Bronchiolar Regions Research Articles

Pharmacokinetics of gatifloxacin after a single oral dose in healthy young adult subjects and adult patients with chronic bronchitis, with a comparison of drug concentrations obtained by bronchoscopic microsampling and bronchoalveolar lavage

Background: Bronchoalveolar lavage (BAL) is an established technique for measuring antibiotic concentrations in the epithelial lining fluid (ELF) of the bronchiolar and alveolar regions; however, the results may not reflect concentrations in bronchial regions. Bronchoscopic microsampling (BMS) is a technique that makes it possible to obtain multiple samples from bronchial ELF. Objective: BMS and BAL were used to analyze the pharmacokinetics of gatifloxacin in bronchial ELF from healthy young adult subjects and adult patients with chronic bronchitis. Methods: Bronchial ELF samples were obtained by BMS at 1, 2, 3, 4, 6, 10, and 24 hours after administration of a single oral dose of gatifloxacin 200 mg in healthy young adult (aged 20–25 years) subjects, and at 1, 2, 4, and 10 hours after a single dose in patients with chronic bronchitis (aged ≥20 years). At least 1 month after the initial BMS, alveolar (BAL) and bronchial (BMS) ELF samples were obtained from another group of healthy subjects 2 hours after administration of a single oral dose of gatifloxacin 200 mg for comparison of gatifloxacin concentrations in samples obtained by the 2 techniques. Results: Bronchial ELF samples were obtained from 8 healthy subjects and 5 patients with chronic bronchitis; alveolar ELF samples were obtained from a separate group of 5 healthy subjects. For the healthy subjects, the mean (SD) AUC 0–24 in serum and bronchial ELF, corrected for mg/kg doses, was 4.6 (1.1) and 7.6 (3.5) mg · h/L, respectively. In the patients with chronic bronchitis, the AUC 0–10 in serum and bronchial ELF, corrected for mg/kg doses, was 3.9 (0.8) and 4.1 (1.5) mg · h/L. The C max in serum and bronchial ELF, corrected for mg/kg doses, was 0.6 (0.2) and 1.4 (0.8) mg/L in healthy subjects and 0.7 (0.2) and 0.7 (0.2) mg/L in patients with chronic bronchitis. In healthy subjects, the C max and AUC 0–24 were significantly higher in bronchial ELF than in serum (both, P < 0.05). Gatifloxacin concentrations were significantly lower in bronchial ELF obtained by BMS than in alveolar ELF obtained by BAL ( P < 0.05). Conclusions: Based on the findings of this study in small numbers of healthy young adult volunteers and patients with chronic bronchitis, BMS appears to be a promising method for measuring drug concentrations and determining the pharmacokinetic profile of gatifloxacin in bronchial ELF. Additional studies are needed to correlate measured concentrations obtained by BMS with clinical and/or microbiologic outcomes in larger populations.

Heavy incense burning in temples promotes exposure risk from airborne PMs and carcinogenic PAHs

We present the mechanistic-based exposure and risk models, appraised with reported empirical data, to assess how the human exposure to airborne particulate matters (PMs) and carcinogenic polycyclic aromatic hydrocarbons (PAHs) during heavy incense burning episodes in temples. The models integrate size-dependent PM levels inside a temple from a published exploratory study associated with a human expiratory tract (HRT) model taking into account the personal exposure levels and size distributions in the HRT. The probabilistic exposure profiles of total-PAH levels inside a temple and internal PAHs doses are characterized by a physiologically based pharmacokinetic (PBPK) model with the reconstructed dose-response relationships based on an empirical three-parameter Hill equation model, describing PAHs toxicity for DNA adducts formation and lung tumor incidence responses in human white blood cells and lung. Results show that the alveolar-interstitial (AI) region has a lower mass median diameter (0.29 microm) than that in extrathoracic (ET(1), 0.37 microm), brochial (BB, 0.36 microm) and bronchiolar (bb, 0.32 microm) regions. The 50% probability (risk=0.5) of exceeding the DNA adducts frequency (DA(f)) ratio of 1.28 (95% CI: 0.55-2.40) and 1.78 (95% CI: 0.84-2.95) for external exposure of B[a]P and B[a]P(eq), respectively. The 10% (risk=0.1) probability or more of human affected by lung tumor is approximately 7.62x10(-5)% (95% CI: 3.39x10(-5)-1.71x10(-4)%) and 3.87x10(-4)% (95% CI: 1.72x10(-4)-8.69x10(-4)%) for internal exposure of B[a]P and B[a]P(eq), respectively. Our results implicate that exposure to smoke emitted from heavy incense burning may promote lung cancer risk. Our study provides a quantitative basis for objective risk prediction of heavy incense burning exposure in temples and for evaluating the effectiveness of management.

