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Objectives: Topical delivery of drugs to the sinuses is challenging and requires also particular administration manoeuvres from the patient. This study was conducted to investigate 1) the delivery efficiency of a pulsating aerosol (Vibrent prototype device) to the sinuses and the nose, 2) the aerosol fraction that will deposit in the lungs and 3) potential differences regarding sinus and nasal deposition ratio when comparing aerosol administration during two different administration routes. Methods: An open label deposition study in healthy volunteers was conducted using 99mTc-DTPA radiolabeled pulsating aerosols in comparison to nasal pump sprays. Deposition and retention of pulsating aerosols was assessed by gamma camera imaging during spontaneous nasal breathing and during closed soft palate administration. Results: Aerosol administration during nasal breathing vs. application with closed soft plate results in significant lung, nasal and sinus deposition. No significant differences were observed for nasal clearance. In comparison, drug delivery using nasal pump sprays resulted in non-significant sinus, 100 % nasal and non-significant lung deposition. The clearance kinetics after nasal pump spray delivery was significantly accelerated. Discussion: The standard application mode of pulsation aerosols with closed soft palate results in negligible lung deposition and therefore limits drug delivery to the nasal cavity only, minimizing unwanted side effects. Administration during spontaneous nasal breathing shows only 10% lung deposition, which is tolerable during drug administration. Relevant paranasal sinus deposition is noted during both application modes and clearance kinetics remains essentially unchanged. In contrast, nasal pump sprays do not show sinus drug delivery and nasal drug residence time is shortened. Conclusion: Pulsating aerosols offer advantageous topical nasal and sinus drug delivery options.

Rationale: Little is known about clearance of ultrafine carbon particles from the different regions of the human lung. These particles may accumulate and present a health hazard because of their high surface area.Objectives: Technetium Tc 99m (99mTc)–radiolabeled 100-nm-diameter carbon particles were inhaled by healthy nonsmokers, asymptomatic smokers, and by patients with chronic obstructive pulmonary disease (COPD).Methods: Using a bolus inhalation technique, particle deposition was targeted either to the airways or to the lung periphery, and retention, clearance, and translocation were measured using retained radiotracer imaging.Measurements and Main Results: In vitro studies revealed that mean leaching of soluble 99mTc-radiotracer from the carbon particles was 4.1 (2.6 [SD]) % after 24 hours. Cumulative 99mTc activity in urine at 24 hours was 1.1 (1.3) % of activity deposited in the lungs. In the lung periphery, particle retention was not affected by smoking or pulmonary disease; retention was 96 (3) ...

The aim of this study was to determine particle clearance and retention from non-alveolated airways of 14 healthy subjects (HS), 10 subjects with asymptomatic bronchial hyperresponsiveness (BHR), and 23 patients with chronic obstructive pulmonary disease (COPD). Monodisperse iron oxide particles of 1.6 micro m geometric and 3.5 micro m aerodynamic diameter labeled with (99m)Tc were delivered to the airways by inspiration of small aerosol boli into shallow volumetric lung depths. In each subject the penetration front depth of the aerosol boli was adjusted to 55% of the Fowler dead space of the airways. Particle deposition was enhanced by about 7 seconds of breath-holding after bolus inhalation. Retention of the particles in the airways during the 48 hours after their administration was assessed by measuring the decline in lung activity with a sensitive gamma counter. Particle deposition was not significantly different among study groups. Twenty-four hour particle retention in the airways was not different among study groups. Sixty-one percent of the particles were retained at 24 hours in HS, 58% in BHR, and 64% in COPD. However, subjects with BHR showed accelerated mucociliary clearance compared to healthy subjects, whereas clearance was retarded in COPD patients. This long-term particle retention in the airways has to be taken into account in aerosol toxicology risk assessment and aerosol therapy dose evaluation.

Ferrimagnetic iron oxide particles were inhaled by 17 healthy volunteers (9 non-smokers, 8 smokers), and the retained particles were magnetized and detected by a SQUID. Stochastic particle transport due to cytoskeletal reorganizations within macrophages (relaxation) and directed particle motion in a weak magnetic twisting field were investigated with respect to viscous and elastic properties of the cytoskeleton. Relaxation and cytoskeletal stiffness were not influenced by cigarette smoking. Relaxation and particle twisting revealed a non-Newtonian viscosity with a pure viscous and a viscoelastic compartment. Viscous and elastic data obtained from relaxation correlated with particle twisting, indicating that the proposed simple model is a reasonable approximation of cytoskeletal mechanical properties.

In order to improve patient convenience and drug availability for patients with alpha 1-protease inhibitor deficiency, the administration via the inhalation route has been considered. This study investigated if it is possible to obtain high values of peripheral aerosol deposition by using optimized and controlled inhalation conditions. Therefore, peripheral deposition was studied in 10 patients with alpha 1-protease inhibitor deficiency (phenotype PiZ) and moderate to severe chronic obstructive pulmonary disease by measuring the 24-hour Clearance of radiolabeled inert iron oxide particles with diameters of 2 microns, 3 microns, and 4 microns. Patients inhaled a large volume of aerosol (1000 to 2000 cm3), which was normalized to the individual lung function, with a flow rate of 200 cm3/S. Due to this breathing pattern, peripheral deposition was for all particle sizes above 50% of the inhaled aerosol. The highest peripheral deposition (68%) was found for 3-microns particles.

