08). Overall, no clinically significant change was indicated in the pulmonary function tests (spirometry, peak expiratory flow, forced oscillation technique).ConclusionShort-term exposure to HVO exhaust concentrations corresponding to EU OELs for one workday did not cause adverse pulmonary function changes in healthy subjects. However, an increase in self-rated mild irritation symptoms, and mild decrease in nasal patency after both HVO exposures, may indicate irritative effects from exposure to HVO exhaust from modern non-road vehicles, with and without aftertreatment systems.

Early laparoscopic cholecystectomy in very elderly patients: a propensity score-matched analysis of a nationwide registry

Background: The role of early laparoscopic cholecystectomy (ELC) in very elderly patients with acute calculous cholecystitis (ACC) is still controversial. The aim of this study is to assess the safety of ELC for ACC in ≥85-year-old patients. Methods: Multicentric retrospective analysis of patients who underwent ELC for ACC between 2013-2018. Patients ≥85-year-old were assigned to group 1, those younger to group 2. The two groups were compared before and after propensity-score matching (PSM). The main outcomes were post-operative complications, length of stay, and readmissions. Results: The study included 1670 subjects. The unmatched comparison revealed a selection bias towards group 1, that was associated with higher Charlson Comorbidity Index (5 vs 1, p<0.001), more ASA III/IV patients (54.2% vs 19.3%, p<0.001), diabetes mellitus (36.8% vs 19.1%, p<0.001), previous abdominal surgery (39.6% vs 27.4%, p=0.010), previous percutaneous cholecystostomy (13.2% vs 2.4%, p<0.001), perforated gallbladder on preoperative imaging (14.4% vs 6.3%, p=0.005) and grade II/III ACC (80.1% vs 69.1%, p=0.016). Group 1 patients also required more conversion to open surgery (20% vs 10.3%, p=0.005) and subtotal cholecystectomy (9.3% vs 3.4%, p=0.012). After the PSM (n=206 patients) the two groups were comparable in terms of baseline characteristics and intraoperative outcomes, with a model exhibiting good discrimination and calibration. No significant differences were observed in total postoperative complications, bile leak, incisional, intrabdominal, urinary and respiratory tract infections, length of stay, and readmissions. Conclusions: ELC for ACC seems safe in selected ≥85-year-old patients. Age itself should not be regarded as a contraindication to surgery with ELC.

A new method to measure real-world respiratory tract deposition of inhaled ambient black carbon

In this study, we present the development of a mobile system to measure real-world total respiratory tract deposition of inhaled ambient black carbon (BC). Such information can be used to supplement the existing knowledge on air pollution-related health effects, especially in the regions where the use of standard methods and intricate instrumentation is limited. The study is divided in two parts. Firstly, we present the design of portable system and methodology to evaluate the exhaled air BC content. We demonstrate that under real-world conditions, the proposed system exhibit negligible particle losses, and can additionally be used to determine the minute ventilation. Secondly, exemplary experimental data from the system is presented. A feasibility study was conducted in the city of La Paz, Bolivia. In a pilot experiment, we found that the cumulative total respiratory tract deposition dose over 1-h commuting trip would result in approximately 2.6 μg of BC. This is up to 5 times lower than the values obtained from conjectural approach (e.g. using physical parameters from previously reported worksheets). Measured total respiratory tract deposited BC fraction varied from 39% to 48% during walking and commuting inside a micro-bus, respectively.To the best of our knowledge, no studies focusing on experimental determination of real-world deposition dose of BC have been performed in developing regions. This can be especially important because the BC mass concentration is significant and determines a large fraction of particle mass concentration. In this work, we propose a potential method, recommendations, as well as the limitations in establishing an easy and relatively cheap way to estimate the respiratory tract deposition of BC.