Comparison of dose conversion factors for radon progeny from the ICRP 66 regional model and an airway tube model of tracheo-bronchial tree

Current epidemiological approaches to radon dosimetry yield a dose conversion factor (DCF) of 4 mSv WLM(-1) while the dosimetric approaches give a value closer to 13 mSv WLM(-1). The present study investigated whether the application of compartment models for the bronchial (BB) and bronchiolar (bb) regions, rather than more anatomically realistic airway tube models, has brought the dosimetric DCF to the higher values. The airway tube model of the tracheo-bronchial tree was used to calculate the effective dose per unit radon exposure. All other elements of the human respiratory tract from the reports of the ICRP or NRC were adopted. A dosimetric derivation of the radon DCF using the airway tube model yielded a value of 14.2 mSv WLM(-1). This value is slightly larger than, but not significantly different from, the result obtained through the ICRP 66 approach. It is concluded that utilization of the airway tube model instead of the regional ICRP 66 compartmental model cannot reconcile the gap between dose conversion factors derived from epidemiological and dosimetric approaches.

Factors affecting the inhalation dose from tritiated dust and flakes

Tritiated dust and flakes were produced in JET during D–T campaigns. Measurements showed some atypical radiological effects; a very large T concentration and off-gas rate. A higher dose per unit intake was foreseen and it is a consequence of the particulate nature of the material and of the expected longer biological retention. Particle size plays an important role in the deposition pattern in the human respiratory tract. Larger particles are mostly deposited in the anterior nasal passage and remaining airways of the head and neck and removed in less than 1 day. Smaller particles are mostly retained in the bronchial and bronchiolar regions and alveoli and cleared in longer periods (up to 1 year). The only clearing mechanism of tritium in the latter case is its absorption into lung fluid, an important phenomenon which can be reproduced by in vitro tests to determine doses and dose conversion factors. Based on a review of initial in vitro tests performed on JET dust and from a literature study related to in vitro dissolution experiments, some recommendations for next in vitro experiments on JET dust were formulated.

Compartmental Human Respiratory Tract Modeling of Airborne Dust Exposure from Feeding in Swine Buildings

A simple size-dependent compartmental model was developed to describe airborne dust exposure dynamics for the human respiratory tract (HRT) in mechanically ventilated swine buildings. Transport mechanisms of airborne dust for HRT include respiration, gravitational settling, turbulent diffusive deposition, inertial impaction, interception deposition loss, and dust clearance. The dominant deposition mechanism in the lung regions was found to be the inertial impaction rate, in which the order of magnitude ranged from 10−3 to 10−1 sec−1. Results demonstrate that the extrathoracic region has a higher airborne dust mass lung/indoor ratios (0.71-0.87) than do the bronchial regions (0.41-0.74), the bronchiolar region (0.12-0.61), and the alveolar-interstitial region (0.01-0.49). The predictions from the HRT model agreed favorably with the experimental deposition profiles in the nasal passage, pharynx, bronchial, bron-chiolar, and alveolar-interstitial regions, whereas the rms errors of the total deposition fraction between predicted values and ICRP66 and Non-ICRP66 were 0.15 and 0.07, respectively. Simulation results show that breathing via the nose has both a higher deposition fraction and a higher exposure dose in the size ranges 0.01-10 μm than does breathing orally.

Pathology of ovine pulmonary adenocarcinoma.