Monodisperse ferrimagnetic iron-oxide particles of 1.4 μm geometric diameter were used to study alveolar macrophage functions (phagocytosis, phagosome transport) and cytoskeletal integrity in healthy subjects and in patients with idiopathic pulmonary fibrosis as well as in cultured macrophages. Dysfunctions in phagocytosis, in phagosome transport and cytoskeletal integrity correlated with an impaired alveolar clearance and could be induced in vitro by cytoskeletal drugs.

Monodisperse ferrimagnetic microparticles (Fe3O4) with 1.3 microm geometric diameter were inhaled to study alveolar long-term clearance in healthy and diseased human subjects. Nineteen younger (age 20 to 39 years) and 20 older (age 40 to 65 years) healthy volunteers participated in the study as well as 15 patients with sarcoidosis (SAR), 12 patients with idiopathic pulmonary fibrosis (IPF), and 15 patients with chronic obstructive bronchitis (COB). In each group the subjects were divided into never smokers (NS) and active smokers (S). Clearance was measured by magnetopneumography (MPG) for 300 days after inhalation. In COB, 50% of the deposited particles were removed from the lungs after 2 days, indicating high bronchial deposits due to bronchial obstructions. In healthy NS, only 10% of the particles were removed after 2 days and cigarette smoking enhanced the fraction of fast-cleared particles. In subjects who smoked, slow clearance was significantly impaired (P. 02). Clearance half-lives (in days) for younger, healthy, NS were 124 +/- 66 (mean +/- SD) compared to 220 +/- 74 for S. Similarly for older subjects, the timeswere 162 +/- 120 for NS and 459 +/- 334 for S. The impairment of alveolar clearance due to cigarette smoking increases by 5.7 +/- 1.3 days/pack-year (P.01). Alveolar clearance was impaired in SAR and in IPF; half-lives were 275 +/- 109 days (P.05) and 756 +/- 345 days (P.02), respectively, compared to healthy NS. Most COB patients were ex-smokers, their long-term clearance was 240 +/- 74 days, which is more than healthy NS (P.01), but less than healthy S and might indicate a recovery of alveolar clearance. In view of studies using totally inert particles like Teflon, we conclude that the lung clearance measured with iron oxide tracer particles primarily reflects clearance by intraphagosomal particle dissolution within alveolar macrophages, which is impaired by cigarette smoke consumption and in patients.

To the Editors: A patient with extensive emphysema was treated with liposomal all-trans retinoic acid (ATRA) using a controlled inhalation manoeuvre. After a gradual increase from 0.1 mg to 3 mg ATRA per day, the patient was treated at a level of 1 mg·day−1 for 4 days per week. Over the 6-month observation period there was an improvement of forced expiratory volume in 1 s (FEV1) from 16% to 21% predicted and an increase from 400 m to 615 m in the 6-min walking test (6MWT), although there was no apparent change in lung morphology with high-resolution computed tomography (HRCT). Biochemical analysis demonstrated a decrease in exhaled isoprostane and a decrease in serum interleukin (IL)-13. In addition, desmosine excretion decreased from 115 μg·g−1 creatinine to

Aerosol-derived airway morphometry (ADAM) and aerosol bolus dispersion (D) are altered in patients or animal models with lung emphysema. This study was performed to examine the sensitivity and specificity of ADAM and D in the detection of emphysema in vivo compared with conventional lung function parameters. The study comprised patients with chronic obstructive bronchitis (COB) without emphysema (group COB; n=19, age 56+/-8 yrs, forced expiratory volume in one second (FEV1)/vital capacity (VC) 66+/-12% predicted) and patients with chronic bronchitis with high-resolution computed tomography-confirmed emphysema (group COB-E; n=20), age 65+/-7 yrs, FEV1/VC 44+/-16% pred). Using monodisperse aerosol particles ADAM assessed the calibres of peripheral airspaces, while D measured convective gas mixing. Among all lung function parameters, ADAM and D showed the highest sensitivity and specificity for separating patients with COB from those with COB-E (area under the receiver operating characteristics curve (pROC) 0.99 and 1.0, respectively). In patients with COB aerosol parameters did not differ from those found in the control group, whereas patients with COB-E exhibited a two-fold increase in peripheral airspace dimensions compared with subjects with COB (0.86+/-0.07 versus 0.37+/-0.02 mm, p=0.0001) and an increase in D by >50% (541+/-74 versus 345+/-42 cm3, p=0.0001). In conclusion, aerosol-derived airway morphometry and aerosol bolus dispersion are powerful tools in the differential diagnosis of chronic obstructive pulmonary disease.

