Biomedical subjects

M L Witten

Publications and source records attributed to M L Witten.

48 records · Page 3Linked to original sources

PubMed1986

An association between aerobic fitness and lung closing volume.

This study was performed to determine whether an association exists between relative aerobic fitness (fitness index) and lung closing volume (CV). The subject population consisted of 100 healthy nonsmoking adults (50 males and 50 females) divided equally into five age groups; 20-29, 30-39, 40-49, 50-59, and over 60 years. Each subject underwent four to six closing volume and forced vital capacity (FVC) tests followed by a modified Balke maximal oxygen uptake test on a motor-driven treadmill with a constant treadmill speed. Relative VO2 maximum (VO2 max, mlO2 X kg-1 X min-1) was determined from the exercise test and was used to define subject rank on the fitness index. CV, as a % of slow vital capacity (SVC), had a negative linear correlation (r = -0.53, P less than 0.05) with the fitness index. Slope of phase III (%N2/L) and FEV1/FVC (forced expired volume in 1 s as a % of forced vital capacity) also had significant correlation coefficients (r = -0.31, r = 0.24, respectively; both P less than 0.05) with the fitness index. The correlation coefficients, with age partialled from the relationships, between FVC/body weight (kg) and VO2 max were r = 0.59 for females and r = 0.43 for males (P less than 0.05, both groups). We hypothesize that the effects of aerobic fitness on lung function may be the result of changes in autonomic nervous system activity and may represent a situation where a high level of aerobic fitness affects the aging process of the lung beta-adrenergic nervous system.

Adult↗

PubMed1986

Variability of pulmonary responsiveness to aerosolized histamine in normal rabbits.

Considerable between-subject variability in pulmonary responsiveness to histamine has been reported in normal human subjects, dogs, guinea pigs, and rhesus monkeys, but rabbits have not been studied. We determined the between- and within-rabbit variability of pulmonary histamine responsiveness in 34 anesthetized and mechanically ventilated New Zealand White rabbits. In 30 rabbits, 5 breaths of aerosolized histamine were delivered in 9 increasing concentrations ranging from 0.01 to 100 mg/ml. Eleven of 30 rabbits were rechallenged with histamine on 1-4 additional occasions over a 3-week period. In the remaining 4 rabbits, 9 doses of distilled H2O were aerosolized to determine the degree of spontaneous variability in measurements of lung resistance (RL) and dynamic lung compliance (Cdyn). We defined an increase in RL of greater than 50% of baseline (TD50RL) and a decrease in Cdyn of greater than 25% of baseline (TD25Cdyn) as being significant based on observations in these 4 rabbits. These limits exceeded the 99.9 percentile of spontaneous variability in RL and Cdyn. Pulmonary responsiveness to histamine varied widely, with a greater than 10,000-fold range in TD50RL and a 1,000-fold range in TD25Cdyn between the most and least sensitive rabbits. The variability of this responsiveness was log-normally distributed. It was not correlated with age, sex, or baseline RL and Cdyn. In contrast, within-rabbit responses to histamine challenge were quite reproducible. Five of 30 rabbits were killed at the conclusion of their histamine challenges for pathologic examination of their lungs. No evidence of airway inflammation was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗

PubMed1985

Acute cigarette smoke exposure increases alveolar permeability in rabbits.

We measured lung clearance of aerosolized technetium-labeled diethylenetriamine pentaacetic acid (99mTcDTPA) as an index of alveolar epithelial permeability in rabbits exposed to cigarette smoke. Eighteen rabbits were randomly assigned to 3 equal-size groups: control, all smoke exposure (ASE), and limited smoke exposure (LSE). Cigarette or sham smoke was delivered by syringe in a series of 5, 10, 20, and 30 tidal volume breaths with a 20-min counting period between each subset of breaths to determine 99mTcDTPA biologic half-life (T1/2). Mean T1/2 minimum (i.e., the smallest T1/2 observed) was significantly lower (p less than 0.05) for ASE and LSE rabbits than by control rabbits. We observed a significant difference at 20 and 30 breath exposures between the control and ASE group mean values (% baseline) for T1/2, arterial blood pressure, and peak airway pressure. A combination of light and electron microscopy showed focal alveolar edema and hemorrhage in the ASE and LSE groups but no alveolar-capillary membrane damage. In summary, acute cigarette smoke exposure increases alveolar permeability as measured by 99mTcDTPA clearance, but there was no detectable ultrastructural alteration of the alveolar-capillary membrane.