Clinical, gross pathology, histopathology and electron microscopy of the ovine pulmonary adenocarcinoma (OPA, jaagsiekte) either natural or experimentally induced in sheep, goat and moufflon are described. OPA is caused by an oncogenic betaretrovirus,jaagsiekte sheep retrovirus (JSRV). Most natural cases of OPA appear in animals 1-4 years old. There is no evidence of sex or breed susceptibility. Sheep affected by OPA show an afebrile respiratory illness associated with loss of weight. A very characteristic clinical sign is moist rales caused by the accumulation of fluid in the respiratory airways which is discharged from the nostrils when the head is lowered. Gross lesions are confined to the lungs but occasionally thoracic or extrathoracic structures are also affected. Two pathologic forms of OPA are currently recognized, classical and atypical. In classical forms the neoplastic lesions occurs particularly in the cranioventral parts of all lung lobes. They are diffuse or nodular, light grey or light purple in colour. On the cut surface the tumour is moist, and frothy fluid may pour from the airways on slight pressure. Atypical forms tend to be more nodular in both early and advanced tumours. They are pearly white in colour, very hard in consistency, very well demarcated from the surrounding parenchyma and their surface is dry. Histology of the lung sections reveals the presence of several foci of epithelial cell neoplastic proliferation in both alveolar or bronchiolar regions. The tumours, derived from type II pneumocytes and Clara cells, proliferate into mostly papillary but also acinar or occasionally solid growths. The tumour generally shows a benign histological pattern but intra- and extrathoracic metastases have been detected in some cases. Several considerations suggest that the tumour should be classified as an adenocarcinoma of the lung. The histology of atypical OPA is similar to that of the classical disease, with an increase in the stromal reaction accompanying the epithelial proliferations. Pathological features of OPA induced experimentally in sheep, or of OPA in goats and moufflon are similar to those described in sheep. Detailed electron microscopy of tumour material confirms that type II pneumocytes and Clara bronchiolar epithelial cells are the origin of the neoplasia. Also included in this chapter is a description of the morphology of the viral particles associated with OPA.

Absorbed fraction of radon progeny in human bronchial airways with bifurcation geometry

Purpose : The absorbed fraction, defined as the portion of the initial particle energy which is absorbed in the tissue of interest, was calculated, under bifurcation geometry of the airway tubes, for alpha-particles emitted from radon progeny in the human respiratory tract. The results are given for all branching generations and compared with the data obtained for the commonly used infinite straight cylinders adopted by the International Commission on Radiological Protection (ICRP) Report 66. Materials and methods : A model was created to calculate the absorbed fraction of alpha-particle energy in the human lung using bifurcation geometry. Monte Carlo simulations of alpha-particle propagation in tissue and air were performed. The stopping powers of alpha-particles were adopted from the International Commission of Radiation Units and Measurements (ICRU) Report 49. Results : The absorbed fractions for the bifurcation geometry are given for the 15 generations in the tracheobronchial tree for alpha-particle energies of 6 and 7.69 MeV. The sources were assumed to be the fast and slow moving mucus. Conclusions : Comparisons with ICRP66 data reveal that the assumption of long, straight cylinders was appropriate in some cases, but not in all. Adoption of the absorbed fractions obtained from the bifurcation model instead of the ICRP66 data caused 'redistribution' of doses in the bronchial (BB) and bronchiolar (bb) regions.

Influences of parameter uncertainties within the ICRP 66 respiratory tract model: particle deposition.