Chronic rhinosinusitis (CRS) is the major disorder of the upper airways, affecting about 10-15% of the total population. Topical treatment regimens show only modest efficacy, because drug delivery to the posterior nose and paranasal sinuses is still a challenge. Therefore, there is a high rate of functional endoscopic sinus surgery in CRS patients. Most nasally administered aerosolized drugs, like nasal pump sprays, are efficiently filtered by the nasal valve and do not reach the posterior nasal cavity and the sinuses, which are poorly ventilated. However, as highlighted in this review, sinus ventilation and paranasal aerosol delivery can be achieved by using pulsating airflow, offering new topical treatment options for nasal disorders. Radioaerosol inhalation and imaging studies in nasal casts and in healthy volunteers have shown 4-6% of the nasally administered dose within the sinuses. In CRS patients, significant aerosol deposition in the sinus cavities was reported before sinus surgery. After surgery, deposition increased to the amount observed in healthy volunteers. In addition, compared with nasal pump sprays, retention kinetics of the radiolabel deposited in the nasal cavity was prolonged, both in healthy volunteers and in CRS patients. These efficiencies may be sufficient for topical aerosol therapies of sinus disorders and, due to the prolonged retention kinetics, may reduce application modes, but have to be proven in future clinical trials. Pulsating aerosols may offer additional new topical treatment options of nasal and sinus disorders before as well as after surgery.

PURPOSE Endobronchial brachytherapy has become more widely used to increase the total local dose of irradiation ("boost") applied for the treatment of lung cancer. Apart from treatment for local stenosis, endobronchial brachytherapy in combination with external irradiation (EI) has the potential to improve local tumor control and perhaps prolong survival, but the real benefit has not been proven yet. To evaluate the possible effects of external irradiation with an additional boost of high dose rate (HDR) brachytherapy, we conducted a prospective randomized study. METHODS AND MATERIALS Design-two groups were compared: Group 1 was treated with external radiotherapy alone (planned dose 60 Gy); Group 2 received an additional boost of HDR brachytherapy of scheduled 4.8 Gy each (at 10 mm from the source axis) before and after external irradiation. Patients-98 patients with advanced inoperable lung cancer were included in the study, 42 in Group 1 and 56 in Group 2. Both groups were comparable with respect to age, sex, tumor stage, Karnofsky performance status (KPS), and histology. RESULTS A mean total external irradiation dose of 50.5 +/- 14.1 Gy in Group 1 and 50 +/- 12.5 Gy in Group 2 was applied. Group 2 received an additional dose of 7.44 +/- 2.6 Gy (at 10 mm depth) through brachytherapy. The median survival time in both groups was comparable (28 weeks and 27 weeks, respectively). In patients with squamous cell carcinoma (68 patients) Group 2 showed an advantage in median survival with borderline significance (40 vs. 33 weeks, p = 0.09). Group 2 showed also a better local tumor control in all patients; patients with squamous cell carcinoma had a significantly longer period of local tumor control. Fatal hemoptysis was the cause of death in 6 (14.2%) patients in Group 1 and 11 (18.9%) in Group 2 (p = 0.53). CONCLUSIONS High dose rate brachytherapy in patients with inoperable lung cancer increased local control in our randomized study when used in combination with external irradiation. Survival time was also longer, but with no clear statistical significance. This applied especially to patients with squamous cell carcinomas. There was no statistically significant difference in the incidence of fatal hemoptysis between the two groups.

ObjectivesChronic rhinosinusitis (CRS) is a common chronic disease of the upper airways and has considerable impact on quality of life. Topical delivery of drugs to the paranasal sinuses is challenging, therefore the rate of surgery is high. This study investigates the delivery efficiency of a pulsating aerosol in comparison to a nasal pump spray to the sinuses and the nose in healthy volunteers and in CRS patients before and after sinus surgery.Methods(99m)Tc-DTPA pulsating aerosols were applied in eleven CRSsNP patients without nasal polyps before and after sinus surgery. In addition, pulsating aerosols were studied in comparison to nasal pump sprays in eleven healthy volunteers. Total nasal and frontal, maxillary and sphenoidal sinus aerosol deposition and lung penetration were assessed by anterior and lateral planar gamma camera imaging.ResultsIn healthy volunteers nasal pump sprays resulted in 100% nasal, non-significant sinus and lung deposition, while pulsating aerosols resulted 61.3+/-8.6% nasal deposition and 38.7% exit the other nostril. 9.7+/-2.0 % of the nasal dose penetrated into maxillary and sphenoidal sinuses. In CRS patients, total nasal deposition was 56.7+/-13.3% and 46.7+/-12.7% before and after sinus surgery, respectively (pConclusionIn contrast to nasal pump sprays, pulsating aerosols can deliver significant doses into posterior nasal spaces and paranasal sinuses, providing alternative therapy options before and after sinus surgery. Patients with chronic lung diseases based on clearance dysfunction may also benefit from pulsating aerosols, since these diseases also manifest in the upper airways.

