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Biomedical subjects

M L Witten

Publications and source records attributed to M L Witten.

At least 19 recordsLinked to original sources
PubMed2004

Drotrecogin alfa (activated) prevents smoke-induced increases in pulmonary microvascular permeability and proinflammatory cytokine IL-1beta in rats.

In an established rat model of smoke inhalation injury, we conducted a dose-response study to examine the protective effects of Xigris [drotrecogin alfa (activated) (DrotAA)], a recombinant form of human activated protein C (APC). DrotAA is a serine protease (approximately 55 kD molecular weight) with the same amino acid sequence and the glycosylation site as human plasma-derived APC. A total of 120 F344/NH rats (half each gender, approximately 175 g body weight) were randomly divided into five groups and exposed nose-only to air or diesel fuel smoke for 20 min. These rats were then i.v. administered with DrotAA in 0, 5, 10, and 20 mg/kg body weight, respectively, immediately following smoke exposure. Treatment with DrotAA significantly attenuated smoke inhalation injury in a dose-dependent manner at 2 hours after insult, as indicated by preserving microvascular permeability and proinflammatory cytokine IL-1beta (but not TNF-alpha and neuropeptide substance P) in bronchoalveolar lavage fluid (BALF). Moreover, the rats treated with 20 mg/ kg of DrotAA had an improvement of the expiration phase of pulmonary dynamic compliance. At all dosages, however, DrotAA also significantly increased all phases of pulmonary resistance compared with either the controls or to smoke inhalation alone. Generally, these data suggest that DrotAA may exert an anti-inflammatory effect by inhibiting cytokine-mediated inflammatory amplification. However, additional studies following a clinical course are needed to confirm the maximum efficiency and possible side effects of this recombined human activated protein C.

Animals↗
PubMed2001

Adverse respiratory effects following overhaul in firefighters.

Overhaul is the stage in which firefighters search for and extinguish possible sources of reignition. It is common practice not to wear respiratory protection during overhaul. Fifty-one firefighters in two groups, 25 without respiratory protection and 26 wearing cartridge respirators, were monitored for exposure to products of combustion and changes in spirometric measurements and lung permeability following overhaul of a structural fire. Testing at baseline and 1 hour after overhaul included forced vital capacity (FVC), forced expiratory volume in one second (FEV1), serum Clara cell protein (CC16), and serum surfactant-associated protein A (SP-A). Overhaul increased CC16 in both groups, indicating increased alveolarcapillary membrane permeability. Contrary to expectations, SP-A increased and FVC and FEV1 decreased in the firefighters wearing cartridge respirators. Changes in FEV1, CC16, and SP-A were associated with concentrations of specific products of combustion or carboxyhemoglobin levels. Firefighter exposures during overhaul have the potential to cause changes in spirometric measurements and lung permeability, and self-contained breathing apparatus should be worn during overhaul to prevent lung injury.

Adult↗
PubMed2001

Age-related differences in pulmonary inflammatory responses to JP-8 jet fuel aerosol inhalation.

Our previous studies have demonstrated that JP-8 jet fuel aerosol inhalation induced lung injury and dysfunction. To further examine JP-8 jet fuel-induced inflammatory mechanisms, a total of 40 male C57BL/6 mice (young, 3.5 months; adult, 12 months; half in each age group) were randomly assigned to the exposure or control groups. Mice were nose-only exposed to room air or atmospheres of 1000 mg/m3 JP-8 jet fuel for 1 h/day for 7 days. Lung injury was assessed by pulmonary mechanics, respiratory permeability, lavaged cell profile, and chemical mediators in bronchoalveolar lavage fluid (BALF). The young and adult mice exposed to JP-8 jet fuel had similar values with regards to increased lung dynamic compliance, lung permeability, BALF cell count, and decreased PGE2. However, there were several different responses between the young-versus-adult mice with respect to BALF cell differential, TNF-alpha, and 8-iso-PGF2,, levels after exposure to JP-8 jet fuel. These data suggest that JP-8 jet fuel may have different inflammatory mechanisms leading to lung injury and dysfunction in the younger-versus-adult mice.

Administration, Inhalation↗
PubMed2000

Proteomic analysis of the renal effects of simulated occupational jet fuel exposure.