Predicting Disease Severity and Viral Spread of H5N1 Influenza Virus in Ferrets in the Context of Natural Exposure Routes

Although avian H5N1 influenza virus has yet to develop the capacity for human-to-human spread, the severity of the rare cases of human infection has warranted intensive follow-up of potentially exposed individuals that may require antiviral prophylaxis. For countries where antiviral drugs are limited, the World Health Organization (WHO) has developed a risk categorization for different levels of exposure to environmental, poultry, or human sources of infection. While these take into account the infection source, they do not account for the likely mode of virus entry that the individual may have experienced from that source and how this could affect the disease outcome. Knowledge of the kinetics and spread of virus after natural routes of exposure may further inform the risk of infection, as well as the likely disease severity. Using the ferret model of H5N1 infection, we compared the commonly used but artificial inoculation method that saturates the total respiratory tract (TRT) with virus to upper respiratory tract (URT) and oral routes of delivery, those likely to be encountered by humans in nature. We show that there was no statistically significant difference in survival rate with the different routes of infection, but the disease characteristics were somewhat different. Following URT infection, viral spread to systemic organs was comparatively delayed and more focal than after TRT infection. By both routes, severe disease was associated with early viremia and central nervous system infection. After oral exposure to the virus, mild infections were common suggesting consumption of virus-contaminated liquids may be associated with seroconversion in the absence of severe disease. Risks for human H5N1 infection include direct contact with infected birds and frequenting contaminated environments. We used H5N1 ferret infection models to show that breathing in the virus was more likely to produce clinical infection than swallowing contaminated liquid. We also showed that virus could spread from the respiratory tract to the brain, which was associated with end-stage disease, and very early viremia provided a marker for this. With upper respiratory tract exposure, infection of the brain was common but hard to detect, suggesting that human neurological infections might be typically undetected at autopsy. However, viral spread to systemic sites was slower after exposure to virus by this route than when virus was additionally delivered to the lungs, providing a better therapeutic window. In addition to exposure history, early parameters of infection, such as viremia, could help prioritize antiviral treatments for patients most at risk of succumbing to infection.

Inhalation dosimetry of hexamethylene diisocyanate vapor in the rat and human respiratory tracts

Hexamethylene diisocyanate (HDI) is a reactive chemical used in the commercial production of polyurethanes. Toxic effects in rodents exposed to HDI vapor primarily occur in the nasal passages, yet some individuals exposed occupationally to concentrations exceeding current regulatory limits may experience temporary reduction in lung function and asthma-like symptoms. Knowledge of interspecies differences in respiratory tract dosimetry of inhaled HDI would improve our understanding of human health risks to this compound. HDI uptake was measured in the upper respiratory tract of anesthetized Fischer-344 rats. Nasal uptake of HDI was >90% in rats at unidirectional flow rates of 150 and 300 ml/min and a target air concentration of 200 ppb. Uptake data was used to calibrate nasal and lung dosimetry models of HDI absorption in rats and humans. Computational fluid dynamics (CFD) models of the nasal passages were used to simulate inspiratory airflow and HDI absorption. Transport of HDI through lung airways was simulated using convection-diffusion based mass transport models. HDI nasal uptake of 90% and 78% was predicted using the rat and human nasal CFD models, respectively. Total respiratory tract uptake was estimated to be 99% in rats and 97% in humans under nasal breathing. Predicted human respiratory uptake decreased to 87% under oral breathing conditions. Absorption rates of inhaled HDI in human lung airways were estimated to be higher than the rat due to lower uptake in head airways. Model predictions demonstrated significant penetration of HDI to human bronchial airways, although absorption rates were sensitive to breathing style.

Induction of mucosal and systemic immunity against respiratory syncytial virus by inactivated virus supplemented with TLR9 and NOD2 ligands

Respiratory syncytial virus (RSV) infection is the most important viral cause of severe respiratory disease in infants and children worldwide and also forms a serious threat in the elderly. The development of RSV vaccine, however, has been hampered by the disastrous outcome of an earlier trial using an inactivated and parenterally administered RSV vaccine which did not confer protection but rather primed for enhanced disease upon natural infection. Mucosal administration does not seem to prime for enhanced disease, but non-replicating RSV antigen does not induce a strong mucosal immune response. We therefore investigated if mucosal immunization with inactivated RSV supplemented with innate receptor ligands, TLR9 (CpG ODN) and NOD2 (L18-MDP) through the upper or total respiratory tract is an effective and safe approach to induce RSV-specific immunity. Our data show that beta-propiolactone (BPL) inactivated RSV (BPL-RSV) supplemented with CpG ODN and L18-MDP potentiates activation of antigen-presenting cells (APC) in vitro, as demonstrated by NF-κB induction in a model APC cell line. In vivo, BPL-RSV supplemented with CpG ODN/L18-MDP ligands induces local IgA responses and augments Th1-signature IgG2a subtype responses after total respiratory tract (TRT), but less efficient after upper respiratory tract (intranasal, IN) immunization. Addition of TLR9/NOD2 ligands to the inactivated RSV also promoted affinity maturation of RSV-specific IgG antibodies and shifted T cell responses from mainly IL-5-secreting cells to predominantly IFN-γ-producing cells, indicating a Th1-skewed response. This effect was seen for both IN and TRT immunization. Finally, BPL-RSV supplemented with TLR9/NOD2 ligands significantly improved the protection efficacy against a challenge with infectious virus, without stimulating enhanced disease as evidenced by lack of eotaxin mRNA expression and eosinophil infiltration in the lung. We conclude that mucosal immunization with inactivated RSV antigen supplemented with TLR9/NOD2 ligands is a promising approach to induce effective RSV-specific immunity without priming for enhanced disease.

