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1.
Inhal Toxicol ; 28(5): 203-15, 2016 Apr.
Article in English | MEDLINE | ID: mdl-27092583

ABSTRACT

Diet-induced obesity has been suggested to lead to increased susceptibility to air pollutants such as ozone (O3); however, there is little experimental evidence. Thirty day old male and female Brown Norway rats were fed a normal, high-fructose or high-fat diet for 12 weeks and then exposed to O3 (acute - air or 0.8 ppm O3 for 5 h, or subacute - air or 0.8 ppm O3 for 5 h/d 1 d/week for 4 weeks). Body composition was measured non-invasively using NMR. Ventilatory parameters and exploratory behavior were measured after the third week of subacute exposure. Bronchoalveolar lavage fluid (BALF) and blood chemistry data were collected 18 h after acute O3 and 18 h after the fourth week of subacute O3. The diets led to increased body fat in male but not female rats. O3-induced changes in ventilatory function were either unaffected or improved with the fructose and fat diets. O3-induced reduction in exploratory behavior was attenuated with fructose and fat diets in males and partially in females. O3 led to a significant decrease in body fat of males fed control diet but not the fructose or fat diet. O3 led to significant increases in BALF eosinophils, increase in albumin, and reductions in macrophages. Female rats appeared to be more affected than males to O3 regardless of diet. Overall, treatment with high-fructose and high-fat diets attenuated some O3 induced effects on pulmonary function, behavior, and metabolism. Exacerbation of toxicity was observed less frequently.


Subject(s)
Air Pollutants/toxicity , Diet, High-Fat , Fructose/pharmacology , Oxidants, Photochemical/toxicity , Ozone/toxicity , Albumins/metabolism , Animals , Blood Cell Count , Body Composition/drug effects , Body Weight/drug effects , Bronchoalveolar Lavage Fluid/cytology , Eating/drug effects , Eosinophils/cytology , Female , Lung/drug effects , Lung/physiology , Macrophages/cytology , Male , Motor Activity/drug effects , Pulmonary Ventilation/drug effects , Rats
2.
Inhal Toxicol ; 26(7): 380-90, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24779854

ABSTRACT

Setting exposure standards for environmental pollutants may consider the aged as a susceptible population but the few published studies assessing susceptibility of the aged to air pollutants are inconsistent. Episodic ozone (O3) is more reflective of potential exposures occurring in human populations and could be more harmful to the aged. This study used radiotelemetry to monitor heart rate (HR), core temperature (T(c)) and motor activity (MA) in adult (9-12 months) and senescent (20-24 months) male, Brown Norway rats exposed to episodic O3 (6 h/day of 1 ppm O3 for 2 consecutive days/week for 13 weeks). Acute O3 initially led to marked drops in HR and T(c). As exposures progressed each week, there was diminution in the hypothermic and bradycardic effects of O3. Senescent rats were less affected than adults. Acute responses were exacerbated on the second day of O3 exposure with adults exhibiting greater sensitivity. During recovery following 2 d of O3, adult and senescent rats exhibited an elevated T(c) and HR during the day but not at night, an effect that persisted for at least 48 h after O3 exposure. MA was elevated in adults but not senescent rats during recovery from O3. Overall, acute effects of O3, including reductions in HR and T(c), were attenuated in senescent rats. Autonomic responses during recovery, included an elevation in T(c) with a pattern akin to that of a fever and rise in HR that were independent of age. An attenuated inflammatory response to O3 in senescent rats may explain the relatively heightened physiological response to O3 in younger rats.


