The effect of route of immunization on the lapine immune response to killed Pasteurella haemolytica and the influence of aerosol challenge with the live organism.
Appearance of anti-Pasteurella haemolytica antibody in the serum and broncho-alveolar washings of rabbits is independent of the route of immunization and is similar in both locations. The most influential factor in development of a humoral response is exposure to live P. haemolytica and prior exposure to the killed bacterium has no significant effect upon titre determined following aerosol challenge with live organisms. (+info)
Factors influencing the deposition of inhaled particles.
Because the initial deposition pattern of inhaled particles of various toxic agents determines their future clearance and insult to tissue, respiratory tract deposition is important in assessing the potential toxicity of inhaled aerosols. Factors influencing the deposition of inhaled particles can be classified into three main areas: (1) the physics of aerosols, (2) the anatomy of the respiratory tract and (3) the airflow patterns in the lung airways. In the physics of aerosols, the forces acting on a particle and its physical and chemical properties, such as particle size or size distribution, density, shape, hygroscopic or hydrophobic character, and chemical reactions of the particle will affect the deposition. With respect to the anatomy of the respiratory tract, important parameters are the diameters, the lengths, and the branching angles of airway segments, which determine the deposition. Physiological factors include airflow and breathing patterns, which influence particle deposition. Various lung models used in predicting particle deposition are reviewed and discussed. The air-way structures of various animal species are compared, showing the unique structure of the human lung compared to the animal species under study. Regional deposition data in man and dog are reviewed. Recent deposition data for small rodents are presented, showing regional difference in deposition with the right apical lobe having the highest relative deposition. (+info)
An animal exposure system using ultrasonic nebulizer that generates well controlled aerosols from liquids.
Various aerosol generators have been developed for animal inhalation experiments and the performance tests of measuring instruments and respirators. It has been, however, difficult to generate aerosols from an aqueous solution or suspension keeping the concentration and particle size distribution constant for a long time. Resolving such difficulties, the present study developed an animal exposure system that generates well-controlled and stable aerosols from liquids. The exposure system consists of an aerosol generator using ultrasonic nebulizer, a mixing chamber and an exposure chamber. The validity of this system was confirmed in the generation of NiCl2 and TiO2 aerosol from solution and suspension, respectively. The concentration levels of NiCl2 aerosol were kept at 3.2 mg/m3 and 0.89 mg/m3 for 5 hours with good coefficients of variation (CVs) of 2.5% and 1.7%, respectively. For TiO2 aerosol, the concentration levels of 1.59 mg/m3 and 0.90 mg/m3 were kept for 5 hours with small CVs of 1.3% and 2.0%, respectively. This exposure system could be sufficiently used for inhalation experiments with even high toxic aerosols such as NiCl2 because a momentary high concentration possibly affects results and an extremely stable concentration is required. (+info)
Acinar flow irreversibility caused by perturbations in reversible alveolar wall motion.
Mixing associated with "stretch-and-fold" convective flow patterns has recently been demonstrated to play a potentially important role in aerosol transport and deposition deep in the lung (J. P. Butler and A. Tsuda. J. Appl. Physiol. 83: 800-809, 1997), but the origin of this potent mechanism is not well characterized. In this study we hypothesized that even a small degree of asynchrony in otherwise reversible alveolar wall motion is sufficient to cause flow irreversibility and stretch-and-fold convective mixing. We tested this hypothesis using a large-scale acinar model consisting of a T-shaped junction of three short, straight, square ducts. The model was filled with silicone oil, and alveolar wall motion was simulated by pistons in two of the ducts. The pistons were driven to generate a low-Reynolds-number cyclic flow with a small amount of asynchrony in boundary motion adjusted to match the degree of geometric (as distinguished from pressure-volume) hysteresis found in rabbit lungs (H. Miki, J. P. Butler, R. A. Rogers, and J. Lehr. J. Appl. Physiol. 75: 1630-1636, 1993). Tracer dye was introduced into the system, and its motion was monitored. The results showed that even a slight asynchrony in boundary motion leads to flow irreversibility with complicated swirling tracer patterns. Importantly, the kinematic irreversibility resulted in stretching of the tracer with narrowing of the separation between adjacent tracer lines, and when the cycle-by-cycle narrowing of lateral distance reached the slowly growing diffusion distance of the tracer, mixing abruptly took place. This coupling of evolving convective flow patterns with diffusion is the essence of the stretch-and-fold mechanism. We conclude that even a small degree of boundary asynchrony can give rise to stretch-and-fold convective mixing, thereby leading to transport and deposition of fine and ultrafine aerosol particles deep in the lung. (+info)
A source of experimental underestimation of aerosol bolus deposition.