Animals↗

PubMedDate not supplied

Inhalation exposure to JP-8 jet fuel alters pulmonary function and substance P levels in Fischer 344 rats.

In a simulated military flightline exposure protocol, Fischer 344 rats (F344) were used to investigate the pulmonary effects of JP-8 jet fuel inhalation. Exposures were nose only and for 1 h daily. Groups were exposed for 7 days (7D) or 28 days (28D). Each exposure group had a matched longitudinal control group (LC7 and LC28). Exposure concentrations of 520 mg m-3 caused an increase in dynamic compliance after 7 days of exposure, but compliance changes were not seen with continued exposure (28D, 495 mg m-3). Pulmonary resistance was increased in both 7- and 28-day JP-8-exposed groups. Changes in pulmonary function were accompanied by a decrease in substance P concentrations from the bronchoalveolar lavage fluid (BALF). No significant change was observed in BALF levels of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin, which is a marker of endothelial cell function. The JP-8-exposed rats gained significantly less weight during the study period than the LC7 and LC28 groups, and the lungs of the 7D group were heavier by wet lung/body weight ratio (WtL/WtB). Alveolar clearance of technetium-labelled diethylenetriamine pentaacetate ([99mTc]DTPA) was increased in jet fuel-exposed groups. Light microscopy showed no pathological evidence of lung injury. Recovery from the early pulmonary effects of JP-8 inhalation occurred with continued exposure, as seen by recovery of pulmonary compliance and WtL/WtB.

6-Ketoprostaglandin F1 alpha↗

PubMedDate not supplied

Effects of aerosol-vapor JP-8 jet fuel on the functional observational battery, and learning and memory in the rat.

To determine whether JP-8 jet fuel affects parameters of the Functional Observational Battery (FOB), visual discrimination, or spatial learning and memory, the authors exposed groups of male Fischer Brown Norway hybrid rats for 28 d to aerosol/vapor-delivered JP-8, or to JP-8 followed by 15 min of aerosolized substance P analogue, or to sham-confined fresh room air. Behavioral testing was accomplished with the U.S. Environmental Protection Agency's Functional Observational Battery. The authors used the Morris swim task to test visual and spatial learning and memory testing. The spatial test included examination of memory for the original target location following 15 d of JP-8 exposure, as well as a 3-d new target location learning paradigm implemented the day that followed the final day of exposure. Only JP-8 exposed animals had significant weight loss by the 2nd week of exposure compared with JP-8 with substance P and control rats; this finding compares with those of prior studies of JP-8 jet fuel. Rats exposed to JP-8 with or without substance P exhibited significantly greater rearing and less grooming behavior over time than did controls during Functional Observational Battery open-field testing. Exposed rats also swam significantly faster than controls during the new target location training and testing, thus supporting the increased activity noted during Functional Observational Battery testing. There were no significant differences between the exposed and control groups' performances during acquisition, retention, or learning of the new platform location in either the visual discrimination or spatial version of the Morris swim task. The data suggest that although visual discrimination and spatial learning and memory were not disrupted by JP-8 exposure, arousal indices and activity measures were distinctly different in these animals.

Administration, Inhalation↗

PubMedDate not supplied

Nedocromil sodium inhibits canine adenovirus bronchiolitis in beagle puppies.