Immunohistochemical detection of the p53 gene product by monoclonal antibodies has been shown to be associated with a poor clinical outcome in carcinomas of the breast and stomach. Because the prognostic relevance of p53 immunostaining in lung cancer is still under debate, we studied the expression pattern and clinical significance of such staining in 73 patients with operable non-small-cell lung cancer. p53 expression was detected on frozen sections with the use of monoclonal antibody p1801, which recognizes both the wild-type and mutant gene product (alkaline phosphatase-anti-alkaline phosphatase method). A tumor was considered p53 positive if more than 1% of the tumor cells were stained. The p53 expression pattern was compared with clinicopathologic parameters, and analysis of follow-up, based on the data of 65 patients, was done by a log rank test (median observation time, 780 days). Nuclear p53 staining was detected in 33 of 73 non-small-cell lung cancers (45.2%). Comparison with clinicopathologic parameters demonstrated that the p53 protein was detected more frequently in younger patients (younger than 50 years, p = 0.014), whereas no correlation was found with sex, tumor differentiation, tumor histologic type, or TNM stage. Surprisingly, follow-up analysis revealed that p53 staining was associated with an increased rate of disease-free survival, especially in patients with early stage tumor disease (p = 0.004) and in male patients (p = 0.023). Counter to previous studies in other solid tumors, immunocytochemical detection of p53 expression does not predict a poor clinical outcome in non-small-cell lung cancer. In early-stage lung cancer it might be associated with an improved disease-free survival, which suggests that the majority of the detected protein inherits the wild-type tumor suppressor function. (J THORAC CARDIOVASC SURG 1995;109:1205-11)

The EvA study is a European Union-funded project under the Seventh Framework Programme (FP7), which aims at defining new markers for chronic obstructive pulmonary disease (COPD) and its subtypes. The acronym is derived from emphysema versus airway disease, indicating that the project targets these two main phenotypes of the disease. The EvA study is based on the concept that emphysema and airway disease are governed by different pathophysiological processes, are driven by different genes and have differential gene expression in the lung. To define these genes, patients and non-COPD controls are recruited for clinical examination, lung function analysis and computed tomography (CT) of the lung. CT scans are used to define the phenotypes based on lung density and airway wall thickness. This is followed by bronchoscopy in order to obtain samples from the airways and the alveoli. These tissue samples, along with blood samples, are then subjected to genome-wide expression and association analysis and markers linked to the phenotypes are identified. The population of the EvA study is different from other COPD study populations, since patients with current oral glucocorticoids, antibiotics and exacerbations or current smokers are excluded, such that the signals detected in the molecular analysis are due to the distinct inflammatory process of emphysema and airway disease in COPD.

In a group of 20 patients with extrinsic allergic alveolitis (10 with farmer's lung, 9 with bird-breeder's lung, and 1 with humidifier's lung), we observed increased levels of soluble serum interleukin-2 receptor (ssIL-2R) with an average of 75.2 pmol (control group average, 40.6 pmol). Analysis of bronchoalveolar lavage cells by immunocytochemistry with a CD25 antibody revealed only a slight increase to 4.2% IL-2R + cells among alveolar lymphocytes but a pronounced rise to 21.2% IL-2R + cells among alveolar macrophages. Furthermore, cytometry revealed a fourfold higher IL-2R expression on a per cell basis for alveolar macrophages as compared with alveolar lymphocytes. A clear-cut positive correlation ( p = 0.006) was found for ssIL-2R and IL-2R + alveolar macrophages, but only a borderline correlation was found for ssIL-2R and IL-2R + alveolar lymphocytes ( p = 0.04). The finding of a concomitant decrease of IL-2R + alveolar macrophages and of ssIL-2R on allergen avoidance further supports the notion that alveolar macrophages may be the main source of the increased ssIL-2R in patients with extrinsic allergic alveolitis. (J ALLERGY CLIN IMMUNOL 1994;94:1057-64.)

Objective: Aerosolized drugs are predominantly delivered by nasal sprays, but they target the anterior nose only, and the administered drug is rapidly cleared. Studies with pulsating aerosols showed improved sinonasal deposition. This study compared clearance kinetics and cumulative dose after nasal spray and pulsating aerosol delivery.Method: Open label deposition study in 15 healthy volunteers using radiolabeled pulsating aerosols generated by a Vibrent nebulizer in comparison to nasal pump sprays. Nasal deposition and retention was assessed by gamma camera imaging at various time intervals over 24-hours in the entire nose and in specified ROIs.Results: Nasal pump spray vs pulsating aerosol application resulted in a nasal deposition of 100% vs 70 ± 16%.Conclusion: As found in earlier studies, nasal clearance of pulsating aerosols is significantly retarded compared with nasal sprays, causing prolonged drug residence time in the nose. Our data suggest that this effect may be related to the small droplet s...

