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Biomedical subjects

G E Hatch

Publications and source records attributed to G E Hatch.

At least 37 records · Page 2Linked to original sources
PubMed1995

Ozone-induced tissue injury and changes in antioxidant homeostasis in normal and ascorbate-deficient guinea pigs.

It has been reported previously that ozone (O3) toxicity from acute (4 hr) exposure is enhanced by ascorbate (AH2) deficiency in guinea pigs. We hypothesized that lung injury from continuous 1-week O3 exposure would also be increased under conditions of AH2 deficiency because of (1) a diminished antioxidant pool to counteract the oxidant challenge, (2) impaired reparation of tissue injury, and/or (3) altered antioxidant redox homeostasis. Female Hartley guinea pigs (260-330 g) were made AH2 deficient by providing a diet similar to guinea pig chow, but having no AH2. The dietary regimen was started 1 week prior to exposure and was continued during exposure to O3 (0, 0.2, 0.4, or 0.8 ppm, 23 hr/day, 7 days) as well as 1 week post-exposure. Bronchoalveolar lavage (BAL) and tissue AH2 were measured in subgroups at the beginning of exposure (1 week on the AH2-deficient diet), at its termination and 1 week post-exposure. AH2 measured in ear tissue punches proved to be an easy and effective monitor for AH2 deficiency. One week on the AH2-deficient diet caused a 70-80% drop in ear, lung and liver AH2, while AH2 in BAL was decreased by 90%. Immediately after the exposure, total BAL protein and albumin (markers of lung permeability) were increased (approximately 50%) at 0.8 ppm with no difference between the dietary groups. O3 caused an increase in total BAL cells and neutrophils in a concentration-dependent manner with only a slight augmentation due to diet. Exposure to O3 caused an increase in lung and BAL AH2 in normal guinea pigs. Glutathione and uric acid were also increased in the lung and BAL after O3 exposure (40-570%) in both dietary groups, and the levels remained elevated during the recovery period. Lung alpha-tocopherol was not changed due to O3. A significant overall diet-related decrease was seen in AH2-deficient guinea pigs, immediately after the exposure and recovery. In summary, lung injury/inflammation following 1 week O3 exposure and recovery were minimally affected by AH2 deficiency. Antioxidants also appeared to increase in response to O3 exposure despite the deficiency in AH2.

Animals↗
PubMed1995

Ozone-induced pulmonary functional, pathological, and biochemical changes in normal and vitamin C-deficient guinea pigs.

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 an 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 AH2 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.

Animals↗
PubMed1995

Asthma, inhaled oxidants, and dietary antioxidants.

The possible influence of dietary antioxidants, especially vitamin C, on the increasing prevalence of asthma is explored. Vitamin C intake in the general population appears to correlate with asthma, suggesting that a diet low in vitamin C is a risk factor for asthma. Epidemiological studies show associations among oxidant exposure, respiratory infections, and asthma in children of smokers. Symptoms of ongoing asthma in adults appear to be increased by exposure to environmental oxidants and decreased by vitamin C supplementation. There is evidence that oxidants produced endogenously by overactive inflammatory cells contribute to ongoing asthma. Vitamin C is the major antioxidant substance present in the airway surface liquid of the lung, where it could be important in protecting against both endogenous and exogenous oxidants. Nitrogen oxides are exemplary of oxidants that could arise from both endogenous and environmental sources, which are protected against by vitamin C, and that may be important in causation and propagation of asthma.

Administration, Oral↗
PubMed1994

Lung injury after silica instillation is associated with an accumulation of iron in rats.

It has been postulated that the incomplete complexation of host iron by the surface of mineral oxides is essential in in vivo lung injury after exposure to these dusts. We investigated the associations between in vivo iron accumulation after intratracheal instillation of silica dust in rats and 1) concentrations of antioxidants and oxidized products in the lung and 2) an index of chronic fibrotic injury. Fifty milligrams of minusil were intratracheally instilled into 60-day-old, male Sprague-Dawley rats. Ionizable Fe3+ complexed to the surface of silica increased from 12.7 +/- 1.4 mumol/g to values as high as 42.5 +/- 9.1 mumol/g dust after instillation. Corresponding to this elevation of surface-adsorbed metal, concentrations of iron in bronchoalveolar lavage fluid, lung tissue, plasma, and liver tissue all increased. Antioxidant molecules in lung tissue, including ascorbate, urate, and glutathione, all decreased, whereas superoxide dismutase increased. Oxidized products in the lung tissue, measured as thiobarbituric acid-reactive products, similarly increased, reflecting an oxidant stress. Dietary depletion of iron stores before instillation of silica dust resulted in low iron stores (hematocrit values of 21.8 +/- 1.9) and low iron concentrations in lavage fluid, lung tissue, and liver tissue. Rats on iron-depleted diets demonstrated a diminished fibrotic injury after dust instillation. Complexation of iron by the dust surface may be central in collagen deposition after silica exposure.