Risk assessment associated with the inhalation of radioactive aerosols requires as an initial step the determination of particle deposition within the various anatomic regions of the respiratory tract. The model outlined in ICRP Publication 66 represents to date one of the most complete overall descriptions of not only particle deposition, but of particle clearance and local radiation dosimetry of lung tissues. In this study, a systematic review of the deposition component within the ICRP 66 respiratory tract model was conducted in which probability density functions were assigned to all input parameters. These distributions were subsequently incorporated within a computer code LUDUC (LUng Dose Uncertainty Code) in which Latin hypercube sampling techniques are used to generate multiple (e.g., 1,000) sets of input vectors (i.e., trials) for all of the model parameters needed to assess particle deposition within the extrathoracic (anterior and posterior), bronchial, bronchiolar, and alveolar-interstitial regions of the ICRP 66 respiratory tract model. Particle deposition values for the various trial simulations were shown to be well described by lognormal probability distributions. Geometric mean deposition fractions from LUDUC were found to be within approximately +/- 10% of the single-value estimates from the LUDEP computer code for each anatomic region and for particle diameters ranging from 0.001 to 50 microm. In all regions of the respiratory tract, LUDUC simulations for an adult male at light exertion show that uncertainties in particle deposition fractions are distributed only over a range of about a factor of approximately 2-4 for particle sizes between 0.005 to 0.2 microm. Below 0.005 microm, uncertainties increase only for deposition within the alveolar region. At particle sizes exceeding 1 microm, uncertainties in the deposition fraction within the extrathoracic regions are relatively small, but approach a factor of 20 for deposition in the bronchial region. Deposition fractions for particles above 1 microm become very uncertain within the deeper regions of the lungs (bronchiolar and alveolar-interstitial).

Defects in Pulmonary Vasculature and Perinatal Lung Hemorrhage in Mice Heterozygous Null for the Forkhead Box f1 Transcription Factor

Decreased pulmonary expression of Forkhead Box f1 (Foxf1) transcription factor was associated with lethal alveolar hemorrhage in 55% of the Foxf1 +/− newborn mice. The severity of the pulmonary abnormalities correlates with the levels of Foxf1 mRNA. Defects in alveolarization and vasculogenesis were observed in subsets of the Foxf1 +/− mice with relatively low levels of expression from the normal Foxf1 allele. Lung hemorrhage was coincident with disruption of the mesenchymal–epithelial cell interfaces in the alveolar and bronchiolar regions of the lung parenchyma and was associated with increased apoptosis and reduced surfactant protein B (SP-B) expression. Finally, the lung defect associated with the Foxf1 +/− mutation was accompanied by reduced expression of vascular endothelial growth factor (VEGF), the VEGF receptor 2 (Flk-1), bone morphogenetic protein 4 (Bmp-4), and the transcription factors of the Brachyury T-Box family (Tbx2–Tbx5) and Lung Kruppel-like Factor. Reduction in the level of Foxf1 caused neonatal pulmonary hemorrhage and abnormalities in alveologenesis, implicating this transcription factor in the regulation of mesenchyme–epithelial interaction critical for lung morphogenesis.

Technetium-99m DTPA inhalation scintigraphy in patients treated with fluoxetine and maprotiline: preliminary results.

Drug-metabolising enzymatic activities have been detected in tracheobronchiolar, bronchiolar and alveolar regions in the lungs. Induction of phospholipidosis by amine drugs such as clorphentermine has also been shown. This study aimed to investigate the effect of fluoxetine and maprotiline, which contain amine groups in their structure, on pulmonary epithelial membrane permeability. Twenty-seven patients (mean age 36+/-12 years) with various psychiatric problems, of whom 17 were treated with fluoxetine and 10 with maprotiline, were included in this study. Technetium-99m diethylene triamine penta-acetic acid (DTPA) aerosol inhalation scintigraphy was performed before and after 4-6 weeks of therapy. Following the inhalation of 1480 MBq 99mTc-DTPA for 3 min, lung images in a 64x64 matrix were obtained every minute for 30 min. Regions of interest were drawn around the periphery of the lungs and on the major airways. Clearance half-times (T 1/2) were calculated by placing a mono-exponential fit on the curves. Penetration index (PI) was calculated on the first-minute image. There was no difference between the clearance rates of 99mTc-DTPA before and after therapy for either the fluoxetine or the maprotiline group. After therapy, a significant decrease in PI was found in patients treated with fluoxetine (PI values before and after therapy: 0.53+/-0.03 and 0.49+/-0.05 respectively, P< or =0.05). This finding might have been due to the induction of increased synaptic serotonin (5-HT) by fluoxetine, which acts by inhibiting the re-uptake of 5-HT on presynaptic membranes. Bronchoconstriction of small and medium airways may be caused by direct and indirect effects of 5-HT on smooth muscle contraction.

