Retention of Teflon particles in hamster lungs: a stereological study.

The significance of aerosols in medicine is increased when the distribution of inhaled aerosols in the different respiratory tract compartments and their interaction with lung structures are known. The aim of this study was to investigate the retention of the hydrophobic Teflon spheres used in human beings so as to analyze their regional distribution and to study their interaction with lung structures at the deposition site. Six intubated and anesthetized Syrian Golden hamsters inhaled aerosols of Teflon particles with an aerodynamic diameter of 5.5 microns by continuous negative-pressure ventilation adjusted to slow breathing. Lungs were fixed by intravascular perfusion within 21 minutes after inhalation was started, and tissue samples were taken and processed for light and electron microscopy. The stereological (fractionator) analysis revealed that particle retention was the greatest in alveoli (72.4%), less in intrapulmonary conducting airways (22.9%), and the least in extrapulmonary mainstem bronchi (0.3%) and trachea (4.4%). Particles were found submerged in the aqueous lining layer and in close vicinity to epithelial cells. In intrapulmonary conducting airways, 21.5% of Teflon particles had been phagocytized by macrophages. This study with highly hydrophobic Teflon particles clearly demonstrates that for spheres of this size, surface tension and line tension forces rather than the particles' surface free energy are decisive for the displacement of particles into the aqueous phase by surfactant. It was this displacement that enabled subsequent interaction with macrophages. Refined knowledge of particle retention may help us to better understand the biological response to inhaled particles.

[The mucociliary system of the lung--role of surfactants]. / Der mukoziliäre Apparat der Lunge--die Rolle des Surfactant.

Many pollution particles enter the organism via the lung. In the lung, on a surface of 140 m2, the blood is separated from the air by a tissue barrier of only 1/1000 mm. The conducting airways (trachea, bronchi, bronchioli) are a very effective aerodynamic filter for inhaled particles. The mucociliary transport system functions like a self-cleaning mechanism within the filter. Inhaled particles and particles deposited in the lungs play a crucial aetiological and therapeutic role. The discussion in health policy on the relationship between the increase in air pollution and lung damage is of great importance at the present time. Epidemiological studies of recent years have shown very clearly that there is a correlation between morbidity and mortality as a consequence of respiratory and cardiogenic problems and the concentration of PM10 particles in ambient air. So far, however, this correlation has not been explained. The intrathoracic airways are coated by a respiratory epithelium. This has an irregular coating of viscous liquid, consisting of a low viscous sol phase and a high viscous gel phase. It seems, however, that those phases are not clearly distinguishable. The gel phase is moved towards the pharynx by the metachronal ciliary beat transporting the particles out of the lungs. Furthermore, at the air-liquid interface, there exists a continuous surfactant film which reduces the surface tension as is the case in the alveoli. When particles are deposited on the airway wall, that is, on the surfactant film, they are wetted by surface forces and displaced into the liquid phases. Thus, the surfaces of the particles are probably changed by the surfactant or by surfactant components. Many of these particles are transported in the liquid (gel phase) towards the pharynx (mucociliary transport), whereas some of them remain in close association with the epithelium (sol phase). Such particles remain in the airways for days or even weeks. They are either phagocytised by macrophages and carried off via the airways or taken up by dendritic cells and transported into the tissue from where they reach the lymph nodes via lymph drainage and are presented to the T-lymphocytes. The displacement of particles into the liquid phases, caused by the surfactant, can be considered as the initial step in a complex cascade of defence processes in the lungs. The surface of the particles is probably modified by surfactant or surfactant components. These modified particles may be directed to that clearance pathway which is most beneficial for our health, that is, out of the lungs or into the lymphatic glands, where an immune reaction can be triggered. We therefore consider surfactant to be a primary immune barrier.

[Pulmonary abscesses and bronchiectasis]. / Lungenabszesse und Bronchiektasen.