Animals↗
PubMed1994

Ozone dose and effect in humans and rats. A comparison using oxygen-18 labeling and bronchoalveolar lavage.

In an effort to improve risk assessments for ozone (O3) we compared the incorporation of inhaled oxygen-18-labeled O3 (18O3) into the lungs of humans and laboratory rats. Cells and fluids obtainable through bronchoalveolar lavage (BAL) were examined after exposure to 18O3 to determine whether excess 18O concentrations (presumed to be reaction products of 18O3) could be detected and equated to the O3 dose to the lung. Three O3 effect measurements (increased BAL protein and neutrophils and decreased BAL macrophages) were also made in subjects or animals exposed in parallel to determine whether there was a correspondence between dose and effect measurements. Eight human male volunteers 18 to 35 yr of age were exposed to 18O3 (0.4 ppm for 2 h) with 15-min alternating periods of heavy treadmill exercise and rest. Rats (F344) were exposed identically, except without exercise. 18O3 was generated directly from pure 18O2. BAL cells and centrifugally separable surfactant material were freeze-dried and analyzed by mass spectrometer for excess 18O. Results showed that the exercising humans had four- to fivefold higher 18O concentrations in all of their BAL constituents than did the rats. The humans also had significant increases in all of the effects markers after 0.4 ppm O3, whereas the rats did not. Rats that were exposed to higher concentrations of 18O3 (2.0 ppm) had levels of 18O in BAL that were more comparable to but still lower than those of exercising humans. Changes in all of the effects markers in these rats were comparable or higher than in exercising humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Risk assessment of oxidant gases and particulate air pollutants: uncertainties and research needs.

The assessment of risks to human health associated with exposure to oxidant air pollutants has not received adequate attention despite the recognized public health threat posed by the ubiquitous presence of these compounds in the environment. In this article, research needs and uncertainties at each of the steps in the risk assessment of oxidant air pollutants are identified: hazard identification, dose-response assessment, exposure assessment, and risk characterization. Many of these limitations and uncertainties arise at the interface between the laboratory and the regulatory arenas. Therefore, as a case study, relevant methodologic problems associated with the application of experimental findings to the risk assessment of respirable dusts are also discussed. These issues include the extrapolation of animal data to the human case and extrapolation from high-dose to environmentally relevant, low-level exposures.

Air Pollutants↗
PubMed1993

Lavage phospholipid concentration after silica instillation in the rat is associated with complexed [Fe3+] on the dust surface.

The basis for surfactant accumulation after silica exposure is not known. As a result of an association between elevations in extracellular surfactant and oxidant exposures, we tested the hypothesis that (1) surfactant-enriched material can function as an in vitro target for oxidants catalyzed by Fe3+ complexed to the surface of silica, and (2) in vivo alveolar accumulation of surfactant after exposure of the lower respiratory tract to silica is associated with the concentration of Fe3+ complexed to the dust surface. Surfactant-enriched material was incubated in both chemical and cellular systems with either Gey's balanced salt solution, acid-washed silica, deferoxamine-treated silica, wetted silica, or iron-loaded silica. The absorbance of oxidized products was associated with concentrations of complexed iron on the surface of the silica dust. Rats (n = 10/group) were intratracheally instilled with either normal saline, 6.0 mg acid-washed silica, 6.0 mg deferoxamine-treated silica, 6.0 mg wetted silica, or 6.0 mg iron-loaded silica. Ninety-six hours after tracheal instillation, silica significantly increased extracellular surfactant as reflected by lipid phosphorous in the total lavage fluid. Lipid accumulation was associated with concentrations of surface complexed iron on the surface of the silica.

Animals↗
PubMed1992

Application of the EPR spin-trapping technique to the detection of radicals produced in vivo during inhalation exposure of rats to ozone.