Radon: characteristics in air and dose conversion factors.

The dose conversion factor (DCF) which gives the relationship between effective dose and potential alpha energy concentration of inhaled short-lived radon decay products is calculated with a dosimetric approach. The calculations are based on a lung dose model with a structure that is related to the new recommended ICRP respiratory tract model. The characteristics of the radon decay products concerning the unattached fraction and the activity size distribution of the radon decay products are important input quantities for the calculation of DCF. Experimental data about these parameters obtained from measurements in homes, at working places, and in the free atmosphere at ground level in the last past years are summarized. Taking into account the measured aerosol characteristics the DCF fractions of the unattached (DCFu) and aerosol-attached (DCFae) radon decay products for different places were calculated. Variation of DCF for different places were caused dominantly by the variation of DCFu of the unattached radon clusters (0.3-32 mSv WLM(-1)). Nose inhalation drastically reduced (about a factor 4) the dose contribution by the unattached cluster. The dose fraction by the radon decay product aerosol (DCFae) varies between 4-10 mSv WLM(-1). Taking into account a relative sensitivity distribution between bronchial, bronchiolar and alveolar regions of the thoracic lung with 0.80:0.15:0.05 and nose breathing the DCF of most of the working places (inhalation rate: 1.2 m3 h(-1)) vary between 5.7-6.7 mSv WLM(-1) depending on the number concentration of the aerosol particles. The DCF-value of 4.2 mSv WLM(-1) for the general public in dwellings with higher aerosol concentration (>4 x 10(4) particles cm(-3)) has about the same value as recommended by ICRP 65 (1994b). Significantly higher are the DCF-values for "normal" aerosol conditions indoors (5 x 10(3)-4 x 10(4) particles cm(-3)) and in the open air (7.3 mSv WLM(-1) and 9.7 mSv WLM(-1)).

Distribution of the CD15 epitope in the mammalian developing lung is opposite in mouse compared with human

The distribution of the expression of the CD15 epitope was characterized by immunohistochemistry in the developing mouse and human lung on embryonic days E9.5-E19 and gestational weeks GW7-GW25, respectively. In the earliest stages in the mouse, the tracheal epithelial cells expressed CD15 on their apical and lateral cell membranes and, in the more proximal regions, also showed a faint cytoplasmatic CD15 expression. Only very few epithelial cells in the bronchial bud regions expressed CD15 on their apical surfaces. In later stages (E12–E17), cells in the proximal parts of the bronchi and bronchioli expressed CD15 on their apical, but also on their lateral membranes, and increasing numbers of cells expressed CD15 cytoplasmatically. Cells in the distal, presumably proliferating, areas of the bud regions were CD15 negative. This distribution pattern of CD15 was consistent until the latest embryonic stages. These results are completely opposite to those found in human developing lung where up to GW20 bronchial and bronchiolar bud regions were CD15 positive, while in the proximal parts of the airways the vast majority of cells were CD15 negative. After GW20, CD15 immunoreactivity in the bud regions vanished and was completely absent on GW25. This difference between human and mouse adds further evidence to profound species differences in the expression of CD15 in various organs, e.g., in the cerebellum or the retina, and should be taken into account when considering functional roles of CD15 and also when relating results from a (transgenic) mouse model to the respective human organ system.

Pulmonary effects in rats inhaling size-separated chrysotile asbestos fibres or p-aramid fibrils: differences in cellular proliferative responses

This study was designed to compare the pulmonary cellular proliferative effects of inhaled, size-separated preparations of chrysotile asbestos fibres with similar aerosol fibre concentrations of para-aramid fibrils. Following fibre preparation, rats were exposed for 2 weeks to aerosols of p-aramid fibrils or chrysotile asbestos fibres at design fibre concentrations of 750 and 400 f/cc. Two week exposures to p-aramid fibrils produced transient pulmonary inflammatory and cell labeling responses in terminal bronchiolar and subpleural regions. Similar to p-aramid, exposure to chrysotile produced a transient increase in neutrophils. In contrast, however, substantial increases compared to controls in pulmonary cell labeling indices were measured on terminal bronchiolar, parenchyma!, subpleural, and mesothelial surfaces immediately after exposure, and some increases persisted for 3 months postexposure. In complementary studies we demonstrated that p-aramid is biodegradable in the lungs of exposed rats; in contrast, the clearance of long chrysotile fibres was slow or insignificant, resulting in a pulmonary retention of long chrysotile asbestos fibres. The dimensional changes of asbestos fibres as well as the pulmonary cell labeling data indicate that chrysotile asbestos fibres may produce greater long-term pulmonary effects when compared to inhaled para-aramid fibrils.