Both primary and secondary pulmonary abscesses are increasingly observed in thoracic surgery units. Primary pulmonary abscesses are related to necrotising pneumonia or aspiration due to alcoholism, drug abuse, dysphagia or gastrointestinal reflux disease. Secondary poststenotic abscesses are related to bronchial obstruction (endobronchial tumour or foreign body aspiration) or to superinfection of pulmonary neoplasia or infarction pneumonia. Bronchoscopy is mandatory if a pulmonary abscess is suspected, to exclude endobronchial obstruction and obtain bacteriological examination by bronchial lavage or transbronchial fine needle aspiration. Transthoracic fine needle aspiration may be helpful for bacteriological examination, since germs found in sputum do not necessarily correlate with those found in the abscess. Pulmonary abscesses are primarily treated by administration of appropriate antibiotics with a remission rate of 80%. In the presence of complications of the abscess or if conservative management fails, percutaneous transthoracic drainage or surgical resection may be indicated. Bronchiectasis is also increasingly seen, especially in refugees and immigrants. The disease is characterised by chronic dilatation of bronchi with paroxysmal cough, mucopurulent secretion and recurrent pulmonary infections. Bronchiectasis is most commonly caused by recurrent bronchial infections during childhood or behind bronchial obstruction. Congenital bronchiectasis is very rare. Viral and bacterial pulmonary infections during childhood are by far the most common causes of bronchiectasis, leading to destruction of the mucociliary apparatus and the cartilage of the segmental bronchi. Bronchiectasis should be treated by an appropriate antibiotic regimen. Resection should only be considered in situations where a conservative regimen fails. Segmentectomy of all involved segments is the surgical treatment of choice in situations with well-localised bronchiectasis and results in long-lasting remission in over 80% of those patients. Patients with bilateral bronchiectasis may be considered for bilateral surgical resection if diffuse and congenital disease has been ruled out.

A new methodology for controlled particle inhalation by small rodents.

In order to investigate the deposition, retention, and clearance mechanisms implicated in particle inhalation under standardized conditions, we developed a continuous negative-pressure ventilation system, whereby the breathing pattern in small rodents could be controlled during exposure to aerosols. Using an on-line open-flow set-up, 19 anesthetized, intubated, and paralyzed Syrian golden hamsters, individually contained within a whole-body box, were artificially ventilated under the said continuous negative-pressure conditions, 1 of 5 different combinations of breathing frequency and tidal volume being established. The animals were then exposed to aerosols containing 6-micron diameter polystyrene spheres, and the deposition of particles in the conducting airways was monitored photometrically. During exposure, the level of respiration (mean lung inflation) was stabilized by means of a negative-pressure vent. Breathing frequency and tidal volume, as well as the compliance of the system, remained virtually unchanged during the course of a single experiment, and in each case, a reproducible deposition of particles was achieved. Our findings indicate that tidal volume, but not breathing frequency, has a marked influence on the particle deposition ratio. Breathing frequency exerts opposing and counterbalancing effects on this latter parameter by enhancing the impaction of particles on the one hand, and by decreasing sedimentation on the other.

Endobronchial photodynamic therapy: comparison of mTHPC and polyethylene glycol-derived mTHPC on human tumor xenografts and tumor-free bronchi of minipigs.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) with mTHPC and polyethylene glycol-derived mTHPC (pegylated mTHPC) was compared on nude mice bearing human squamous cell carcinoma and adenocarcinoma xenografts. The same treatment regimens were applied to the bronchi of tumor-free minipigs to assess injury to normal tissue. STUDY DESIGN/MATERIALS AND METHODS: Laser light (652 nm, 20 J/cm2) was delivered as surface radiation to the xenografts 4 days after intraperitoneal administration of 0.1 mg/kg mTHPC or an equimolar dose of pegylated mTHPC, respectively. The extent of tumor necrosis was assessed by histomorphometry. Endobronchial PDT was performed on the bronchi of minipigs with the same drug and light doses at drug-light intervals ranging from 12-96 hr. RESULTS: Both sensitizers produced larger necrosis of squamous cell carcinoma and adenocarcinoma xenografts than was observed in untreated controls (P < 0.005). Pegylated mTHPC led to larger tumor necrosis than mTHPC in squamous cell carcinoma (P < 0.001), but not in adenocarcinoma xenografts. mTHPC-PDT resulted in ulceration and necrosis of bronchial mucosa in minipigs at drug-light intervals ranging from 12-48 hr, which was not observed after use of pegylated mTHPC. CONCLUSIONS: In this setting, pegylated mTHPC had advantages as a photosensitiser compared to mTHPC.