Deposition of fractal-like soot aggregates in the human respiratory tract

Deposition of diesel exhaust particles in the human respiratory tract is calculated in terms of the equivalent mobility diameter while accounting for the aggregate's number of primary spherules, N p , and its mass mobility fractal dimension. The size and shape of the soot particles studied correspond to emissions from diesel engines under different loading conditions. The aggregate's morphology, characterized by the aggregate mass mobility fractal dimension D fm , is shown to significantly affect its age- and ventilation-specific deposition patterns in the human respiratory tract and hence, the exposure experienced by the receptor. Reporting respiratory tract deposition of diesel soot solely in terms of the aggregate mobility diameter, which lumps together size and shape, precludes a close look at deposition patterns of real particles and does not provide a complete picture for exposure inference. For sedentary adults, soot aggregates tend to deposit in the pulmonary region, with large open aggregates depositing to a greater extent than large compact aggregates. In most cases, and for open structured aggregates in particular, the aggregate deposition exceeds the deposition of their equivalent volume spheres. Whereas adults experience higher total respiratory tract soot deposition, infants are more susceptible to proximal deposition of open aggregates ( D fm <2.2). For an adult performing intense activity both the tracheobronchial and the alveolar deposition fractions are smaller than at rest, whereas extrathoracic deposition increases during intense activity. Alveolar deposition of soot aggregates is evident mainly during rest and is more pronounced for small aggregates ( N p <50).

Neonatal total IgE and respiratory tract infections in children with intrauterine smoke exposure

BackgroundExposure to environmental tobacco smoke (ETS) is known to increase the risk of respiratory tract infections (RTI). Some children, however, may be more susceptible to the harmful effects of ETS...

Did a ban on diesel-fuel reduce emergency respiratory admissions for children?

This paper assesses whether a ban on diesel-powered motor vehicles in Lebanon has reduced emergency respiratory admissions for children less than 17 years of age in Beirut. Monthly admissions for total respiratory complaints, asthma, bronchitis, pneumonia, and upper respiratory tract infections, from October to February, were compared before and after the ban, using Poisson regression models and adjusting for rainfall, humidity and temperature. Analyses were repeated excluding the flu months of January and February. A test of significance of p < or = 0.05 was used. Air pollution is not systematically monitored in Lebanon and no ambient particulate concentration data were available. A significant drop in admissions for respiratory symptoms (p < or = 0.05) and upper respiratory tract infection (p < or = 0.001) from 1 year pre-ban to 1 year post-ban has been recorded. When flu months are excluded, a significant drop (p < or = 0.001) in admissions for all studied categories, except pneumonia, is observed. The effect of the ban however was negligible in the second year. When 2 year pre-ban versus 2 year post-ban are considered excluding flu months, statistically non-significant reductions are recorded for asthma and upper respiratory tract infection (p < or = 0.1). The study hence suggests an impact of the diesel ban on respiratory health only during the first year after the ban. This finding is weakened by the absence of supporting evidence from air quality monitoring and speciation of particulate matter, which are lacking in Lebanon and most developing countries.