There is an increasing demand for accurate preoperative and intraoperative staging of bronchial carcinoma with respect to neoadjuvant therapy protocols and parenchyma-sparing operations. This study prospectively evaluated accuracy of computed tomographic scan and surgical assessment for staging of bronchial carcinoma in 108 consecutive patients. The stage of the primary tumor (T stage) was correctly determined in 85% of the patients, and surgical evaluation correctly determined the T stage in 92%. Invasion of major mediastinal structures posed a major problem for computed tomographic scan. On a node-by-node basis, computed tomographic scan predicted involvement of lymph nodes in 81% (sensitivity 29%, specificity 93%, positive predictive value 49%, negative predictive value 85%). The surgeon correctly determined the lymph node status in 69% of lymph nodes (sensitivity 90%, specificity 63%, positive predictive value 39%, negative predictive value 96%). On a patient-by-patient basis, computed tomographic scan correctly predicted the nodal status in 58% of patients. Accuracy of computed tomographic scan and surgical assessment in determination of the lymph node status strongly depended on tumor type and lymph node region (hilar or mediastinal region) studied. This was partly due to the fact that adenocarcinomas exhibited a high proportion of tumor-positive normal-sized lymph nodes, whereas squamous cell carcinomas showed a high proportion of enlarged tumor-free lymph nodes. In conclusion, computed tomographic scan and surgical assessment are sufficiently accurate for determination of the tumor stage but are insufficient in determining the nodal status. (J T horac C ardiovasc S urg 1992;104:413-20)

Background: Although there is a high incidence of nasal disorders including chronic sinusitis, there is limited success in the topical drug delivery to the nose and the paranasal sinuses. This is caused by the nose being an efficient filter for inhaled aerosol particles and the paranasal sinuses being virtually non-ventilated. Method: The objective of this study was to visualize the efficiency of sinus ventilation in healthy volunteers using dynamic 81m Kr-gas imaging in combination with pulsating airflows. Furthermore, the deposition and retention of 99m Tc-DTPA aerosol particles was assessed. Results: The ventilation of the maxillary and frontal sinuses could be visualized by gamma camera imaging during pulsating airflow. In addition, using pulsating airflow, between 3% and 5% of nasally deposited aerosols penetrated into the paranasal sinuses while during application without pulsation aerosol deposition was below 1%. Furthermore pulsation increased aerosol deposition in the nasal airways by a factor of three. Conclusions: The study demonstrates the high efficiency of a pulsating airflow in paranasal sinus ventilation and aerosolized drug delivery. This proves that topical drug delivery to the paranasal sinuses in relevant quantities is possible and indicates further clinical studies are necesarry.

Objective Approximately 10 to 15 percent of the European and U.S. population have chronic rhinosinusitis, but effective treatment remains a challenge. There has been limited success using topical drug delivery to the nose and the paranasal cavities/sinuses, in part because most nasally administered aerosol drug formulations are efficiently filtered at the nasal valve and fail to reach the osteomeatal area and sinuses. Study Design Feasibility study. Setting Nuclear medicine department. Subjects and Methods Pulsating airflows were applied to the nasal cavity and sinus ventilation was studied in five healthy human volunteers using dynamic 81mKr-gas gamma camera imaging. Furthermore, deposition and retention of 99mTc-DTPA radiolabeled aerosols delivered by nasal pump sprays or by pulsating aerosols was assessed in each volunteer over a 24-hour period. Results Only the pulsating airflow demonstrated efficient 81mKr-gas ventilation of the paranasal sinuses. No drug was deposited into the sinuses using nasal pump sprays, but up to 6.5 percent of the nasally administered drug was deposited into the sinuses using pulsating airflow. Clearance kinetics of the drug was reduced after pulsating aerosol delivery compared to nasal pump sprays. Residence time of the drug at the site of deposition was up to three-fold longer with pulsating aerosol delivery than with nasal pump sprays. Conclusion Our data support the hypothesis that topical drug delivery in relevant quantities to the nose and osteomeatal areas, including the paranasal sinuses, is possible using pulsating airflows. Furthermore, the frequency of drug applications may be reduced due to a delayed clearance and longer residence time.

Background Early onset lung cancer shows some familial aggregation, pointing to a genetic predisposition. This study was set up to investigate the role of candidate genes in the susceptibility to lung cancer patients younger than 51 years at diagnosis. Methods 246 patients with a primary, histologically or cytologically confirmed neoplasm, recruited from 2000 to 2003 in major lung clinics across Germany, were matched to 223 unrelated healthy controls. 11 single nucleotide polymorphisms of genes with reported associations to lung cancer have been genotyped. Results Genetic associations or gene-smoking interactions was found for GPX1(Pro200Leu) and EPHX1(His113Tyr). Carriers of the Leu-allele of GPX1(Pro200Leu) showed a significant risk reduction of OR = 0.6 (95% CI: 0.4–0.8, p = 0.002) in general and of OR = 0.3 (95% CI:0.1–0.8, p = 0.012) within heavy smokers. We could also find a risk decreasing genetic effect for His-carriers of EPHX1(His113Tyr) for moderate smokers (OR = 0.2, 95% CI:0.1–0.7, p = 0.012). Considered both variants together, a monotone decrease of the OR was found for smokers (OR of 0.20; 95% CI: 0.07–0.60) for each protective allele. Conclusion Smoking is the most important risk factor for young lung cancer patients. However, this study provides some support for the T-Allel of GPX1(Pro200Leu) and the C-Allele of EPHX1(His113Tyr) to play a protective role in early onset lung cancer susceptibility.