Video-assisted thoracoscopic surgery for fibrinopurulent pleural empyema in 67 patients.

BACKGROUND: The roles of different drainage procedures in the management of empyema have to be redefined now that video-assisted thoracoscopic surgery (VATS) has been introduced. The debridement of fibrinopurulent stage II empyema with the use of VATS was assessed prospectively in regard to control of infection and restoration of pulmonary function. METHODS: Between January 1992 and May 1996, all patients at our institution with fibrinopurulent empyema that did not respond to chest tube drainage and antibiotic therapy were treated by debridement with the use of VATS. The patients were followed up prospectively by clinical and radiologic assessments 3 and 6 months after the operation and by spirometry 6 months after the operation. RESULTS: Video-assisted thoracoscopic surgery was initiated in 67 patients, but conversion to open decortication was required because of the finding of advanced disease in 19 patients (28%). Forty-eight patients underwent successful debridement with the use of VATS. The mean operative time was 82.1 minutes (range, 50 to 135 minutes), the mean duration of postoperative chest tube placement was 4.1 days (range, 2 to 8 days), and the mean duration of postoperative hospitalization was 12.3 days (range, 4 to 42 days). No wound infections were observed during the postoperative course. Both the 30-day mortality rate and the recurrence (ie, need for thoracotomy) rate were 4%. The mean predicted vital capacity was 84.8% +/- 14.9% and the mean predicted forced expiratory volume in 1 second was 88.6% +/- 19.2% 6 months after the operation. CONCLUSIONS: Debridement with the use of VATS is safe and efficient for stage II empyema, but open decortication should be used for more advanced disease.

[3 siblings with identical, rare pneumopathy]. / 3 Geschwister mit identischer, seltener Pneumopathie.

Pulmonary alveolar microlithiasis was found in three siblings. Only the youngest of them, a former smoker, developed endstage lung disease. The other two are asymptomatic with normal lung function despite impressive changes on all chest radiographs. The role of smoking in perpetuating microlithiasis and furthering the progression of this disease is discussed.

In vivo determination of surface tension in the horse trachea and in vitro model studies.

We measured the surface tension in the trachea of the non-anaesthetised horse from the spreading behaviour of fluid drops, using videotracheoscopy. To do this, we placed small oil drops onto the tracheal wall with a thin Teflon tubing inserted into a videocolonoscope used in humans. Either 5 ml of saline (control) or 5 ml of bovine lipid extract surfactant (BLES) at 4 mg/ml were administered. Tracheal surface tension was 31.9 +/- 0.54 mN/m (Mean +/- SEM, n = 30) in the control experiments and 24.5 +/- 0.51 mN/m (Mean +/- SEM, n = 21) in the entire trachea after the administration of BLES. These values were determined from calibration curves relating film surface tension to the relative diameter of test fluid droplets. In the calibration experiments, the test fluid droplets were placed onto a surfactant film at various surface tensions in either a modified Langmuir-Wilhelmy balance or a captive bubble surfactometer. The spreading behaviour of a given test fluid droplet in the model studies did not only depend on the film surface tension but also on the thickness of the aqueous layer below the surfactant film. Hence, the computed surface tensions in the trachea depend on the choice of which in vitro model is applied.

Ultrastructure of the aqueous lining layer in hamster airways: is there a two-phase system?