We examined the measurement error in inhaled and exhaled aerosol concentration resulting from the bolus delivery system when small volumes of monodisperse aerosols are inspired to different lung depths. A laser photometer that illuminated approximately 75% of the breathing path cross section recorded low inhaled bolus half-widths (42 ml) and negative deposition values for shallow bolus inhalation when the inhalation path of a 60-ml aerosol was straight and unobstructed. We attributed these results to incomplete mixing of the inhaled aerosol bolus over the breathing path cross section, on the basis of simultaneous recordings of the photometer with a particle-counter sampling from either the center or the edge of the breathing path. Inserting a 90 degrees bend into the inhaled bolus path increased the photometer measurement of inhaled bolus half-width to 57 ml and yielded positive deposition values. Dispersion, which is predominantly affected by exhaled bolus half-width, was not significantly altered by the 90 degrees bend. We conclude that aerosol bolus-delivery systems should ensure adequate mixing of the inhaled bolus to avoid error in measurement of bolus deposition. (+info)
Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin.
TNF and lymphotoxin-alpha (LT alpha) may act at various stages of the host response to Mycobacterium tuberculosis. To dissect the effects of TNF independent of LT alpha, we have used C57BL/6 mice with a disruption of the TNF gene alone (TNF-/-). Twenty-one days following aerosol M. tuberculosis infection there was a marked increase in the number of organisms in the lungs of TNF-/- mice, and by 28-35 days all animals had succumbed, with widespread dissemination of M. tuberculosis. In comparison with the localized granulomas containing activated macrophages and T cells in lungs and livers of C57BL/6 wild-type (wt) mice, cellular infiltrates in TNF-/- mice were poorly formed, with extensive regions of necrosis and neutrophilic infiltration of the alveoli. Phenotypic analysis of lung homogenates demonstrated similar numbers of CD4+ and CD8+ T cells in TNF-/- and wt mice, but in TNF-deficient mice the lymphocytes were restricted to perivascular and peribronchial areas rather than colocated with macrophages in granulomas. T cells from TNF-/- mice retained proliferative and cytokine responses to purified protein derivative, and delayed-type hypersensitivity to purified protein derivative was demonstrable. Macrophages within the lungs of TNF-/- and wt mice showed similar levels of MHC class II and inducible nitric oxide synthase expression, and levels of serum nitrite were comparable. Thus, the enhanced susceptibility of TNF-/- is not compensated for by the presence of LT alpha, and the critical role of TNF is not in the activation of T cells and macrophages but in the local organization of granulomas. (+info)
Efficacy of RD3-0028 aerosol treatment against respiratory syncytial virus infection in immunosuppressed mice.
RD3-0028, a benzodithiin compound, has antiviral activity against respiratory syncytial virus (RSV) in cell culture. We used a mouse model of RSV infection to determine the in vivo effect of RD3-0028. Cyclophosphamide (CYP)-treated, immunosuppressed mice were inoculated intranasally. The lungs of the mice were removed on day 4. The virus titers of the lungs of RD3-0028-treated mice were compared to the virus titers of the lungs of virus-inoculated, untreated control mice. In an effort to increase the therapeutic effectiveness of this compound, RD3-0028 was administered by aerosol to RSV-infected mice by using a head-exposure system. Aerosols generated from reservoirs containing RD3-0028 (7 mg/ml) administered for 2 h twice daily for 3 days significantly reduced the pulmonary titer of RSV-infected mice. It is clear that the minimal effective dose of RD3-0028 for RSV-infected mice is significantly less than that of ribavirin, the only compound currently available for use against RSV disease. Furthermore, the RD3-0028 aerosol administration appeared to protect the lungs of infected, CYP-treated mice against tissue damage, as evidenced by the preservation of the lung architecture and a reduction in pulmonary inflammatory infiltrates. RD3-0028 aerosol was not toxic for mice at the therapeutic dose. The present study demonstrates the effectiveness of aerosol administration of RD3-0028 for RSV-infected mice. (+info)
Particle deposition in the trachea: in vivo and in hollow casts.
The pattern of deposition within the respiratory tract of potentially harmful particulates is a major factor in assessing any risk from individual and community exposures. Although the trachea is the most easily observed of the conductive airways, very little information concerning its particle collection characteristics is available, information which is essential for a complete and realistic description of particle deposition patterns within the entire respiratory tract. Data on tracheal deposition are also needed for development of accurate predictive models for particle deposition. The pattern of particle deposition in the trachea, and its relation to air flow, was studied in a hollow cast of the human larynx-tracheobronchial tree. Results were compared with data obtained in humans in vivo and from previous studies in hollow casts. In addition, the relevance of tracheal deposition in the hollow cast test system to deposition in vivo was examined by a direct comparison of deposition in a cast prepared from the lungs of donkeys previously studied in a series of in vivo tests. The disturbance of the air flow within the trachea caused by the larynx promoted the deposition of suspended particulates throughout the length of the trachea, and especially in proximal regions. This proximal deposition was due both to direct impaction from the air jet coming from the glottis and to effects of the tubulent flow. Turbulence produced inhomogenous deposition patterns within the trachea for particles of all sizes, although its effect was more pronounced as size decreased. Tracheal deposition in the human cast was within the range of normal in vivo tracheal depostion only when a larynx was used during cast test exposures; this emphasizes the need for the use of realistic experimental test systems for the study of particle deposition patterns. The relative patterns of deposition in casts of the donkey trachea and in the same tracheas in vivo were similar. (+info)