Ozone is known to induce lipid peroxidation of lung tissue, although no direct evidence of free radical formation has been reported. We have used the electron paramagnetic resonance (EPR) spin-trapping technique to search for free radicals produced in vivo by ozone exposure. The spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN) was administered ip to male Sprague-Dawley rats. The rats were then exposed for 2 hr to either 0, 0.5, 1.0, 1.5, or 2.0 ppm ozone with 8% CO2 to increase their respiratory rate. A six-line 4-POBN/radical spin adduct signal (aN = 15.02 G and a beta H = 3.27 G) was detected by EPR spectroscopy in lipid extracts from lungs of rats treated with 4-POBN and then exposed to ozone. Only a weak signal was observed in the corresponding solution from rats exposed to 0 ppm ozone (air with CO2 only). The concentration of the radical adduct increased as a function of ozone concentration. After administration of 4-POBN, rats were exposed for either 0.5, 1.0, 2.0, or 4.0 hr to either 0 or 2.0 ppm ozone (with CO2). The radical adduct concentration of the ozone-exposed groups at exposure times of 2.0 and 4.0 hr was significantly different from that of the corresponding air control groups. A correlation was observed between the radical adduct concentration and the lung weight/body weight ratio. These results demonstrate that ozone induces the production of free radicals in rat lungs during inhalation exposure and that radical production may be involved in the induction of pulmonary toxicity by ozone. This is the first direct evidence for ozone-induced free radical production in vivo.

Administration, Inhalation↗
PubMed1992

Role of surface complexed iron in oxidant generation and lung inflammation induced by silicates.

Inhalation of silicates induces a variety of lung diseases in humans. The molecular mechanism(s) by which these dusts cause disease is not known. Because several naturally occurring mineral oxides have large amounts of transition metal ions on their surfaces, we tested the hypothesis that surface complexation of iron may be an important determinant of their ability to induce disease. Silica, crocidolite, kaolinite, and talc complexed considerable concentrations of Fe3+ onto their surfaces from both in vitro and in vivo sources. The potential biological importance of iron complexation was assessed by examining the relationship between surface [Fe3+] and the ability of silicates to mediate oxidative degradation of deoxyribose in vitro, induce a respiratory burst and elicit leukotriene B4 (LTB4) release by alveolar macrophages (AM) in vitro, and cause acute alveolitis after intratracheal insufflation. For these studies, three varieties of silicate dusts were used: iron-loaded, wetted (unmodified), and deferoxamine-treated to remove Fe3+. The ability of silicates to catalyze oxidant generation in an ascorbate/H2O2 system in vitro, to trigger respiratory burst activity and LTB4 release by AM, and to induce acute lung inflammation in the rat all increased with surface complexed Fe3+. The results of these studies suggest that surface complexation of iron may be an important determinant in the pathogenesis of disease after silicate exposure.

Adsorption↗
PubMed1991

Reduction of neutrophil influx diminishes lung injury and mortality following phosgene inhalation.

Phosgene inhalation causes a severe noncardiogenic pulmonary edema characterized by an influx of neutrophils into the lung. To study the role of neutrophils in lung injury and mortality after phosgene, we investigated the effects of leukocyte depletion with cyclophosphamide, inhibiting the generation of the chemotaxin leukotriene B4 with the 5-lipoxygenase inhibitor AA861 and impairing neutrophil migration with the microtubular poison colchicine. Cyclophosphamide, AA861, and colchicine injected before exposure significantly reduced percent neutrophils, protein, and thiobarbituric acid-reactive products in bronchoalveolar lavage fluid of rats exposed to phosgene (0.5 ppm X 60 min). Cyclophosphamide, AA861, and colchicine also significantly decreased mortality from phosgene (2.0 ppm X 90 min) in mice. Colchicine significantly reduced neutrophil influx, lung injury, and mortality even when given 30 min after phosgene exposure. We conclude that lung injury and mortality after phosgene exposure are associated with an influx of neutrophils into the lung. Prevention of neutrophil migration with colchicine may hold therapeutic potential in phosgene poisoning.

Administration, Inhalation↗
PubMed1990

Pulmonary effects due to subchronic exposure to oil fog.