We analyzed protein expression in the cytosolic fraction prepared from whole kidneys in male Swiss-Webster mice exposed 1 h/day for five days to aerosolized JP-8 jet fuel at a concentration of 1000 mg/m3, simulating military occupational exposure. Kidney cytosol samples were solubilized and separated via large-scale, high-resolution two-dimensional electrophoresis (2-DE) and gel patterns scanned, digitized and processed for statistical analysis. Significant changes in soluble kidney proteins resulted from jet fuel exposure. Several of the altered proteins were identified by peptide mass finger-printing and related to ultrastructural abnormalities, altered protein processing, metabolic effects, and paradoxical stress protein/detoxification system responses. These results demonstrate a significant but comparatively moderate JP-8 effect on protein expression in the kidney and provide novel molecular evidence of JP-8 nephrotoxicity. Human risk is suggested by these data but conclusive assessment awaits a noninvasive search for biomarkers in JP-8 exposed humans.

Aerosols↗
PubMed2000

Non-invasive measurement of organ density in a rat simulated microgravity model.

BACKGROUND: Spaceflight has caused serious concerns to the health and well-being of astronauts, both while in space and post-mission on Earth. The deleterious health effects due to microgravity are not well understood and though these effects may be caused by multiple factors, fluid shifts within the body may play a major role. HYPOTHESIS: We believe that 45 degrees C HDT will cause significant changes in organ density as measured by spiral computed tomography in a 1-h experimental time period. METHODS: There were 20 male Fischer 344 rats that were randomly selected to be in an experimental or control group. The experimental group (n = 12) was subjected to a 45 degrees head down tilt microgravity exposure (45 degrees HDT) for 1 h, and the control group (n = 8) remained in the prone position for the same amount of time. At the end of 1 h, the density of the brain, lungs, heart, liver, and left and right kidneys were measured using spiral computed tomography (SCT) while the rats remained in their experimental positions. RESULTS: With the exception of the right kidney, we demonstrated that there was a significant change (p < 0.05) in the densities of all tested organs in the 45 degrees HDT group when compared with the control group. The brain showed the largest percent increase at 45.6% while the lungs showed the least amount of change at 8.7%. CONCLUSIONS: We conclude there are significant increases in organ density, as measured by SCT, in male 45 degrees HDT rats compared with prone controls.

Adaptation, Physiological↗
PubMed1999

Proteomic analysis of simulated occupational jet fuel exposure in the lung.

We analyzed protein expression in the cytosolic fraction prepared from whole lung tissue in male Swiss-Webster mice exposed 1 h/day for seven days to aerosolized JP-8 jet fuel at concentrations of 1000 and 2500 mg/m3, simulating military occupational exposure. Lung cytosol samples were solubilized and separated via large scale, high resolution two-dimensional electrophoresis (2-DE) and gel patterns scanned, digitized and processed for statistical analysis. Significant quantitative and qualitative changes in tissue cytosol proteins resulted from jet fuel exposure. Several of the altered proteins were identified by peptide mass fingerprinting, confirmed by sequence tag analysis, and related to impaired protein synthetic machinery, toxic/metabolic stress and detoxification systems, ultrastructural damage, and functional responses to CO2 handling, acid-base homeostasis and fluid secretion. These results demonstrate a significant but comparatively moderate JP-8 effect on protein expression and corroborate previous morphological and biochemical evidence. Further molecular marker development and mechanistic inferences from these observations await proteomic analysis of whole tissue homogenates and other cell compartment, i.e., mitochondria, microsomes, and nuclei of lung and other targets.

Animals↗
PubMed1999

Modulation of bronchial epithelial cell barrier function by in vitro jet propulsion fuel 8 exposure.

The loss of epithelial barrier integrity in bronchial and bronchiolar airways may be an initiating factor in the observed onset of toxicant-induced lung injuries. Acute 1-h inhalation exposures to aerosolized jet propulsion fuel 8 (JP-8) have been shown to induce cellular and morphological indications of pulmonary toxicity that was associated with increased respiratory permeability to 99mTc-DTPA. To address the hypothesis that JP-8 jet fuel-induced lung injury is initiated through a disruption in the airway epithelial barrier function, paracellular mannitol flux of BEAS-2B human bronchial epithelial cells was measured. Incubation of confluent cell cultures with non-cytotoxic concentrations of JP-8 or n-tetradecane (C14), a primary constituent of JP-8, for a 1-h exposure period resulted in dose-dependent increases of paracellular flux. Following exposures of 0.17, 0.33, 0.50, or 0.67 mg/ml, mannitol flux increased above vehicle controls by 10, 14, 29, and 52%, respectively, during a 2-h incubation period immediately after each JP-8 exposure. C14 caused greater mannitol flux increases of 37, 42, 63, and 78%, respectively, following identical exposure conditions. The effect on transepithelial mannitol flux reached a maximum at 12 h and spontaneously reversed to control values over a 48-h recovery period, for both JP-8 and C14 exposure. These data indicate that non-cytotoxic exposures to JP-8 or C14 exert a noxious effect on bronchial epithelial barrier function that may preclude pathological lung injury.