For particle retention and clearance, the structure and surface properties of the airway lining layer are important. Due to difficulties of its preservation, structural analysis has been hampered, and, hence, the existence of two distinct and continuous phases and how much osmiophilic material is available are unclear. It was the objective of this study to investigate the ultrastructure of the aqueous lining layer in the intrathoracic conducting airways of hamsters. By means of transmission electron microscopy, we investigated the ultrastructure of the airway lining layer in hamsters whose lungs have been fixed by the application of fixative dissolved in nonpolar fluorocarbon, either by instillation via the trachea or injection into the gas exchange parenchyma, together with intravascular perfusion of aqueous fixatives. The results were compared to lungs fixed by intravascular perfusion only. In twelve hamsters, the airway lining layer was found to consist of an aqueous phase and was coated by an osmiophilic film that follows fairly closely the upper-extending contours of cilia protruding from epithelial cells. Substantially less osmiophilic material was preserved in extrapulmonary airways and when nonaqueous fixative was injected. We found that the aqueous lining layer of the intrathoracic airways in hamsters essentially surrounds and covers the cilia, the microvilli, and any other structures like macrophages or deposited particles contained in it and is coated by an osmiophilic film of variable thickness. In healthy animals, a gel phase is expected to be very thin, not clearly separated from the periciliary fluid, and located just beneath the osmiophilic film.

Mucus quality on horse tracheal epithelium: microscopic grading based on transparency.

The aim of this ex-vivo study on excised tracheas of healthy horses was to characterise the microscopic heterogeneity of mucus quality by a visual grading system based on transparency and to determine whether differences in mucus quality, assessed by a visual grading system, influence tracheal mucus velocity (TMV). Small pieces of each trachea were mounted into a humidified chamber under a microscope. Mucus quality was visually subdivided into four grades (MG) and ciliary beat frequency and TMV were determined. Mucus on excised horse tracheal epithelium does not form a homogenous layer. We observed flakes and streams of a great heterogeneity, which by the characteristic of transparency can be qualified and quantified. Visual characterisation of mucus was able to explain a considerable part of TMV variation. Therefore, it can be considered as a suitable non-invasive method for the evaluation of mucus quality and transport effectiveness.

Pulmonary function in rheumatoid arthritis treated with low-dose methotrexate: a longitudinal study.

Lung volumes and gas exchange were investigated prospectively in 96 patients with rheumatoid arthritis selected without regard to pulmonary disorders and treated with i.m. methotrexate (MTX) injections [mean weekly dose 13.0 mg (5th-95th percentile (5-95 PC) 7.6-20.8)]. Individual changes over time during MTX treatment [mean duration 2.9 yr (5-95 PC 0.4-5.3)] were assessed by regression analyses in each individual. Forced vital capacity (FVC) remained stable in the majority of patients [mean annual change +0.8% (5-95 PC -8.1 to +14.0) of calculated normal value]. In addition, transfer factor using the indicator gas CO (TL,CO) was unaltered in most patients [mean annual change -2.1% (5-95 PC -16.2 to +11.8) of predicted value]. However, there were significant decreases in the forced expiratory volume in 1 s (FEV1) before and after inhalation of 0.2 mg salbutamol [mean annual change -0.8% (5-95 PC -8.4 to +3.2) and -1.3% (5-95 PC -7.8 to +3.9) of the FVC measured, respectively]. In addition, there were significant increases in alveolar-arterial Po2 gradients (P(A-a),O2) at rest and after exercise [mean annual change +1.7 mmHg (5-95 PC -5.2 to +12.2) and +1.8 mmHg (5-95 PC -3.5 to 9.0), respectively]. Nevertheless, the amounts were small in view of the reliability of the methods applied and reflect, at least in part, the normal process of ageing. The annual change in FEV1/FVC was negatively correlated with FEV1/FVC at baseline (Rs = -0.46, P < 0.001). The annual change in TL,CO was also negatively correlated with TL,CO at baseline (Rs = -0.31, P = 0.028). No other risk factors for deterioration of lung volumes or gas exchange were found, including mean weekly MTX dose, age, gender, smoking, presence of rheumatoid factor and pulmonary function at baseline. We conclude that MTX has no major effect on pulmonary function in the majority of patients and that there is no evidence that patients with pre-existing pulmonary disease are at increased risk for further deterioration of lung function.