Nedocromil sodium is a nonsteroidal anti-inflammatory drug used to control asthmatic attacks. Our hypothesis is that nedocromil sodium inhibits virus-induced airway inflammation, a common trigger of asthma. We nebulized nedocromil sodium into beagle dogs (n = 10, mean +/- SEM ages: 149 +/- 13 days) before and after inoculation with canine adenovirus type 2 (CAV2). Control dogs (n = 10) received saline aerosols and were either infected with CAV2 (Sal/CAV2, n = 7, mean +/- SEM ages: 140 +/- 11 days) or were not infected (Sal/Sal, n = 3, ages: 143 +/- 0 days). All dogs were anesthetized with choralose (80 mg/kg i.v.), intubated, and mechanically ventilated. Pulmonary function tests and bronchoalveolar lavage (BAL) were performed using standard techniques. Pulmonary function tests revealed no significant change between the nedocromil sodium and non-nedocromil-treated groups. The percentage of infected bronchioles was quantitated as the number of inflamed airways of 40 bronchioles examined times 100 for each dog. Nedocromil-treated dogs had significantly (p < 0.05) less mucosal inflammation (mean +/- SEM, 39% +/- 5%), epithelial denudation (36% +/- 5%), and BAL neutrophilia (11 +/- 3) than did Sal/CAV2 dogs (51% +/- 6%, 57% +/- 4%, and 33% +/- 8%, respectively). We concluded that pretreatment with nedocromil sodium aerosols attenuated CAV2-induced airway inflammation in these beagle puppies.

Adenoviridae Infections↗

PubMedDate not supplied

Short-term pulmonary response to inhaled JP-8 jet fuel aerosol in mice.

B6.A.D. (Ahr(d)/Nat(s)) mice were utilized to investigate the short-term pulmonary response to JP-8 jet fuel (JP-8) aerosol inhalation. Mice were nose-only exposed to atmospheres of 0 to 118 mg/m3 for 1 h/d over a period of 7 days to further test the hypothesis that JP-8 concentrations below the permissible exposure level (PEL) of 350 mg/m3 will induce lung injury. At 24 to 30 hours after the final exposure, pulmonary function and respiratory permeability were measured on anesthetized mice and then randomly assigned for bronchoalveolar lavage or histopathology. Bronchoalveolar lavage fluid (BALF) was analyzed for total protein, lactic dehydrogenase (LDH), N-acetyl-beta-D-glucosaminidase (NAG), and cytology. Respiratory permeability increases were observed following doses of 48 and 118 mg/m3 and were supported by concomitant BALF increases in total protein and LDH. Conversely, NAG and alveolar macrophage levels decreased following the same exposure concentrations. Morphological lung injury was characterized by the targeting of bronchiolar epithelium and consisted of perivascular edema, Clara cell vacuolization, and necrosis. Alveolar injury included sporadic pulmonary edema, intra-alveolar hemorrhage, and alterations in type II epithelial cells. These results indicate that repeated inhalation of aerosolized JP-8 induces physiological, biochemical, cellular, and morphological lung injury. This study also provides evidence for the reevaluation of the 350 mg/m3 PEL for more volatile petroleum distillates with regard to respirable aerosols.

Administration, Inhalation↗

PubMedDate not supplied

Early alterations of lung injury following acute smoke exposure and 21-aminosteroid treatment.

In a simulated fire-related smoke exposure protocol, New Zealand white rabbits were utilized to investigate the potential effects of the 21-aminosteroid (lazaroid) analog U75412E on the early events of acute lung injury. Inhalation of a total of 1.6 mg/kg U75412E aerosolized at a rate of 1.53 mg/min at 0.5 hr after smoke exposure significantly attenuated the extent of lung injury at 1 hr, as evidenced by decreased bronchoalveolar lavage (BAL) concentration of total protein, 6-keto-prostaglandin F1-alpha, and blood gas defect. Histopathologic examination demonstrated that the lazaroid significantly attenuated smoke-induced lung injury as evidenced by a decrease in wet lung/body weight ratio, necrosis, and sloughing of airway epithelial cells. Electron microscopy showed that the lazaroid decreased smoke-induced interstitial edema and the vacuolization of alveolar type II epithelium (21.6 +/- 9.7 vs 8.5 +/- 3.6 vacuoled blebs/cell, smoke only vs smoke + lazaroid). However, U75412E did not attenuate smoke-induced changes in BAL concentration of tumor necrosis factor-alpha, total cell count, and granulocyte percentage. These observations suggest that U75412E may exert its action through cooperative mechanisms, such as the modulation of arachidonic acid metabolism, in addition to its characterized antioxidative effects.