Spherical monodisperse ferromagnetic iron oxide particles of 1.9 μm geometric and 4.2 μm aerodynamic diameter were inhaled by seven patients with primary ciliary dyskinesia (PCD) using the shallow bolus technique, and compared to 13 healthy non-smokers (NS) from a previous study. The bolus penetration front depth was limiting to the phase1 dead space volume. In PCD patients deposition was 58+/-8 % after 8 s breath holding time. Particle retention was measured by the magnetopneumographic method over a period of nine months. Particle clearance from the airways showed a fast and a slow phase. In PCD patients airway clearance was retarded and prolonged, 42+/-12 % followed the fast phase with a mean half time of 16.8+/-8.6 hours. The remaining fraction was cleared slowly with a half time of 121+/-25 days. In healthy NS 49+/-9 % of particles were cleared in the fast phase with a mean half time of 3.0+/-1.6 hours, characteristic of an intact mucociliary clearance. There was no difference in the slow clearance phase between PCD patients and healthy NS. Despite non-functioning cilia the effectiveness of airway clearance in PCD patients is comparable to healthy NS, with a prolonged kinetics of one week, which may primarily reflect the effectiveness of cough clearance. This prolonged airway clearance allows longer residence times of bacteria and viruses in the airways and may be one reason for increased frequency of infections in PCD patients.

Spherical monodisperse ferromagnetic iron oxide particles of 1.9-microm geometric and 4.2-microm aerodynamic diameter were inhaled by 13 healthy nonsmoking subjects using the shallow bolus technique. The bolus width was 100 ml, and the penetration front depth was 150 +/- 27 ml. The mean flow rate during inhalation and exhalation was 250 ml/s. The Fowler dead space and the phase 1 dead space of the airways were 282 +/- 49 and 164 +/- 34 ml, respectively. Deposition was below 20% without breath holding and 51 +/- 8% after an 8-s breath-holding time. We attempted to confine the bolus deposition to the bronchial airways by limiting the bolus front depth to the phase 1 dead space volume. Particle retention was measured by the magnetopneumographic method over a period of 9 mo. Particle clearance from the airways showed a fast and a slow phase; 49 +/- 9% followed the fast phase with a mean half-time of 3.0 +/- 1.6 h and characterized the mucociliary clearance. The remaining fraction was cleared slowly with a half-time of 109 +/- 78 days. The slow clearance phase was comparable to clearance measurements from the lung periphery of healthy nonsmokers, which allowed macrophage-dependent clearance mechanisms of the slow cleared fraction to be taken into account. Despite the fact that part of the slowly cleared particles may originate from peripheral deposition, the data demonstrate that mucociliary clearance does not remove all particles deposited in the airways and that a significant fraction undergoes long-term retention mechanisms, the origin of which is still under discussion.

Glucocorticoids (GC) are frequently used for therapy of various inflammatory lung diseases by either systemic or inhalative application. Because the oral application often has various side effects and because the inhalative application is not as potent, new formulations of GCs are required. We evaluated the effect of a liposomal (Lip) formulation of methylprednisolone (MP) on the expression of lipopolysaccharide (LPS)-induced proinflammatory tumor necrosis factor (TNF) and antiinflammatory interleukin-10 (IL-10) in human alveolar macrophages (AM). AM were obtained from bronchoalveolar lavage fluids of patients with various inflammatory lung diseases and precultured 20 h+/-MP, either liposomal or free, and then stimulated with LPS. Cells were harvested for analysis of mRNA levels by real-time reverse transcriptase polymerase chain reaction (RT-PCR); supernatants were used to measure protein concentrations by ELISA. We confirm the suppression of LPS-induced TNF production by an average of factor 7 at the mRNA level and factor 3 at the protein level. On the other hand, we detected a strong increase of the IL-10 production by MP. At the mRNA level, liposomal MP alone led to an 18-fold increase, and the LPS-induced IL-10 mRNA was enhanced by factor 2. At the protein level, MP alone had no effect, but LPS-induced IL-10 was increased by factor 2.5. Our data show that liposomal MP can consistently induce IL-10 and reduce TNF when macrophages are exposed for a prolonged period of time. In all respects, liposomal MP had similar activities as free MP, but liposomes were selectively taken up by monocytes and macrophages and not by lymphocytes in blood and in the lung. This suggests that liposomal glucocorticoids when applied locally in the lung may act efficiently but with less side effects.