Ozone-Induced Pulmonary Functional, Pathological, and Biochemical Changes in Normal and Vitamin C-Deficient Guinea Pigs

Ozone-Induced Pulmonary Functional, Pathological, and Biochemical Changes in Normal and Vitamin C-Deficient Guinea Pigs. Kodavanti, U. P., Hatch, G. E., Starcher, B., Giri, S. N., Winsett, D., and Costa, D. L. (1995). Fundam. Appl. Toxicol. 24, 154-164.Since Vitamin C (ascorbate, AH2) is an important airway antioxidant and is an essential component of tissue repair, and since acute (4 hr) O3 toxicity is enhanced by AH2 deficiency, we hypothesized that longer-term O3 effects might also be increased. Female Hartley guinea pigs (260-330 g) were fed either and AH2-sufficient or an AH2-deficient diet 1 week prior to exposure, and were maintained on their respective diets during 1 week of continuous exposure to O3 (0, 0.2, 0.4, and 0.8 ppm, 23 hr/day), and during 1 week postexposure recovery in clean air. The AH2-deficient diet caused lung AH2 to drop to about 30% of control in 1 week, and to below 10% by the end of exposure and recovery. Body weight gains during exposure were decreased in the 0.8 ppm O3 group, while the AH2 deficiency began to affect body weights only during recovery. O3 caused a concentration-dependent decrease in total lung capacity, vital capacity, carbon monoxide diffusing capacity, nitrogen washout, and static compliance, while increasing forced expiratory flow rates and residual or end-expiratory volume (suggestive of pulmonary gas-trapping). The lung/body weight ratio and fixed lung displacement volume were also increased in O3-exposed animals. Lung pathology consisted of mononuclear cell and neutrophil infiltration, airway as well as alveolar epithelial cell hyperplasia, and general decrease in epithelial cell cytoplasm. Thickening of the interstitium and an apparent increase in collagen staining were seen at the terminal bronchiolar regions. Some of these effects were marginally exacerbated in AH2-deficient guinea pigs. One week postexposure to air reversed all O3-induced abnormalities, irrespective of AH3 deficiency. Whole lung hydroxyproline and desmosine were not changed at any time by either O3 or AH2 deficiency. Measurement of lung prolyl hydroxylase activity suggested that AH2 deficiency as well as O3 exposure may have increased the tissue levels of this enzyme. The lack of a significant increase in toxicity with the longer-term exposure scenario suggests that AH2 has minimal influence on other compensatory mechanisms developed over time.

Covalent binding of o, p′-DDD in rabbit lung and isolated rabbit lung cells

The irreversible binding of o, p′-DDD was examined in isolated lung cells, in lung microsomes and in vivo in male New Zealand White rabbits. Non-ciliated bronchiolar (Clara) cells had the highest capacity to bind o, p′-DDD, followed by alveolar type II cells. A fraction of mixed unidentified lung cells was also able to bind o, p′-DDD while no binding was observed in alveolar macrophages. The activation of o, p'-DDD was shown to be mediated by cytochrome P-450 in both lung microsomes and isolated lung cells. In vivo, the binding was preferentially localized in the lung alveolar and bronchiolar regions. The binding of o, p′-DDD observed in vivo may thus be caused by the capacity of several cell types to activate o, p'-DDD.

Chrysotile asbestos inhalation induces tritiated thymidine incorporation by epithelial cells of distal bronchioles.