Subject(s)
Aging , Air Pollutants/toxicity , Bradycardia/chemically induced , Hypothermia/chemically induced , Inhalation Exposure/adverse effects , Neurotoxicity Syndromes/physiopathology , Ozone/toxicity , Animals , Behavior, Animal/drug effects , Body Temperature Regulation/drug effects , Heart Rate/drug effects , Male , Motor Activity/drug effects , Oxidants, Photochemical/toxicity , Rats, Inbred BN , Severity of Illness Index , Tachyphylaxis , Toxicity Tests, Acute , Toxicity Tests, Subchronic , Toxicokinetics
3.
Toxicol Appl Pharmacol ; 273(3): 551-60, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-24103449

ABSTRACT

Air pollutants have been associated with increased diabetes in humans. We hypothesized that ozone would impair glucose homeostasis by altering insulin signaling and/or endoplasmic reticular (ER) stress in young and aged rats. One, 4, 12, and 24 month old Brown Norway (BN) rats were exposed to air or ozone, 0.25 or 1.0 ppm, 6 h/day for 2 days (acute) or 2 d/week for 13 weeks (subchronic). Additionally, 4 month old rats were exposed to air or 1.0 ppm ozone, 6 h/day for 1 or 2 days (time-course). Glucose tolerance tests (GTT) were performed immediately after exposure. Serum and tissue biomarkers were analyzed 18 h after final ozone for acute and subchronic studies, and immediately after each day of exposure in the time-course study. Age-related glucose intolerance and increases in metabolic biomarkers were apparent at baseline. Acute ozone caused hyperglycemia and glucose intolerance in rats of all ages. Ozone-induced glucose intolerance was reduced in rats exposed for 13 weeks. Acute, but not subchronic ozone increased α2-macroglobulin, adiponectin and osteopontin. Time-course analysis indicated glucose intolerance at days 1 and 2 (2>1), and a recovery 18 h post ozone. Leptin increased day 1 and epinephrine at all times after ozone. Ozone tended to decrease phosphorylated insulin receptor substrate-1 in liver and adipose tissues. ER stress appeared to be the consequence of ozone induced acute metabolic impairment since transcriptional markers of ER stress increased only after 2 days of ozone. In conclusion, acute ozone exposure induces marked systemic metabolic impairments in BN rats of all ages, likely through sympathetic stimulation.


Subject(s)
Glucose Intolerance/pathology , Metabolic Diseases/pathology , Ozone/toxicity , Adiponectin/blood , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Age Factors , Animals , Biomarkers/metabolism , Diabetes Mellitus/chemically induced , Diabetes Mellitus/pathology , Endoplasmic Reticulum Stress/drug effects , Glucose Intolerance/chemically induced , Glucose Tolerance Test , Insulin/blood , Insulin Receptor Substrate Proteins/genetics , Insulin Receptor Substrate Proteins/metabolism , Insulin Resistance , Leptin/blood , Lipoproteins, HDL/blood , Lipoproteins, IDL/blood , Liver/drug effects , Liver/metabolism , Male , Metabolic Diseases/chemically induced , Osteopontin/blood , Phosphorylation , Rats , Rats, Inbred BN , Reverse Transcriptase Polymerase Chain Reaction , Risk Factors , Triglycerides/blood , alpha-Macroglobulins/metabolism
4.
Inhal Toxicol ; 25(3): 141-59, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23421486

ABSTRACT

Ozone (O3) is a pervasive air pollutant that produces pulmonary and cardiovascular dysfunction and possible neurological dysfunction. Young and old individuals are recognized as being susceptible to O3; however, remarkably little is known about susceptibility with senescence. This study explored the pulmonary, cardiovascular and neurological effects of O3 exposure in adult (4 m) and senescent (20 m) Brown Norway rats exposed to 0 or 0.8 ppm O3 for 6 h, 1 d/week, for 17 weeks. Ventilatory function was assessed 1 and 7 d after each exposure (Buxco). Heart rate, blood pressure (tail cuff) and motor activity were measured biweekly. Blood, aorta and bronchoalveolar lavage fluid (BALF) were analyzed 24 h after the last exposure for pulmonary inflammation, serum biomarkers and aorta mRNA markers of vascular disease. Measures of normal ventilatory function declined following each O3 exposure in both adult and senescent rats, however, senescent rats took weeks to exhibit a decline. Evidence for residual respiratory effects of O3 7 d after exposure in both age groups was observed. O3 had no effect on either heart rate or blood pressure, but decreased motor activity in both age groups. BALF indicated mild neutrophilic inflammation and protein leakage in adults. Age affected 17/58 serum analytes, O3 affected 6/58; 2/58 showed an age-O3 interaction. Leptin, adiponectin, lipocalin and insulin were increased in senescent rats. Overall, adult rats exhibited more immediate effects of episodic O3 than senescent rats. Residual effects were, however, obtained in both ages of rat, especially for ventilatory endpoints.