6-Ketoprostaglandin F1 alpha↗

PubMedDate not supplied

Changes in lung permeability correlate with lung histology in a chronic exposure model.

In a simulated military flight-line exposure protocol, the effects of JP-8 jet fuel exposure on lung epithelial permeability were evaluated in male Fischer 344 rats (F344). Exposures were nose-only and for one hour daily. Groups were exposed for 7, 28, and 56 days. A protocol for administering a low dose (500mg/m3/hr) and a high dose (813-1094mg/m3/hr) of JP-8 jet fuel was used. Longitudinal sham-exposure groups (no jet fuel) for 7, 28, and 56 days were included in the protocol. Lung epithelial permeability was measured by clearance of technetium-labeled diethylenetriamine pentaacetate (99mTcDTPA, molecular weight = 492 daltons, physical half-life = 6.02 hours). The percent clearance of 99mTcDTPA per minute was calculated. Alveolar epithelial clearance for JP-8-exposed rats was dependent on both exposure concentration and duration. It was noted that at low-dose exposure concentrations alveolar epithelial clearance of 99mTcDTPA returned to low levels (LD56 = 1.09% per min; LC56 = 0.98% per min), suggesting recovery as evidenced by microscopic exam. The corresponding 56-day high-dose group (n = 10) had a significantly higher (p < 0.05) value of 2.25% per minute. The 28-day low-dose (n = 15) and high-dose (n = 20) groups had clearance values that were significantly increased from their longitudinal control group (n = 17). The alveolar epithelial permeability values were 2.51, 1.95, and 1.20, respectively. The seven-day longitudinal control, low-dose, and high-dose groups had alveolar permeability values of 1.57, 2.16, and 2.07, respectively. The lung histology correlated with the clearance values. Electron micrographs showed that all groups had interstitial edema resulting from endothelial damage. There was apparent thickening of the alveolar septa, and alveolar macrophages were activated in all groups. Lung permeability data, as determined by 99mTcDTPA alveolar clearance, indicated that lung injuries peaked at 28 days of jet fuel exposure, and this finding corresponded with the histology data. There was a discrepancy in the seven-day group between the number of cells and the 99mTcDTPA clearance values. The HD7 group had a total cell count significantly higher than all other groups, but the 99mTcDTPA clearance values in that group were not significantly different from that of any other group.

Aircraft↗

PubMedDate not supplied

Neutral endopeptidase (NEP) and its role in pathological pulmonary change with inhalation exposure to JP-8 jet fuel.

Through a simulated flightline exposure protocol, Fischer 344 rats (F344) were subjected to an aerosol/vapor mix of the military jet fuel, JP-8. Previous studies with this model of lung injury have revealed significant increases in pulmonary resistance, increased alveolar clearance of 99mTcDTPA, and a decrease in bronchoalveolar lavage fluid (BALF) concentration of the neuropeptide substance P (SP). Exposures to JP-8 were nose-only and for one hour daily. Six groups of Fischer 344 rats were exposed for 7, 28, or 56 days at two JP-8 concentrations (low dose = 469-520 mg/m3/hr, high dose = 814-1263 mg/m3/hr). Exposed groups were matched with longitudinal controls. In response to JP-8 inhalation, exposure animals demonstrated a dose-dependent as well as duration-determined reduction in BALF SP concentration. Both JP-8 concentrations caused significant pathological changes in lower pulmonary structures.

Administration, Inhalation↗

PubMedDate not supplied

Piriprost pretreatment attenuates the smoke-induced increase in 99mTcDTPA lung clearance.