Total respiratory tract deposition of fine micrometer-sized particles in healthy adults: empirical equations for sex and breathing pattern

Accurate dose estimation under various inhalation conditions is important for assessing both the potential health effects of pollutant particles and the therapeutic efficacy of medicinal aerosols. We measured total deposition fraction (TDF) of monodisperse micrometer-sized particles [particle diameter (Dp) = 1, 3, and 5 microm in diameter] in healthy adults (8 men and 7 women) in a wide range of breathing patterns; tidal volumes (Vt) of 350-1500 ml and respiratory flow rates (Q) of 175-1,000 ml/s. The subject inhaled test aerosols for 10-20 breaths with each of the prescribed breathing patterns, and TDF was obtained by monitoring inhaled and exhaled aerosols breath by breath by a laser aerosol photometer. Results show that TDF varied from 0.12-0.25, 0.26-0.68, and 0.45-0.83 for Dp = 1, 3, and 5 microm, respectively, depending on the breathing pattern used. TDF was comparable between men and women for Dp = 1 microm but was greater in women than men for Dp = 3 and 5 microm for all breathing patterns used (P < 0.05). TDF increased with an increase in Vt regardless of Dp and Q used. At a fixed Vt TDF decreased with an increase in Q for Dp = 1 and 3 microm but did not show any significant changes for Dp = 5 microm. The varying TDF values, however, could be consolidated by a single composite parameter (omega) consisting of Dp, Vt, and Q. The results indicate that unifying empirical formulas provide a convenient means of assessing deposition dose of particles under varying inhalation conditions.

Particle Deposition in Spontaneously Hypertensive Rats Exposed via Whole-Body Inhalation: Measured and Estimated Dose

A plethora of epidemiological studies have shown that exposure to elevated levels of ambient particulate matter (PM) can lead to adverse health outcomes, including cardiopulmonary-related mortality. Subsequent animal toxicological studies have attempted to mimic these cardiovascular and respiratory responses, in order to better understand underlying mechanisms. However, it is difficult to quantitate the amount of PM deposited in rodent lungs following inhalation exposure, thus making fundamental dose-to-effect assessment and linkages to human responses problematic. To address this need, spontaneously hypertensive rats were exposed to an oil combustion-derived PM (HP12) via inhalation while being maintained in whole-body plethysmograph chambers. Rats were exposed 6 h/day to 13 mg/m(3) of HP12 for 1 or 4 days. Immediately following the last exposure, rats were sacrificed and their tracheas and lung lobes harvested and separated for neutron activation analysis. Total lower respiratory tract deposition ranged from 20-60 microg to 89-139 microg for 1- and 4-day exposures, respectively. Deposition data were compared to default and rat-specific estimates provided by the Multiple Path Particle Deposition (MPPD) model, yielding model predictions that were < 33% of the measured dose. This study suggests that HP12 exposure decreased particle clearance, as the mass of HP12 in the lungs following a 4-day protocol was nearly four times that observed after a 1-day exposure. This work should improve the ability of risk assessors to extrapolate rat-to-human exposure concentrations on the basis of lung burdens and, thus, better relate inhaled doses and resultant toxicological effects.

Analysis of Total Respiratory Deposition of Inhaled Ultrafine Particles in Adult Subjects at Various Breathing Patterns

Ultrafine particles are ubiquitous in the ambient air, and their unique physicochemical characteristics may pose a potential health hazard. Accurate lung dose information is essential to assess a potential health risk from exposure to these particles. In the present study, we measured total respiratory tract deposition fraction (TDF) of inert ultrafine aerosols (NMD = 0.04, 0.06, 0.08, and 0.10 μm and σg 1.3) in a group of young healthy adults (11 males and 11 females). A fast-response ultrafine condensation particle counter was used for continuous monitoring of inhaling aerosols breath by breath. Six different breathing patterns were used: three different tidal volumes (Vt = 500, 750, and 1000 ml) and two different flow rates for each Vt. The mean respiratory time (Tm) ranged from 2 to 4 s. The measured data showed that TDF increased with a decrease in particle size, thereby an increase in diffusion coefficient (D), and with an increase in Tm and Vt. For a given particle size both Tm and Vt were almost e...