Male and in some cases female rats were exposed to an oil fog generated by flash vaporization and subsequent condensation of light-weight lubricating oil. Exposures were for 3.5 h/d, 4d/wk for 13 wk. Males were exposed at concentrations of 1.5, 0.5, 0.2 or 0.0 mg/l (1500, 500, 200, and 0 mg/m3) and a particle size of approximately 1 micron (mass median aerodynamic diameter). A number of biologic endpoints were assessed the day after the last exposure and, in some cases, after a 4 wk recovery period. Effects of 1.5 mg/l on male and female rats were compared. Diffuse accumulation of macrophages in the alveoli was observed in all oil fog exposed groups. The degree of severity was concentration dependent. Histopathologic changes were more prominent in males than in females and represented the most notable gender-related differences. Histologic effects observed one day and 4 wk post exposure were similar. Minimal histopathologic changes and minimal increase in lavage fluid protein were the only effects observed at the 0.2 mg/l exposure level. There was a significant increase in lavage fluid protein, percent lavagable polymorphonuclear leukocytes and lung wet and dry weight following exposure to both 0.5 and 1.5 mg/l. At the highest exposure concentration effects on lung weights were still evident 4 wk post exposure. Pulmonary function endpoints including total lung capacity, vital capacity, residual volume, diffusing capacity to CO, compliance, and end expiratory volume (EEV) were unaffected by oil fog exposure with the exception of EEV in males exposed at the 1.5 mg/l level. All of the changes observed following oil fog exposure were consistent with a mild inflammatory edema.

Aerosols↗
PubMed1989

Incorporation and disappearance of oxygen-18 in lung from mice exposed to 1 ppm 18O3.

In this study, 18O3 was used as a tracer for inhaled ozone in mice. The amount of ozone-derived oxygen (ODO) in the lungs was determined by measuring the amount of oxygen-18 in excess of the natural abundance level which remained covalently bound to organic constituents of lung following exposure to 1 ppm 18O3 for less than or equal to 60 min. The rate of disappearance of ODO from the lungs was determined by quantifying the rate of decrease of oxygen-18 in excess of the natural abundance level in lung from mice exposed to 1 ppm 18O3 for 45 min. With exposure to 1 ppm 18O3. ODO accumulated in lung at a rate of 4.38 pmol/mg dry weight/min. Ozone-derived oxygen had a half-life in lung of approximately 6 hr. We estimate that a minimum of 44 pmol of O3 reacted with lung every minute of exposure to 1 ppm O3.

Animals↗
PubMed1989

A method for comparison of animal and human alveolar dose and toxic effect of inhaled ozone.

Present models for predicting the pulmonary toxicity of O3 in humans from the toxic effects observed in animals rely on dosimetric measurements of O3 mass balance and species comparisons of mechanisms that protect tissue against O3. The goal of the study described was to identify a method to directly compare O3 dose and effect in animals and humans using bronchoalveolar lavage fluid markers. The feasibility of estimating O3 dose to alveoli of animals and humans was demonstrated through assay of reaction products of 18O-labeled O3 in lung surfactant and macrophage pellets of rabbits. The feasibility of using lung lavage fluid protein measurements to quantify the O3 toxic response in humans was demonstrated by the finding of significantly increased lung lavage protein in 10 subjects exposed to 0.4 ppm O3 for 2 h with intermittent periods of heavy exercise. The validity of using the lavage protein marker to quantify the response in animals has already been established. The positive results obtained in both the 18O3 and the lavage protein studies reported here suggest that it should be possible to obtain a direct comparison of both alveolar dose and toxic effect of O3 to alveoli of animals or humans.

Administration, Inhalation↗
PubMed1989

Unattenuated structural and biochemical alterations in the rat lung during functional adaptation to ozone.

Acute ozone (O3) exposure in humans produces changes in pulmonary function that attenuate with repeated exposure. This phenomenon, termed adaptation, has been produced in unanesthetized rats. Rats exposed to O3 (0, 0.35, 0.5, or 1.0 ppm) for 2.25 h for 5 consecutive days showed an increased frequency of breathing and a decreased tidal volume on Days 1 and 2 of exposure at all O3 concentrations. However, by Day 5 these breathing responses to O3 were diminished in rats exposed to 0.35 and 0.5 ppm, but not in rats exposed to 1.0 ppm. In addition, a flow limitation in smaller airways was observed after the second day of exposure to 0.5 ppm O3 that initially attenuated and then disappeared by the fifth day of exposure. In contrast to these findings, a light microscopic examination of fixed lung tissue sections from rats exposed to 0.5 ppm indicated a 5-day progressive pattern of epithelial damage and inflammation in the terminal bronchiolar region. A sustained 37% increase in lavageable protein was also observed over the course of the 5-day exposure regimen to 0.5 ppm. Lung glutathione increased initially, but it was within the control range on Days 4 and 5. Lung ascorbate was significantly elevated above control levels on Days 3 and 5. These data suggest that attenuation of the pulmonary function response to O3 occurs in laboratory rats with repeated exposure while biochemical and morphologic aspects of the tissue response continue to progress.

