William D. Bennett

Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism.

BACKGROUND Active sodium absorption is the dominant mechanism of ion transport in airway epithelium, but its role in pulmonary physiology and airway host defense is unknown. To address this question, we studied the function of airway epithelial cells and determined the frequency of pulmonary symptoms in patients with systemic pseudohypoaldosteronism, a salt-losing disorder caused by loss-of-function mutations in the genes for the epithelial sodium channel. METHODS In nine patients 1.5 to 22 years of age who had systemic pseudohypoaldosteronism, we tested for mutations in the genes for the epithelial sodium channel, estimated the rate of sodium transport in the airway, determined the volume and ion composition of airway surface liquid, reviewed clinical features, collected laboratory data pertinent to pulmonary function, and, in three adults, measured mucociliary clearance. RESULTS The patients with systemic pseudohypoaldosteronism had loss-of-function mutations in the genes for the epithelial sodium-channel subunits, no sodium absorption from airway surfaces, and a volume of airway surface liquid that was more than twice the normal value. The mean (+/-SE) mucociliary transport rate was higher in the 3 adult patients than in 12 normal subjects (2.0+/-0.7 vs. 0.5+/-0.3 percent per minute, P=0.009). Young patients (those five years of age or less) all had recurrent episodes of chest congestion, coughing, and wheezing, but no airway infections with Staphylococcus aureus or Pseudomonas aeruginosa. Older patients (those more than five years of age) had less frequent respiratory symptoms. CONCLUSIONS Patients with systemic pseudohypoaldosteronism fail to absorb liquid from airway surfaces; the result is an increased volume of liquid in the airways. These results demonstrate that sodium transport has a role in regulating the volume of liquid on airway surfaces.

Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration

Cigarette smoke (CS) exposure induces mucus obstruction and the development of chronic bronchitis (CB). While many of these responses are determined genetically, little is known about the effects CS can exert on pulmonary epithelia at the protein level. We, therefore, tested the hypothesis that CS exerts direct effects on the CFTR protein, which could impair airway hydration, leading to the mucus stasis characteristic of both cystic fibrosis and CB. In vivo and in vitro studies demonstrated that CS rapidly decreased CFTR activity, leading to airway surface liquid (ASL) volume depletion (i.e., dehydration). Further studies revealed that CS induced internalization of CFTR. Surprisingly, CS‐internalized CFTR did not colocalize with lysosomal proteins. Instead, the bulk of CFTR shifted to a detergent‐resistant fraction within the cell and colocalized with the intermediate filament vimentin, suggesting that CS induced CFTR movement into an aggresome‐like, perinuclear compartment. To test whether airway dehydration could be reversed, we used hypertonic saline (HS) as an osmolyte to rehydrate ASL. HS restored ASL height in CS‐exposed, dehydrated airway cultures. Similarly, inhaled HS restored mucus transport and increased clearance in patients with CB. Thus, we propose that CS exposure rapidly impairs CFTR function by internalizing CFTR, leading to ASL dehydration, which promotes mucus stasis and a failure of mucus clearance, leaving smokers at risk for developing CB. Furthermore, our data suggest that strategies to rehydrate airway surfaces may provide a novel form of therapy for patients with CB.—Clunes, L. A., Davies, C. M., Coakley, R. D., Aleksandrov, A. A., Henderson, A. G., Zeman, K. L., Worthington, E. N., Gentzsch, M., Kreda, S. M., Cholon, D., Bennett, W. D., Riordan, J. R., Boucher, R. C., Tarran, R. Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration. FASEB J. 26, 533–545 (2012). www.fasebj.org

Targeting Delivery of Aerosols to Different Lung Regions

With the increasing use of aerosolized drugs, there is a need to understand the means by which these drugs can most effectively be targeted to desired regions of the lung. Several attempts have been made at targeting aerosols in the lung by changing particle sizes and breathing patterns with varying degrees of success. Recent use of such techniques as shallow, aerosol bolus delivery and extremely slow inhalations of aerosols in diagnostic lung tests may also prove beneficial for targeting drug delivery to the conducting airways. This review discusses the potential for utilizing aerosol delivery techniques for selectively targeting aerosol deposition along both serial and parallel pathways in the lung. Based on a review of previous studies concerning factors that determine aerosol and gas distribution in the lung, the potential for utilizing various breathing techniques in concert with variations in particle sizes are considered. Further research on the factors that determine distribution of aerosol in the diseased lung may help in designing successful targeting strategies for the future.