Airway surfactant, a primary defense barrier: mechanical and immunological aspects.

Epidemiologic studies have shown strong associations between mortality and morbidity from respiratory and cardiac causes and exposure to fine (PM10), but not coarse, particulates. A plausible mechanistic explanation for these associations is lacking. It has been shown that particles may be retained for an extended period of time in the airways, and that their clearance is inversely proportional to particle size. Such particles are localized in close association with the airway epithelium, and if they consist of low surface energy material, will be coated with an osmiophilic layer, consistent with surfactant. Particles are displaced into this position by surface and line tension forces exerted by the surfactant film at the air-aqueous interface. Particle displacement due to line tension is much greater for smaller particles in the micrometer range. The surface forces acting on the particles leave deep indentations on the epithelial cells. During the displacement process they may come into contact with airway macrophages in the mucous layer and/or dendritic cells situated in the airway epithelium. The smallest particles may even penetrate the mucosa to enter the interstitial compartment. In addition to altering the physical properties of particles, surfactant coatings reduce particle toxicity and enhance phagocytosis by opsonization. We speculate that surfactant acts as a primary defense barrier and plays a role in antigen presentation and elimination at the air-mucus interface of the airways.

Efficiency of airway macrophage recovery by bronchoalveolar lavage in hamsters: a stereological approach.

Macrophages play a central role in the defence of the respiratory tract against deposited particles. In addition to the well-studied alveolar macrophages, airway macrophages have been recognized as an important clearance factor. Bronchoalveolar lavage (BAL) has been used for functional and morphological investigations of macrophages in vitro, assuming that all macrophages are removed with equal probability from the lung surface. Airway macrophages have been found in close contact with the epithelial cells. These macrophages may not be easily removed by lavage, and they might constitute a functionally different macrophage population. We have tested the hypothesis that there exists a population of macrophages in the conducting airways that resists removal by lavage. We lavaged the lungs of four hamsters and fixed the lungs, thereafter, by intravascular perfusion. The number of macrophages in the intrapulmonary conducting airways was estimated with an unbiased stereological technique, the fractionator, and compared to the number of macrophages in the airways of four hamsters whose lungs had not been lavaged prior to fixation. This in situ study revealed that, in hamster lungs, 42% of the airway macrophages were not removed by BAL and that about 5% of all macrophages in the BAL fluid were airway macrophages. Additionally, ultrastructural alterations of the airway epithelium were found. It is concluded that there exists a population of airway macrophages that resists lavage. This is an aspect which has to be considered in studies performed with macrophages obtained by BAL, since they could represent a functionally different macrophage population.

[When should the family physician contact the cardiological transplantation team?]. / Wann muss der Hausarzt mit dem kardiologischen Transplantationsteam Kontakt aufnehmen?

End stage heart failure has a poor prognosis and may be treated by cardiac transplantation, which offers these seriously sick patients a good chance of survival with an usually outstanding quality of life as compared to the preoperative state. The indication for heart transplant depends on hemodynamic and symptomatic evaluation as well as functional values. Spiro-ergometric assessment of peak oxygen consumption is used by an increasing number of cardiac transplant centres in order to achieve helpful data considering the ideal timing of transplantation. Correct assessment of the measured peak oxygen uptake is only suitable after the onset of tailored treatment of chronic heart failure; moreover, thinking about timing of heart transplantation, it is requested to be well informed on the spontaneous course of the underlying disease. Availability of appropriate organs depends on logistic factors, especially ABO blood group matching. In summary, these data may provide enough information whether and when patients should be scheduled for cardiac transplant. Ambulatory chronic heart failure clinics which are part of cardiac transplant programs are specialized institutions for the investigation of the underlying cardiac disease and for the institution of an appropriate therapy as well as for continuous observation of these patients. These chronic heart failure clinics are working very closely together with general practitioners and specialists involved in the treatment of these patients.

[Beta blockers and bronchial asthma]. / Betablocker und Asthma bronchiale.