Alkanes↗
PubMed1999

NK1-receptor activation prevents hydrocarbon-induced lung injury in mice.

Recent evidence suggests that neurokinin (NK)-receptor activation may have a protective role in maintaining lung integrity when challenged by airborne toxicants such as sulfur dioxide, ozone, acrolein, or hydrocarbons. To investigate the effect of NK1-receptor activation on hydrocarbon-induced lung injury, B6.A.D. (Ahr d/Nats) mice received subchronic exposures to JP-8 jet fuel (JP-8). Lung injury was assessed by the analysis of pulmonary physiology, bronchoalveolar lavage fluid, and morphology. Hydrocarbon exposure to target JP-8 concentrations of 50 mg/m3, with saline treatment, was characterized by enhanced respiratory permeability to 99mTc-labeled diethylenetriaminepentaacetic acid, alveolar macrophage toxicity, and bronchiolar epithelial damage. Mice administered [Sar9,Met(O2)11]substance P, an NK1-receptor agonist, after each JP-8 exposure had the appearance of normal pulmonary values and tissue morphology. In contrast, endogenous NK1-receptor antagonism by CP-96345 administration exacerbated JP-8-enhanced permeability, alveolar macrophage toxicity, and bronchiolar epithelial injury. These data indicate that NK1-receptor activation may have a protective role in preventing the development of hydrocarbon-induced lung injury, possibly through the modulation of bronchiolar epithelial function.

Aerosols↗
PubMed1999

Functional alterations of alveolar macrophages subjected to smoke exposure and antioxidant lazaroids.

Acute inhalation of diesel fuel-polycarbonate plastic (DFPP) smoke causes severe lung injury, leading to acute respiratory distress syndrome (ARDS) and death. It has been reported that the initiation of acute lung injury is associated with the activation of pulmonary alveolar macrophages (PAM). To further explore the pathogenesis, alveolar macrophages (AM) of New Zealand rabbits ventilated and exposed to a 60 tidal volume of DFPP smoke in vivo were recovered at 1 h post-smoke. Smoke exposure induced significant increases in both mRNA and protein levels for PAM tumor necrosis factor-alpha (TNF-alpha), when compared to smoke control. Smoke also induced a biphasic response (inhibited at 2 h, enhanced at 24 h after cell isolation) in the production of superoxide (O2-) by PAM. However, aerosolized lazaroid, U75412E (1.6 mg/kg body weight), significantly attenuated smoke-induced expression in AM TNF-alpha at the protein level but not at the mRNA level, and smoke-induced changes in AM production of O2-. This study suggests that highly expressing AM TNF-alpha following smoke may be a key contributor to the cascade that establishes an acute injury process and exacerbates oxidant-derived cell injury. Whereas, the lazaroid may ameliorate smoke-induced lung injury by attenuating AM TNF-alpha release, in addition to its primary antioxidative mechanism.

Aerosols↗
PubMed1999

Quantitative phase contrast images to quantitate flow in a rat model of microgravity.

A magnetic resonance angiographic (MRA) technique for noninvasive measurement of flow in the inferior vena cava (IVC) was used to study blood flow changes in a simulated microgravity model. Microgravity was simulated in adult male Fischer 344 rats (n = 12, with each rat acting as its own control) using a tail harness to elevate the hindquarters, producing a non-weight bearing hindlimb (NWH) model. Quantitative phase contrast images of flow within the IVC were obtained initially and after a 2-week NWH protocol. Inferior vena cava blood flow was determined by converting the intensity at the respective magnetic resonance pixels into a corresponding flow by Doppler techniques. Average values for flow determined with MR angiography were 351.8 (SEM = 49) mm3 x s(-1) initially and 524.5 (SEM = 46) mm3 x s(-1) after exposure to 2 weeks of the NWH protocol. Post 2-week NWH flow increased 49.1% over the initial NWH value. Using a paired t-test, a significant difference was found between the rats' IVC flow values in the initial and post-NWH groups (p < 0.004). The changes in IVC blood flow due to 45 degrees NWH may contribute to the overall changes observed in the cardiovascular system during simulated microgravity.