Deposition of fine particles in children spontaneously breathing at rest

Recent epidemiological studies suggest that children may be more susceptible than adults to effects of inhaled particulate matter. To determine if children receive an increased lung dose of particles compared to adults we measured fractional deposition (DF) of fine particles in children, age 7-14 yr (n = 16), adolescents, age 14-18 yr (n = 11), and adults, age 19-35 yr (n = 12). Each subject inhaled 2-mum monodisperse Carnauba wax particles while following a breathing pattern previously determined by respiratory inductance plethysmography for that subject (i.e., that subjects spontaneous pattern at rest). Breath-by-breath DF (ratio of particles not exhaled/total particles inhaled) was determined by photometry at the mouth. Among the children there was no variation in DF with subject age or height, but DF was dependent on intersubject variation in tidal volume (Vt) (p < .001). DF for the children versus the adolescents was 0.22 +/- 0.08(sd) and 0.20 +/- 0.03, respectively (NS), also not different from ...

Regional deposition of coarse particles and ventilation distribution in healthy subjects and patients with cystic fibrosis

The efficacy of inhaled pharmaceuticals depends, in part, on their site of respiratory deposition. Markedly nonuniform ventilation distribution may occur in persons with obstructive airways diseases and may affect particle deposition. We studied the relationship between regional deposition (RDep) and regional ventilation (RVent) in a group of 12 cystic fibrosis (CF) patients with mild to moderate airway obstruction (63 +/- 8% predicted FEV1) and 11 healthy nonsmoking volunteers (104 +/- 13% predicted FEV1) using planar scintigraphic methods. RDep was assessed from initial deposition and 24-h retention images for monodisperse technetium-99m-labeled iron oxide particles (5-microm MMAD). Regional volumes and RVent were assessed from xenon-133 equilibrium and washout, respectively. Six regions of interest per lung were established by dividing each lung into thirds by height and approximately half by width. The two lower regions of the left lung were not analyzed due to activity in the stomach. Remaining regions were categorized as central (two interior-most regions) and peripheral (eight exterior regions). RDep and RVent were computed for the eight peripheral regions. Tracheobronchial (TB) deposition was estimated for each of the peripheral regions as the difference between initial activity and decay-corrected 24-h retention or parenchymal deposition. RDep was computed as the fraction of material within a region normalized to regional volume. RVent for each region was determined by normalizing the xenon washout rate for that region by the total washout rate for the eight peripheral regions. Significant linear associations were found between RDep and RVent in both the healthy subjects and CF patients. In healthy subjects, RDep in the TB airways was positively associated with RVent (p = 0.03). In CF patients, RDep in the TB airways was negatively associated with RVent (p = 0.04) and RDep in the parenchyma was positively associated with RVent (p < 0.001). The initial pattern of RDep in the lung was not significantly associated with RVent in either group. These data suggest that significant coarse particle deposition may occur in the TB airways of poorly ventilated lung regions in CF patients, whereas, particle deposition in the TB airways of the healthy subjects follows ventilation.

Acute pulmonary function response to ozone in young adults as a function of body mass index

Recent studies have shown enhanced responsiveness to ozone in obese mice. Adiposity has not been examined as a possible modulator of ozone response in humans. We therefore examined the relationship between body mass index and the acute spirometric response to ozone (O3) exposure among 197 nonasthmatic young adults (aged 18–35 yr) studied in our human exposure facility from 1992 to 1998. Each subject had been exposed to 0.42 ppm O3 for 1.5 h with intermittent exercise designed to produce a minute ventilation of 20 L/min/m2 body surface area (BSA). Spirometry (pulmonary function) was measured pre- and immediately postexposure to determine acute ozone-induced changes. The decrement in forced expiratory volume in 1s (ΔFEV1) as percent of baseline was significantly correlated with BMI, r = −0.16, p = .03, with a slightly stronger correlation in women (n = 75), r = −0.22, p = .05, and no significant correlation in men. BMI had a greater range in women than in men in our study. In women greater ozone-induced decrements were seen in overweight (BMI > 25 kg/m2) than in normal weight (BMI 18.5 to 25 kg/m2), and in normal weight than in underweight (BMI < 18.5 kg/m2) for all spirometric variables considered (p trend ≤ .022). Although our population studied was predominantly normal weight, we found that higher body mass index may be a modest risk factor for adverse pulmonary effects associated with ozone exposure, especially for women.

