Edgar C. Kimmel

Lung function and airway inflammation in rats following exposure to combustion products of carbon-graphite/epoxy composite material: comparison to a rodent model of acute lung injury.

Pulmonary function and inflammation in the lungs of rodents exposed by inhalation to carbon/graphite/epoxy advanced composite material (ACM) combustion products were compared to that of a rodent model of acute lung injury (ALI) produced by pneumotoxic paraquat dichloride. This investigation was undertaken to determine if short-term exposure to ACM smoke induces ALI; and to determine if smoke-related responses were similar to the pathogenic mechanisms of a model of lung vascular injury. We examined the time-course for mechanical lung function, infiltration of inflammatory cells into the lung, and the expression of three inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2) and interferon-gamma (IFN-gamma). Male Fischer-344 rats were either exposed to 26.8-29.8 g/m(3) nominal concentrations of smoke or were given i.p. injections of paraquat dichloride. Measurements were determined at 1, 2, 3, and 7 days post exposure. In the smoke-challenged rats, there were no changes in lung function indicative of ALI throughout the 7-day observation period, despite the acute lethality of the smoke atmosphere. However, the animals showed signs of pulmonary inflammation. The expression of TNF-alpha was significantly increased in the lavage fluid 1 day following exposure, which preceded the maximum leukocyte infiltration. MIP-2 levels were significantly increased in lavage fluid at days 2, 3, and 7. This followed the leukocyte infiltration. IFN-gamma was significantly increased in the lung tissue at day 7, which occurred during the resolution of the inflammatory response. The paraquat, which was also lethal to a small percentage of the animals, caused several physiologic changes characteristic of ALI, including significant decreases in lung compliance, lung volumes/capacities, distribution of ventilation, and gas exchange capacity. The expression of TNF-alpha and MIP-2 increased significantly in the lung tissue as well as in the lavage fluid. Increased MIP-2 levels also preceded the maximum neutrophil infiltration. The differences in the time-course and primary site of TNF-alpha, MIP-2, and IFN-gamma expression; and the differences in the temporal relationship between their expression and infiltration of inflammatory cells may have accounted for the differences in lung function between paraquat treated and ACM smoke exposed animals.

Carbon dioxide accumulation during small animal, whole body plethysmography: Effects on ventilation, indices of airway function, and aerosol deposition

Barometric (whole body) plethysmography is used to examine changes in ventilation and breathing pattern in unrestrained animals during exposure to therapeutic or toxic aerosols. Whole body plethysmographs (WBP) may be operated with a bias flow in order to maintain an adequate supply of oxygen and remove expired CO(2). However, some aerosol generation and delivery methods may require operation of the WBP without bias flow, which would artificially deplete aerosol concentration. Under these conditions, expired CO(2) accumulates in the plethysmograph and stimulates ventilation, increasing total aerosol deposition, shifting regional deposition, and significantly altering some airway function indices. We characterized these effects in guinea pigs using a commercially available 4.5-L WBP, with and without a 1 L/min bias flow. CO(2)-induced changes in breathing frequency (f), tidal volume (Vt), minute ventilation (Ve), and indices of airway function -- including enhanced pause (penh), flow derived parameter (FDP), and respiratory duty cycle -- were measured. Without bias flow, CO(2) in the plethysmograph increased steadily to 5.4% after 30 min compared to a steady state 0.9% with bias flow. This resulted in a moderate suppression of f, and significant increases in Vt and Ve by factors of 1.5 and 1.4, respectively. Changes in regional deposition were stimulated for 300 mg/m(3) polydisperse aerosols with mass median aerodynamic diameters of 0.3, 1, 3, or 7 microm and geometric standard deviations of 1.7. Percent increase in aerosol deposition from CO(2) inhalation ranged from 24% to 90%, by mass, depending on aerosol size distribution and respiratory tract region. In addition, fractional deposition shifted toward the pulmonary region. Empirical indices of airway constriction, penh and FDP, also were increased significantly to 1.7 and 1.3 times their respective baseline values. The study quantifies the effect of inadvertent coexposure to CO(2) on ventilation, aerosol deposition, and airway function in WBP evaluation of aerosol effects in airway function.

A SMALL ANIMAL PLETHYSMOGRAPH/EXPOSURE TUBE FOR DETERMINATION OF RESPIRATORY MECHANICS DURING EXPOSURE, USING A NONINVASIVE METHOD TO MEASURE INTRAPLEURAL PRESSURE

The real-time measurement of changes in respiratory mechanics, primarily dynamic compliance (C dyn) and airway resistance (R L) , is often used to assess the pulmonary toxicity of inhaled materials, irritants thought to cause reactivity response in the airways. Simple volume displacement plethysmography for measurement of ventilation in spontaneously breathing animals can be adapted for the determination of C dyn and R L by including measurement of intrapleural pressure (Ppl). Accurate estimates of Ppl can be obtained by measurement of esophageal pressure (Pes) using transoral insertion of a water-filled catheter. Measurement of Pes does not require surgical intervention as is often required for the measurement of Ppl directly. However, the use of conventional head-out plethysmography to measure ventilation and respiratory mechanics during exposure usually precludes the use of a transoral esophageal catheter to measure Pes. Thus, invasive methods must be used to measure Ppl. The combination headout plethysmograph/nose-only exposure tube (PET), described in this article is suitable for the measurement of R L and C dyn using transoral catheterization for the determination of Pes during exposure. In addition to avoidance of surgical intervention, use of the PET does not interfere with the animals normal breathing or require extraordinary procedures for connection to a nose-only exposure chamber. Ventilation, breath waveform, and respiratory mechanics measurements in 36 Long-Evans rats demonstrated that neither short-term restraint in the PET nor subsequent insertion of the esophageal catheter significantly altered ventilation or individual breath structure. R L and C dyn measured in normal rats using the PET did not differ from R L and C dyn determined using more traditional plethysmographic methods.

A typical path model of tracheobronchial clearance of inhaled particles in rats.

A mathematical description of particle clearance from the ciliated conducting airways (tracheobronchial region) of the lungs in rats was developed, assuming that particles on the mucus blanket behave as a fluid and adhere to principles of fluid flow described by the continuity equation. Effective particle transport velocities for given generations of airways were estimated from reported tracheal mucus velocities. Using typical rat airway geometry and estimated particle transport velocities, solutions of sets of rate equations for transport from each generation of airways were summed to estimate total particle clearance from the tracheobronchial region of the lung as a function of time. Aerosol particle size distribution (MMAD ranging from 0.1 to 4.2 μm, and sg from 1 to 2.7) and concentration data from several investigators were used to predict short-term, tracheobronchial clearance (retention) in rats up to 24 h following exposure. Comparisons between predicted and observed retention showed an average difference between model predictions, and observed fractional retention of initial lung or body burden was 4.9%, with a tendency toward underprediction of clearance of particles >3.0 μm.

A simple, inexpensive solid fuel furnace for small scale combustion toxicity studies

WE DEVELOPED A rugged, inexpensive, and easily manufactured aerosol generator to conduct studies of the physicochemical characteristics and potential acute inhalation toxicity of Spectronix Fire Extinguishant (SFE) atmospheres [1,2]. SFE is a pyrotechnic mixture which, when ignited, burns at temperatures in excess of 1200°C generating a fine dry powder aerosol fire suppressant. The generator (furnace) was designed to withstand these temperatures and permit the use of a carrier gas for transport of the aerosol from the generator assembly to a 0.7 m3 exposure chamber [3]. The furnace is basically a vertical tube in which the sample is placed in a shallow ceramic dish that is supported by a sintered metal