Animals↗
PubMed1999

Response to 45 degrees head-down tilt as measured by organ weight/body weight ratios and spiral computed tomography.

BACKGROUND: Exposure to microgravity or simulated microgravity causes significant shifts in body fluids which may initiate physiological adaptations to the microgravity stressor. It is imperative to understand the physiological adaptations to microgravity in order to develop appropriate countermeasures to the deleterious aspects (i.e., muscle and bone wasting) of long-term spaceflights. HYPOTHESIS: The significant shifts in body fluids by 45 degrees head-down tilt can be measured by changes in organ weight/body weight (OW/BW) ratios and non-invasively by spiral computed tomography. METHODS: In a previous study (14), rats were weighed and exposed to either 45 degrees head-down tilt (45HDT) or a prone control position for one of the following experimental times: 0.5 h, 1 h, 2 h, 4 h, 8 h, or 24 h. A radioactive tracer was injected intramuscularly immediately prior to the start of the experimental time periods. At the end of the experiment, the major organs were harvested, weighed, and measured for gamma radiation levels. We used the organ weights from this previous study to calculate OW/BW ratios for the present study. Additionally, in the present study, rats in the 14-d experimental groups were weighed, lightly anesthetized to facilitate placement in the 45HDT position, and placed in a specially designed 45HDT cage (45HDT group) or left unrestrained in the cages (control group). At the end of the 14-d experimental time period, the rats were anesthetized and their lung densities measured with spiral computed tomography. RESULTS: The OW/BW ratios for the liver, kidneys, and spleen of 24 h 45HDT rats were significantly lower (p<0.05) than control values while at 1 h the 45HDT rats had a higher kidney OW/BW ratio. Lung density from the 14-d 45HDT rats was 24.4% greater than control rats' values. CONCLUSIONS: The physiological change due to the 45HDT position to simulate microgravity begins as early as 1 h, and the kidney appears to be the first organ affected. Spiral computed tomography may offer a viable method of non-invasively measuring organ densities in the 45HDT model. The OW/BW data generated in the present study does not correlate with the changes in radioactive tracer distribution data from our previous study.

Adaptation, Physiological↗
PubMed1997

A free radical scavenger (Lazaroid U75412E) attenuates tumor necrosis factor-alpha generation in a rabbit model of smoke-induced lung injury.

The lazaroid (21-aminosteroid) analogue U75412E was evaluated in rabbits exposed to diesel fuel-polycarbonate plastic smoke. Inhalation of total of 4.6 mg U75412E aerosolized at a rate of 1.53 mg/min for 3 min before or after smoke significantly prevented or limited the extent of alveolar hypoventilation, interstitial edema, and tumor necrosis factor-alpha (TNF-alpha) by pulmonary alveolar macrophages (PAM) ex vivo observed at 2 h. The smoke-induced changes in wet lung/body weight ratios and the production of superoxide (O2-) by PAM ex vivo were also attenuated by the drug treatment after smoke exposure (p < 0.05). This study suggests that lazaroids may ameliorate the oxygen-radical-initiated cytokine processes and inflammation cascade as a result of the smoke insult.

Analysis of Variance↗
PubMed1997

Fractal analysis of lung alveoli during the acute phase vs. repair phase of an adenoviral infection in canines.

Acute viral respiratory infections are commonly associated with alterations in lung growth. Recently, fractal techniques have been demonstrated to show changes in alveolar perimeter after canine adenovirus type 2 (CAV2) infection in a beagle puppy model. In the present study, we investigated whether the fractal dimension (Df) of the alveolar perimeter was changed in the acute phase (2-3 weeks after inoculation, 131d CAV2 group) or during the recovery phase (approximately 22 weeks after inoculation, 235d CAV2 group) after a single bout of CAV2. There were sham CAV2 groups, 130d and 238d controls, corresponding to the CAV2 groups. The Df of alveolar perimeter length was significantly increased in the 235d CAV2 puppies compared to all of the other beagle puppy groups. On the other hand, the fractal dimensions for alveolar perimeter length for the other beagle puppy groups were very similar. In a related human study of patients (age range of 25 h to 19 y, N = 11), who died of non-respiratory causes, showed no consistent change in Df of alveolar perimeter length with normal lung growth and development. We conclude that fractal analysis of alveolar perimeter length can be used as an index of permanent lung injury after insult to the growing lungs.