Focusing on Children's Inhalation Dosimetry and Health Effects for Risk Assessment: An Introduction

Substantial effort has been invested in improving childrens health risk assessment in recent years. However, the body of scientific evidence in support of childrens health assessment is constantly advancing, indicating the need for continual updating of risk assessment methods. Childrens inhalation dosimetry and child-specific adverse health effects are of particular concern for risk assessment. When focusing on this topic within childrens health, key issues for consideration include (1) epidemiological evidence of adverse effects following childrens exposure to air pollution, (2) ontogeny of the lungs and effects on dosimetry, (3) estimation and variability of childrens inhalation rates, and (4) current risk assessment methodologies for addressing children. In this article, existing and emerging information relating to these key issues are introduced and discussed in an effort to better understand childrens inhalation dosimetry and adverse health effects for risk assessment. While much useful evidence is currently available, additional research and methods are warranted for improved childrens health risk assessment.

Nasal Contribution to Breathing and Fine Particle Deposition in Children Versus Adults

Both the route of breathing, nasal versus oral, and the effectiveness of the nose to filter inhaled, fine particles may differ between children and adults. This study compared (1) the nasal contribution to breathing at rest and during mild to moderate exercise in children (age 6–10 yr) versus young adults and (2) the nasal deposition efficiency (NDE) of fine particles (1 and 2 μm MMAD, GSD < 1.2) under resting and light exercise breathing conditions in the same children and adults. Nasal contribution to breathing was assessed by respiratory inductance plethysmography and a nasal mask with flow meter during incremental exercise on a bicycle ergometer. Fine particle deposition fractions for nasal and oral breathing were assessed by inhalation of monodisperse carnauba wax particles and laser photometry to determine inhaled/exhaled concentrations. There was a trend for children to have a lesser nasal contribution to breathing at rest and during exercise, but the differences from adults were not statistically significant. Children did, however, have significantly decreased NDE for 2-μm particles under light exercise breathing conditions compared to adults, suggesting less efficient nasal filtering for larger particles and higher flow conditions. These results suggest that the lungs of children may be exposed to higher concentrations of inhaled, ambient particles than adults.

ENHANCED DEPOSITION OF FINE PARTICLES IN COPD PATIENTS SPONTANEOUSLY BREATHING AT REST

Particulate air pollution has been linked to acute increases in mortality among individuals with preexisting cardiorespiratory disease. While these individuals may be predisposed to acute toxic effects, they may also receive an increased dose of particles to their lungs compared to healthy subjects. We measured fractional deposition (DF) of inhaled, fine particles in subjects with moderate-severe chronic obstructive pulmonary disease (COPD; n = 13) and an age-matched group of subjects (n = 11) with normal pulmonary function, mean age = 62 versus 67 yr, and FEV1 (% pred) = 33 versus 90, respectively. Each subject inhaled 2- m monodisperse, Carnauba wax particles while following a breathing pattern previously determined by respiratory inductance plethysmography (RIP) for that subject (i.e., that subjects spontaneous pattern at rest). Breath-by-breath DF (ratio of particles not exhaled to total particles inhaled) was determined by photometry at the mouth. The COPD patients had greater DF than normals, 0.40 ...

The relationship of mucus concentration (hydration) to mucus osmotic pressure and transport in chronic bronchitis

RATIONALE Chronic bronchitis (CB) is characterized by persistent cough and sputum production. Studies were performed to test whether mucus hyperconcentration and increased partial osmotic pressure, in part caused by abnormal purine nucleotide regulation of ion transport, contribute to the pathogenesis of CB. OBJECTIVES We tested the hypothesis that CB is characterized by mucus hyperconcentration, increased mucus partial osmotic pressures, and reduced mucus clearance. METHODS We measured in subjects with CB as compared with normal and asymptomatic smoking control subjects indices of mucus concentration (hydration; i.e., percentage solids) and sputum adenine nucleotide/nucleoside concentrations. In addition, sputum partial osmotic pressures and mucus transport rates were measured in subjects with CB. MEASUREMENTS AND RESULTS CB secretions were hyperconcentrated as indexed by an increase in percentage solids and total mucins, in part reflecting decreased extracellular nucleotide/nucleoside concentrations. CB mucus generated concentration-dependent increases in partial osmotic pressures into ranges predicted to reduce mucus transport. Mucociliary clearance (MCC) in subjects with CB was negatively correlated with mucus concentration (percentage solids). As a test of relationships between mucus concentration and disease, mucus concentrations and MCC were compared with FEV1, and both were significantly correlated. CONCLUSIONS Abnormal regulation of airway surface hydration may slow MCC in CB and contribute to disease pathogenesis.