Worsening or precipitation of asthma by beta-adrenoceptor antagonists is well recognized. Severe bronchoconstriction may be induced even in 'mild' asthmatics, and the dose of beta blocker required may be low, as in the case of eye drops of timolol, a nonselective beta blocker used to treat glaucoma. The severity of bronchoconstrictor response is not predictable. Nonselective beta blockers are more likely to precipitate bronchospasms in patients with asthma. The mechanism of beta-blocker-induced asthma is still not certain. Normal subjects develop neither a deterioration in lung function nor an increased bronchial hyperreactivity; therefore, beta blocker drugs should in general be avoided by asthma patients. Safe alternative therapies exist for both hypertension (calcium antagonists, ACE inhibitors, diuretics) and ischemic heart disease (calcium antagonists, nitrates).

The effect of particle inhalation on macrophage number and phagocytic activity in the intrapulmonary conducting airways of hamsters.

The number and functions of macrophages in the lungs are crucial factors for prevention and development of lung disease caused by inhaled particles. To examine whether airway macrophages are attracted to the site of particle deposition and what proportion of these macrophages is involved in phagocytosis, aerosols of 6-microns polystyrene particles (PSP) were inhaled by Syrian Golden hamsters under controlled conditions through an inhalation tubule and their lungs were fixed by intravascular perfusion within 20 min (PSP-1, PSP-1a), 40 min (PSP-2), and 24 h (PSP-3) after the beginning of the inhalation. The number and the phagocytic activity of airway macrophages were studied in situ with a fractionator, a stereologic method, on light microscopic sections. No significant increase in macrophage number was detected for the groups PSP-1 and PSP-1a. The increase for group PSP-2 was, however, between 2- and 3-fold, whereas for group PSP-3 the increase was between 1.5- and 2.5-fold with respect to control animals, which had inhaled ambient air through an intubation tubule (C-2) and whose lungs had been fixed after 40 min. There were no significant differences among the four groups with respect to the proportion of airway macrophages that had phagocytized polystyrene microspheres. Twelve to fifteen percent of the macrophages were found to be involved in phagocytosis. In the case of the mean number of particles per phagocytizing macrophage, there was a significant decrease for the PSP-3 group with respect to the pool of the three groups PSP-1, PSP-1a, and PSP-2 taken together. These studies demonstrate (1) that airway macrophages are rapidly recruited to the sites of particle deposition and (2) that only a small proportion of very active macrophages contributes to the clearance of particles, suggesting a great potential of airway macrophages to interact with many more particles than the hamsters were exposed to in this study.

[Lung tumors: symptoms, clinical signs, evaluation and staging]. / Lungentumoren: Symptome, klinische Zeichen, Abklärung und Staging.

The signs and symptoms of the predominantly malignant lung tumors primarily depend on the site and the local infiltration of the tumor as well as on the extent of metastatic dissemination and the paraneoplastic syndromes. The investigation--mainly on an outpatient basis--includes three phases. The first step is the cytological and/or histological identification of the tumor, usually by means of chest X-ray, sputum examination, bronchoscopy or more invasive methods. Beginning with computed tomography, the goal of the second step is the staging of the extent of the disease. Patients with small-cell lung cancer [SCLC], which is considered to be primarily nonresectable, are classified as having either limited or extensive disease. A survival difference has been reported between the two stages. In order to define the potentially resectable forms [25%] of non-small-cell lung cancer [NSCLC], the TNM classification is applied. Finally, it has to be estimated whether the patient is fit for major surgery.

[Pulmonary nodules]. / Lungenrundherde.

Solitary pulmonary nodules 3 cm or greater in diameter should be regarded as probably malignant. Single spherical lesions of smaller size are in about 30% primarily bronchogenic carcinomas, in 10% solitary metastatic deposits and in about 60% benign nodules, commonly infectious granulomas. The generally accepted criteria for benignity are the detection of a "benign" pattern of calcification, no growth over the preceding two years, minimal exposure to tobacco, and the age under 30 years. In general, resectable malignant solitary nodules should be identified and removed. Metastatic tumor deposits are the most common cause of multiple nodules.