We studied the effects of acute smoke exposure on lung permeability, eicosanoids, and inflammatory cell activity. Thirty-five New Zealand white rabbits were anesthetized, paralyzed, and exposed to 60 tidal volume breaths of diesel fuel-polycarbonate plastic smoke or sham smoke within 10 min. At 1 h postexposure the rabbits were killed and their lungs were removed for bronchoalveolar lavage (BAL) or pathologic procedures. Smoke exposure caused decreases in technetium-labeled diethylenetriamine pentaacetate (99mTcDTPA, mol. wt. 492 Da) biological half-life (t1/2), BAL plasminogen activator, and BAL leukotriene B4 (LTB4). In addition, alveolar macrophage acid phosphatase enzyme activity increased in smoke-exposed rabbits. The leukotriene synthesis inhibitor, piriprost (U-60,257), given before smoke exposure, caused attenuation of the changes in 99mTcDTPA uptake and plasminogen activator, swelling of type I alveolar cell epithelium, a large increase in lung inflammatory cells, and decreases in BAL LTB4, prostaglandin E2 (PGE2), and TxB2 (stable metabolite of thromboxane, TxA2). We conclude that changes in alveolar-capillary barrier permeability and plasminogen activator activity occur within 1 h after exposure to smoke and may play an early role in the inflammatory process associated with smoke inhalation injury. Furthermore, piriprost attenuates the smoke-induced increase in alveolar-capillary barrier permeability and decrease in plasminogen activator activity and causes a swelling of type I alveolar epithelium. However, our data suggest that neither lung eicosanoids or the alveolar macrophage lysis process plays a major role in the smoke-induced increase in alveolar-capillary barrier permeability.

Animals↗

PubMedDate not supplied

The effects of chronic sidestream cigarette smoke exposure on eicosanoid production by tracheal epithelium.

Environmental exposure to sidestream cigarette smoke (SSCS) has been associated with an increased incidence of pulmonary infection and bronchospasm. Chronic exposure to SSCS could modify the release of bronchoreactive eicosanoids by tracheal epithelium, the site of initial contact by lung with inhaled toxins. To assess this possibility, New Zealand white rabbits were placed in an environmental chamber flushed with 3 L of SSCS, 15 min/day for 20 days. Eighteen hours after the last exposure the animals were sacrificed and the tracheas were explanted. At 7 days, the epithelial cell outgrowths were exposed to media containing endotoxin (10 micrograms/mL) or acrolein (50 microM), an aldehyde commonly found in smoke, or to control media. After a 2-h exposure, media were assayed for eicosanoids by radioimmunoassay. PGE2 was produced in epithelium from normal animals (5.7 +/- 1.3 ng/10(6) cells), and was not significantly different in SSCS-exposed epithelium. When incubated in medium containing acrolein, PGE2 production increased significantly in SSCS-exposed epithelium (14.9 +/- 2.5, p < .05) but not in control groups. Endotoxin also increased PGE2 production in SSCS-exposed cells (12.6 +/- 3.3 ng/10(6), p < .05). Baseline production of 6-keto PGF1 alpha was 10.8 +/- 3.2 ng/10(6) cells in non-SSCS controls and did not change significantly in these cells with the addition of endotoxin or acrolein. In acrolein plus SSCS-exposed cells, 6-keto PGF1 alpha increased, in a dose-dependent manner, to 88.1 +/- 26.1 ng/10(6) (p < .05 compared to all normals, SSCS-exposed controls, and SSCS plus LPS). TxB2 release in control, non-SSCS-exposed cells was 13.3 +/- 2.8 ng/10(6) cells and was significantly increased (P < .05) only in the SSCS plus acrolein group (60.7 +/- 16.2 ng/10(6) cells). The results indicate that even brief, recurrent exposure to SSCS can change the production of cyclooxygenase products, particularly PGE2, 6- keto PGF1 alpha, and TxB2. This may reflect an altered ability of SSCS-exposed tracheal epithelium to respond to environmental (e.g., acrolein) or bacterial (e.g., endotoxin) insults.

6-Ketoprostaglandin F1 alpha↗