Acute Disease↗
PubMed1997

Changes in radioactive tracer distribution in rats after 24 hours of 45 degrees hind limb unweighting.

INTRODUCTION: Changes in radioactive tracer distribution were examined in rats after exposure to a simulated microgravity model of 45 degrees head down tilt (45HDT) or 45 degrees hind limb unweighting (45HU) for up to 24 h. METHODS: Rats were randomly assigned to either 45HDT (or 45HU) experimental groups or control groups for each time point of 0.5 h, 1 h, 2 h, 4 h, 8 h, or 24 h. The 0.5-h through 8-h experimental rats were anesthetized and placed head-down on a ramp at 45 degrees, while control rats were placed in a prone position. Non-anesthetized rats in the 24-h experimental group were tail-suspended at 45 degrees, while control rats were allowed unrestrained movement. Technetium-labeled diethylenetriamine pentaacetate (99mTcDTPA, physical half-life of 6.02 h, MW = 492 amu) and indium-labeled diethylenetriamine pentaacetate (111In DTPA, physical half-life of 3.5 d, MW = 545 amu) were used to measure body organ distributions of the radioactive tracers at the 0.5-h-8-h and 24-h time points, respectively. Major organs were harvested after each time period and measured for radioactive counts. Light and electron micrographs were examined. RESULTS: Mean 111InDTPA counts for the lungs, kidneys, and brains of the 24 h 45HU groups were significantly higher than control counts. Light and electron microscopy demonstrated the development of pulmonary edema in the alveolar septal areas after 2 h of 45HDT, and a shift in edema to the pulmonary airways and pulmonary arteries after 24 h of 45HU. CONCLUSIONS: Pulmonary edema development, accompanied by a significant increase in 111InDTPA lung, kidney, and brain counts in the 24-h 45HU groups, suggests vascular injury in the microcirculation of these organs.

Animals↗
PubMed1997

Human alveolar fractal dimension in normal and chronic obstructive pulmonary disease subjects.

We have determined that fractal analysis of the alveolar perimeter (Df) changes with aging in human lung tissue in twenty-nine patients, age range of 25 hours to 76 years, who died of non-respiratory related causes. There was a very significant difference (p = 0.0004) in Df between the young (less than 16 years old, N = 9, mean Df of 1.047 [0.01]) and adult (greater than 16 years old, N = 20, mean Df of 1.093 [0.013]) groups. Furthermore, there was a significant difference in Df between the Adult group and the group of patients who died of chronic obstructive pulmonary disease (COPD, N = 10) (p = 0.012). Additionally, the Df values for the COPD and cystic fibrosis (CF, N = 5) groups were virtually identical; 1.061 and 1.070, respectively. Regression analysis showed a significant (p = 0.0041) exponential relationship with a correlation coefficient of 0.59 between aging and Df. We have demonstrated that the correlation between Df and aging in humans is an exponential function and that the end-stage pulmonary diseases of COPD and CF decrease Df.

Adolescent↗
PubMed1996

The prophylactic effects of U75412E pretreatment in a smoke-induced lung injury rabbit model.

The effects of the lazaroid analogue U75412E (21-[4-(3-ethylamino-2-pyridinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9]-(11)-triene-3,20-dione) were examined in an acute lung injury rabbit model. Standard doses of 0, 8 and 16 mM U75412E were aerosolized and ventilated into the lungs for 3 min. via an endotracheal tube. A 60 tidal volume dose of diesel fuel-polycarbonate plastic smoke was then instilled, followed by mechanical ventilation for one hour. Pretreatment with 16 mM U75412E significantly increased blood PaO2 and pH values, and decreased blood PaCO2 as compared to smoke only exposures. It also significantly decreased the total cell counts and granulocytes in bronchoalveolar lavage fluid, and the ability of pulmonary alveolar macrophages to produce tumour necrosis factor-alpha in vitro after cell isolation and culture. Histopathology indicated that 16 mM U75412E pretreatment attenuated increases in wet lung/body weight ratios, inflammatory focus, and interstitial oedema associated with smoke insult. In summary, U75412E pretreatment may possess the potential to improve acute smoke-induced lung injury, in part, through modulation of tumour necrosis factor-alpha production from pulmonary alveolar macrophages.

Animals↗