Previous studies in a rat model of asbestosis have demonstrated increased incorporation of tritiated thymidine by bronchiolar and alveolar epithelial cells 19 to 72 h after a single, 5-h exposure to chrysotile asbestos. This increase in thymidine labeling occurred at the first alveolar duct bifurcations, where terminal bronchioles end and where asbestos deposition is most concentrated. To determine whether airways more proximal than the terminal bronchioles exhibit a similar type of proliferative response to asbestos, incorporation of tritiated thymidine by airway epithelial cells was determined by light microscopic autoradiography. Incorporation by the epithelium in regions of the trachea, mainstem bronchi, and bronchioles was measured in lung tissue from sham-exposed and chrysotile asbestos-exposed rats, zero and 33 h after exposure. Sham-exposed animals and those studied immediately after exposure exhibited no increases in tritiated thymidine incorporation at any airway level. Tritiated thymidine incorporation by epithelial cells of bronchioles in peripheral regions of the lungs was significantly increased, as much as 20-fold, 33 h after chrysotile exposure. In the same asbestos-exposed animals, epithelial cells of the trachea, the bronchi, and the larger bronchioles did not exhibit increased cell labeling. The fact that asbestos was deposited throughout all airway levels, yet increased thymidine incorporation is observed primarily in the peripheral bronchiolar regions, raises interesting questions regarding the mechanisms of asbestos-induced cell proliferation.

Cytochrome P-450 content and its induction in primary rat liver tumors

Partial "sympathectomy" in the neonatal BALB mice was achieved by the treatment with guanethidine. The number of neurons in the stellate ganglion decreased to 20% of the control values and remained constant throughout the subsequent period of 1 month. Partial "chemical sympathectomy" did not affect the postnatal growth and development of the lungs. Partial "chemical sympathectomy" significantly increased the number of secreting cells in bronchiolar and alveolar regions. Secretory activity of the alveolocyte population, type two, synthetizing and secreting surfactant also increased. It has been concluded that the partial "chemical sympathectomy" stimulated the alveolar surfactant secretion.

Physical, chemical and physiological factors influencing entry of xenobiotics into the body via the pulmonary system

The respiratory system has an extremely large surface area covered with a thin aqueous film of either mucus or a lipoprotein surfactant-containing fluid. The large total surface area and minute separation between the air space and the blood make the lung an efficient organ for the rapid, systemic absorption of xenobiotics with a variety of physicochemical characteristics. Gases are absorbed throughout the entire respiratory system, the dominant driving force being diffusion. Highly water soluble gases are rapidly absorbed and may be cleared significantly through the surfaces of the upper respiratory tract before penetrating the deeper recesses of the lung. Inhaled particles are deposited in the respiratory system according to their size. Particles with aerodynamic diameters of 5 to 30 μm are similarly trapped in the nasopharyngeal region; those from 1 to 5 μm are largely deposited in the tracheal and bronchiolar regions, the major portion of particles smaller than 1 μm penetrate to the alveoli. Solute absorption studies indicate that the respiratory epithelium behaves like a lipoid–pore type membrane. Lipid soluble compounds are most rapidly absorbed at rates roughly related to their lipid/water partition coefficient at pH 7.4. Lipid insoluble substances are absorbed by nonsaturable diffusion with absorption rates related to the size of the molecules, i.e., the higher the molecular weight, the slower is the absorption. Organic ions can be absorbed by diffusion and by saturable, carrier-mediated processes. Pulmonary exposure to substances known to produce lung damage, i.e., ozone, silica, or acids, can alter carrier-mediated absorption of solutes and increase the passive absorption of lipid insoluble compounds alone or of both lipid soluble and lipid insoluble compounds. Age appears to be an important factor in absorption rate of lipid insoluble compounds. The lungs of 3- to 12-day-old rats absorb lipid insoluble compounds twice as rapidly as those of 18- to 27-day-old or adult animals. Age is unimportant, however, in the absorption of lipid soluble compounds. Species differences also exist for the absorption rates of lipid insoluble compounds but not for those of lipid soluble compounds. Mice will absorb lipid insoluble compounds 2 to 3 times more rapidly than rats, while rats absorb 1.3 to 3 times more rapidly than the rabbit.