Pulmonary lymphangioleiomyomatosis is a rare disease that occurs mainly in women of reproductive age. The clinical characteristics include recurrent spontaneous pneumothorax and progressive dyspnea. The features of chest computed tomography are nearly pathognomonic with the detection of bilateral thin-walled cysts.A 32-year-old female presented with sudden-onset right-sided chest pain, which aggravated during inspiration, dyspnea at exertion, and cough. She had a history of bilateral recurrent spontaneous pneumothorax. Physical examination showed reduced pulmonary sounds on the right side. Chest X-ray confirmed the diagnosis of recurrent right-sided pneumothorax. Computed tomography showed multiple bilateral bullae. Video-assisted pleurectomy, bulla resection, and bulla coagulation were performed. The diagnosis of pulmonary lymphangioleiomyomatosis was confirmed by pulmonary biopsy. After pleurectomy, the patient remained symptom-free without recurrent pneumothorax.Pulmonary lymphangioleiomyomatosis is a rare cause of recurrent pneumothorax and should be considered a differential diagnosis, especially in young women with diffuse bilateral bullous emphysema or tuberous sclerosis.

Since asymptomatic, nonspecific airway hyperresponsiveness (BHR) may be due to an enhanced local inflammatory response, we studied molecular markers of inflammation in induced sputum from subjects with asymptomatic BHR (n = 14) compared with control subjects (n = 13) and patients with chronic obstructive pulmonary disease (COPD) (n = 10). Pulmonary lung function parameters were measured by spirometry and body plethysmography. Hyperresponsiveness was defined based on histamine challenge. Induced sputum samples were collected and the solid phase was isolated and analyzed for leukocyte numbers and differential and for cytokines (ELISA). IL-8 was 2.4-fold increased (p = 0.036) in the sputum of subjects with asymptomatic BHR (24.8 +/- 22.0 ng/mL; +/- SD) and 11.2-fold enhanced in patients with COPD (117.8 +/- 106.3 ng/mL) as compared with control subjects (10.5 +/- 7.7 ng/mL). In control subjects, no IL-5 was measured, however, sputum of those with asymptomatic BHR contained IL-5 at 0.044 +/- 0.090 ng/mL fluid and COPD patients at 1.00 +/- 2.01 ng/mL. GM-CSF could not be detected in sputum samples of any subjects investigated. Number of total leukocytes was higher in those with asymptomatic BHR and COPD (with BHR: 9.4 +/- 10.8 x 10(5); COPD: 83.5 +/- 182.5 x 10(5)) compared with persons without BHR (2.9 +/- 3.4 x 10(5)). PMN were increased in patients with asymptomatic BHR (4.1 +/- 5.3 x 10(5)) (38.8 +/- 24.7%) and COPD (32.9 +/- 71.0 x 10(5)) (75.4 +/- 18.6%) compared with controls (0.7 +/- 0.9 x 10(5)) (25.8 +/- 25.7%). In contrast to PMN counts in those with asymptomatic BHR (0.06 +/- 0.11 x 10(5)) (1.5 +/- 3.7%), eosinophil counts were only slightly increased compared with control subjects (0.01 +/- 0.02 x 10(5)) (0.6 +/- 0.9%). This study supports the hypothesis that BHR in asymptomatic people is associated with airway inflammation that may predispose to development of chronic diseases such as COPD.

The simultaneous occurrence of pulmonary fibrosis and emphysema may present considerable problems in clinical assessment. Recent studies have shown that Aerosol Derived Airway Morphometry (ADAM) and Aerosol Bolus Dispersion (ABD) are changed in patients with pulmonary emphysema. This study was performed to assess the effect of simultaneous lung fibrosis in patients with emphysema on ADAM and ABD. ADAM and ABD measurements were performed in 20 patients with lone high resolution CT scan (HRCT) confirmed emphysema (E), and compared to those in 15 emphysematics with HRCT-confirmed superimposed pulmonary fibrosis (FE). In both groups the peripheral effective airspace dimension (EAD) (E: 0.63 +/- 0.20 mm; FE: 0.60 +/- 0.27 mm, N.S.) was increased by more than a factor of two compared to that of healthy subjects (0.28 +/- 0.05 mm) (p0.001). Patients with E showed a significantly higher bolus dispersion than patients with FE (724 +/- 122 cm3 vs. 546 +/- 80 cm3; p0.001). However, in patients with FE, bolus dispersion was still significantly higher than in previously published control groups of healthy subjects (546 +/- 80 cm3 vs. 455 +/- 68 cm3; p0.001). The results of this study confirm that ADAM and ABD are powerful tools for identifying emphysema even in patients with superimposed pulmonary fibrosis.