Ultrafine Particle Deposition in Humans During Rest and Exercise

Ultrafine particles (diameter < 100 nm) may be important in the health effects of air pollution, in part because of their predicted high respiratory deposition. However, there are few measurements of ultrafine particle deposition during spontaneous breathing. The fractional deposition for the total respiratory tract of ultrafine carbon particles (count median diameter = 26 nm, geometric standard deviation = 1.6) was measured in 12 healthy subjects (6 female, 6 male) at rest (minute ventilation 9.0 ± 1.3 L/min) using a mouthpiece exposure system. The mean ± SD fractional deposition was 0.66 ± 0.11 by particle number and 0.58 ± 0.13 by particle mass concentration, similar to model predictions. The number deposition fraction increased as particle size decreased, reaching 0.80 ± 0.09 for the smallest particles (midpoint count median diameter = 8.7 nm). No gender differences were observed. In an additional 7 subjects (2 female, 5 male) alternating rest with moderate exercise (minute ventilation 38.1 ± 9.5 L/min), the deposition fraction during exercise increased to 0.83 ± 0.04 and 0.76 ± 0.06 by particle number and mass concentration, respectively, and reached 0.94 ± 0.02 for the smallest particles. Experimental deposition data exceeded model predictions during exercise. The total number of deposited particles was more than 4.5-fold higher during exercise than at rest because of the combined increase in deposition fraction and minute ventilation. Fractional deposition of ultrafine particles during mouth breathing is high in healthy subjects, and increases further with exercise.

Methodology for the measurement of mucociliary function in the mouse by scintigraphy.

The objective of the study was to develop a scintigraphic method for measurement of airway mucociliary clearance in small laboratory rodents such as the mouse. Previous investigations have characterized the secretory cell types present in the mouse airway, but analysis of the mucus transport system has been limited to in vitro examination of tissue explants or invasive in vivo measures of a single airway, the trachea. Three methods were used to deposit insoluble, radioisotopic colloidal particles: oropharyngeal aspiration, intratracheal instillation, and nose-only aerosol inhalation. The initial distribution of particles within the lower respiratory tract was visualized by gamma-camera, and clearance of particles was followed intermittently over 6 h and at the conclusion, 24 h postdelivery. Subsets of mice underwent lavage for evidence of tissue inflammation, and others were restudied for reproducibility of the methods. The aspiration and instillation methods of delivery led to greater distributions of deposited activity within the lungs, i.e., approximately 60--80% of the total respiratory tract radioactivity, whereas the nose-only aerosol technique attained a distribution of 32% to the lungs. However, the aerosol technique maximized the fraction of particles that cleared the airway over a 24-h period, i.e, deposited onto airway epithelial surfaces and cleared by mucociliary function such that lung retention at 24 h averaged 57% for delivery by aerosol inhalation and > or =80% for the aspiration or intratracheal instillation techniques. Particle delivery methods did not cause lung inflammation/injury with use of inflammatory cells and chemoattractant cytokines as criteria. Scintigraphy can discern particle deposition and clearance from the lower respiratory tract in the mouse, is noninvasive and reproducible, and includes the capability for restudy and lung lavage when time course or chronic treatments are being considered.

Autoantibodies directed against bactericidal/permeability-increasing protein in patients with cystic fibrosis: association with microbial respiratory tract colonization.

Cystic fibrosis (CF) is associated with the appearance of serum autoantibodies directed against bactericidal/permeability-increasing protein (BPI). To determine the age-specific seroprevalence rates of anti-BPI-IgG and IgA in a population of patients with CF and to correlate anti-BPI antibody concentrations with microbial respiratory tract colonization and pulmonary function variables at the time of serum sampling and 6 years thereafter. Determination of BPI antibodies of the IgG and IgA isotypes using a commercial enzyme-linked immunosorbent assay in sera of a CF serum bank of 1992; correlation of anti-BPI antibody concentrations with age, clinical score, pulmonary function variables in 1992 and 1998, total serum immunoglobulin isotype concentrations and respiratory tract colonization with Pseudomonas aeruginosa and Aspergillus spp. Seventy-one patients (age in 1992, 14.1 +/- 7.5 years) were studied. Reactivities for anti-BPI-IgG and IgA were found in 28 (39%) and 26 (37%) patients, respectively. The seroprevalence of anti-BPI-IgA, but not IgG, increased significantly with age. P. aeruginosa colonization was associated with elevated concentrations of anti-BPI-IgG (P = 0.003) and IgA (P = 0.037). There were significant negative correlations between pulmonary function variables (vital capacity, forced expiratory volume in 1 s) in 1992 and 1998, respectively, and concentrations of anti-BPI-IgG or IgA in a multiple regression analysis. Anti-BPI-IgG, but not IgA, remained significantly associated with P. aeruginosa colonization (P = 0.006) and with reduced vital capacity (P = 0.01) in 1998 after correction for total serum isotype concentration. Anti-BPI-IgG are strongly associated with concurrent P. aeruginosa colonization and with long term restrictive pulmonary function abnormalities.