Adaptation, Physiological↗
PubMed1988

Detection of CCl4-induced oxidation of hepatic tissue in vivo by oxygen-18 tracing.

Oxidation of rat hepatic tissue was measured as incorporation of oxygen-18 (18O) from 18O2 following exposure to carbon tetrachloride (CCl4). Anesthetized rats were injected with CCl4 and allowed to breathe 18O2 for 1 hr, and then livers were homogenized, fractionated, and dried. The dried fractions were pyrolyzed to CO by an oxygen elemental analyzer, the CO was oxidized to CO2, and isotope ratio mass spectrometry was used to determine the abundance of 18O in the CO2. Rats that breathed 18O2 (21% in N2) for 1 hr had significant incorporation of 18O into lipids, solutes, and macromolecules of the liver. Injection with CCl4 increased incorporation of 18O into all liver fractions, although this increase was significant only in the lipid fraction. Rats pretreated with phenobarbital and then given CCl4 had significantly increased 18O in all liver fractions although it was greatest in the lipid fraction. About 5 mumol of 18O per gram of dry liver was incorporated in phenobarbital/CCl4-treated rats, of which 60% was in the water-soluble fraction, 17% in the lipids, and 16% in the macromolecules. Piperonyl butoxide administration abolished the CCl4-induced 18O incorporation. Thus, 18O incorporation appeared to provide a measure of oxidation in all tissue fractions following in vivo CCl4-induced liver injury.

Animals↗
PubMed1987

Changes in lung ATP concentration in the rat after low-level phosgene exposure.

Inhibition of mitochondrial respiratory activity and decreased lung adenosine triphosphate (ATP) concentration occur following exposure to 240 ppm.min phosgene. To determine the relationship between energy stores and the onset of phosgene-induced pulmonary edema, we measured the ATP concentration in rapidly frozen rat lung tissue before and during pulmonary edema. Male Sprague-Dawley rats were exposed to phosgene for four hours at concentrations of 0.05 to 1.0 ppm (12, 30, 60, 120, and 240 ppm.min). Lung wet and dry weight and ATP concentration were measured immediately after exposure and for three days postexposure. The accumulation of lavage fluid protein (LFP) was also measured as an index of damage or edema due to phosgene. Lung dry weight was significantly elevated one day postexposure to 0.5 ppm phosgene, while the LFP was elevated by 0.2 ppm phosgene. Time course studies at these doses of phosgene showed that decreased ATP levels preceded the onset of edema or increase in lung weight. The ATP values expressed on a per-lung basis showed that ATP levels were significantly lowered immediately following phosgene exposure, suggesting that the ATP changes were not the result of edema. This study is the first demonstration of a biochemical change that occurs following exposure to phosgene at a level significantly below the threshold limit value for this gas.

Adenosine Triphosphate↗
PubMed1987

Pulmonary alterations in rats due to acute phosgene inhalation.

This study evaluated the relationship between low-level phosgene (COCl2) exposure and pulmonary change or damage. Male Sprague-Dawley rats were exposed to phosgene for 4 hr at concentrations of 0.125 to 1.0 ppm (30, 60, 120, and 240 ppm X min). We examined the dose-related changes in body weight, lung wet and dry weights, lavage fluid protein concentrations (LFP), total cell count, and cell differential in rats exposed to phosgene under carefully controlled conditions. These parameters were measured at the conclusion of single acute exposures and for 3 days postexposure. Significant changes in lung weights (wet and dry) were observed following exposure to 120 and 240 ppm X min phosgene and the LFP was significantly altered at 60 ppm X min. The changes in lung wet and dry weights pooled over all times and phosgene concentrations each correlated significantly with the change in LFP induced by phosgene. The total number of cells in the lavage fluid of phosgene-exposed rats was increased, and the most sensitive cellular indicator of phosgene inhalation was the increase in the percentage of polymorphonuclear leukocytes (PMNs). These results confirm that LFP concentration and cellular differentials can be used as an index of lung damage due to phosgene. A dose-response relationship for the measured parameters was observed. Over the dosage range studied, the return of all measured parameters to near control levels within 3 days following exposure showed that the pulmonary damage was reversible or rapidly reparable. Although the acute effects were shown to be reversible, studies on chronic, low-level phosgene exposures are necessary to determine safe levels for industrial employees.

Administration, Inhalation↗