Inhalation drug delivery for both topical and systemic treatments has many advantages over oral, intravenous, or subcutaneous drug delivery. Because some drugs should be deposited within the bronchial tree and others should deposit within the respiratory zone of the lung, it should be possible to determine and influence the preferential site of drug deposition to develop efficient inhalation therapy strategies. In this article, a method that allows estimation of the longitudinal distribution of deposited particles in the lungs of individual subjects is introduced. From the photometrically measured deposition of monodisperse di-2-ethylhexyl sebacate (DEHS) droplets, the longitudinal distribution of deposited particles (i.e., the number of particles that are deposited in a certain lung volume element) can be assessed. In this study in four healthy volunteers the distribution of deposited particles was assessed for different airflow rates, tidal volumes (VTS), and particle sizes. The results showed that there are considerable differences in the longitudinal distribution of deposited particles between subjects and that the distribution is strongly dependent on particle size: if particle size is increased, the site of particle deposition is shifted proximally. Particles with diameters greater than approximately 5 microns cannot penetrate to a volumetric lung depth (VP) greater than approximately 600 cm3 even if the VT is increased. Airflow rate has a minor effect on the distribution of deposited particles, but if airflow rate increases, the site of particle deposition is slightly shifted peripherally. This method can be used to investigate individual patterns of drug deposition in human lungs noninvasively and to develop and optimize inhalation strategies for inhalation drug delivery.

Aerosol-derived airway morphometry (ADAM) and aerosol bolus dispersion (ABD) test are altered in patients with emphysema. We examined the diagnostic power of these aerosol methods in comparison with the noninvasive "gold-standard" HRCT in 50 consecutive patients with various lung diseases. The severity of airflow limitation was mild to moderate in the group of patients without emphysema and moderate to severe in the group of patients with HRCT-confirmed emphysema (FEV(1), 78 +/- 23% pred versus 53 +/- 33% pred; p0. 001). Among all lung function parameters under consideration ADAM showed the highest sensitivity and specificity for separating patients with emphysema from those without emphysema (area under the operating characteristics curve: p(ROC), 0.92), followed by ABD (p(ROC), 0.90), a marker for ventilation inhomogeneities. In patients with HRCT-confirmed macroscopic emphysema, peripheral air-space dimensions (EAD) at a relative volumetric lung depth V(pr) of 0.20 measured by ADAM were 155% larger, and bolus dispersion (ABD) at a lung depth of V(p) 600 ml was 53% larger than those observed in patients with other lung diseases (EAD = 0.84 +/- 0.53 mm versus 0.33 +/- 0.10 mm, p0.0001; ABD = 706 +/- 154 cm(3) versus 462 +/- 109 cm(3); p0.0001). EAD showed a significant correlation with the HRCT visual score (r = 0.78, p = 0.01). ABD showed weak significant correlations with all HRCT parameters under consideration (visual score, pixel density, mean lung density) (r = 0.45 to 0.66; p0.05). ADAM and ABD are powerful tools for the noninvasive diagnosis of macroscopic emphysema.

Background Magnetic microparticles being ingested by alveolar macrophages can be used as a monitor for intracellular phagosome motions and cytoskeletal mechanical properties. These studies can be performed in the human lung after voluntary inhalation. The influence of cigarette smoking and lung diseases on cytoskeleton dependent functions was studied. Methods Spherical 1.3 μm diameter ferrimagnetic iron oxide particles were inhaled by 17 healthy volunteers (40 – 65 years), 15 patients with sarcoidosis (SAR), 12 patients with idiopathic pulmonary fibrosis (IPF), and 18 patients with chronic obstructive bronchitis (COB). The retained particles were magnetized and aligned in an external 100 mT magnetic field. All magnetized particles induce a weak magnetic field of the lung, which was detected by a sensitive SQUID (superconducting quantum interference device) sensor. Cytoskeletal reorganizations within macrophages and intracellular transport cause stochastic magnetic dipole rotations, which are reflected in a decay of the magnetic lung field, called relaxation. Directed phagosome motion was induced in a weak magnetic twisting field. The resistance of the cytoplasm to particle twisting was characterized by the viscosity and the stiffness (ratio between stress to strain) of the cytoskeleton. Results One week after particle inhalation and later macrophage motility (relaxation) and cytoskeletal stiffness was not influenced by cigarette smoking, neither in healthy subjects, nor in the patients. Patients with IPF showed in tendency a faster relaxation (p = 0.06). Particle twisting revealed a non-Newtonian viscosity with a pure viscous and a viscoelastic compartment. The viscous shear was dominant, and only 27% of the shear recoiled and reflected viscoelastic properties. In patients with IPF, the stiffness was reduced by 60% (p < 0.02). An analysis of the shear rate and stress dependence of particle twisting allows correlating the rheological compartments to cytoskeletal subunits, in which microtubules mediate the pure viscous (non-recoverable) shear and microfilaments mediate the viscoelastic (recoverable) behavior. The missing correlation between relaxation and particle twisting shows that both stochastic and directed phagosome motion reflect different cytoskeletal mechanisms. Conclusion Faster relaxation and a soft cytoskeleton in patients with IPF indicate alterations in cytoskeleton dependent functions of alveolar macrophages, which may cause dysfunction's in the alveolar defense, like a slower migration, a retarded phagocytosis, a disturbed phagosome lysosome fusion and an impaired clearance.