Subject(s)
Behavior, Animal/drug effects , Cardiovascular Diseases/chemically induced , Heart/drug effects , Lung/drug effects , Oxidants, Photochemical/toxicity , Ozone/toxicity , Adiponectin/metabolism , Age Factors , Aging , Animals , Biomarkers/metabolism , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/physiopathology , Disease Susceptibility , Heart/physiopathology , Hemodynamics/drug effects , Insulin/metabolism , Leptin/metabolism , Lipocalins/metabolism , Lung/metabolism , Lung/physiopathology , Male , Motor Activity/drug effects , Rats , Rats, Inbred BN , Respiratory Function Tests
5.
Inhal Toxicol ; 16(6-7): 391-405, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15204755

ABSTRACT

Epidemiological studies have reported statistically significant associations between the levels of ambient particulate matter (PM) and the incidence of morbidity and mortality, particularly among persons with cardiopulmonary disease. While similar effects have been demonstrated in animals, the mechanism(s) by which these effects are mediated are unresolved. To further investigate this phenomenon, the cardiovascular and thermoregulatory effects of an oil combustion-derived PM (HP-12) were examined in spontaneously hypertensive (SH) rats. The particle used in this study had considerably fewer water-soluble metals than the residual oil fly ash (ROFA) particles widely used in previous animal toxicity studies, with Zn and Ni constituting the primary water-leachable elements in HP-12. Rats were surgically implanted with radiotelemeters capable of continuously monitoring electrocardiogram (ECG), heart rate (HR), systemic arterial blood pressure (BP), and core temperature (T(co)). Animals were divided into four dose groups and were administered one of four doses of HP-12 suspended in saline vehicle (0.00, 0.83, 3.33, 8.33 mg/kg; control, low, mid, and high dose, respectively) via intratracheal instillation (IT). Telemetered rats were monitored continuously for up to 7 days post-IT, and were sacrificed 4 or 7 days post-IT. Exposures to mid- and high-dose HP-12 induced large decreases in HR (decreasing 30-120 bpm), BP (decreasing 20-30 mmHg), and T(co) (decreasing 1.2-2.6 degrees C). The decreases in HR and BP were most pronounced at night and did not return to pre-IT values until 72 and 48 h after dosing, respectively. ECG abnormalities (rhythm disturbances, bundle branch block) were observed primarily in the high-dose group. This study demonstrates substantial dose-related deficits in cardiac function in SH rats after IT exposure to a low-metal content, combustion-derived particle.


Subject(s)
Air Pollutants/toxicity , Cardiovascular System/drug effects , Industrial Oils , Animals , Blood Pressure/drug effects , Body Temperature/drug effects , Dose-Response Relationship, Drug , Electrocardiography , Incineration , Male , Particle Size , Rats , Rats, Inbred SHR , Time Factors , Trachea
6.
Inhal Toxicol ; 16(6-7): 407-19, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15204756

ABSTRACT

A consistent association between exposure to high concentrations of ambient particulate matter (PM) and excess cardiopulmonary-related morbidity and mortality has been observed in numerous epidemiological studies, across many different geographical locations. To elicit a similar response in a controlled laboratory setting, spontaneously hypertensive rats were exposed to an oil combustion-derived PM (HP-12) and monitored for changes in pulmonary function and indices of pulmonary injury. Rats were implanted with radiotelemeters to monitor electrocardiogram, heart rate, systemic arterial blood pressure, core temperature, and activity. Animals were divided into four groups and exposed via intratracheal instillation (IT) to suspensions of HP-12 (0.0, 0.83, 3.33, and 8.33 mg/kg; control, low, mid, and high dose, respectively) in saline vehicle. Telemetered rats were monitored continuously for 4-7 days post-IT and pulmonary function was examined using a whole-body plethysmograph system for 6 h/day on post-IT days 1-7. At 24, 96, and 192 h post-IT, bronchoalveolar lavage fluid (BALF) was obtained from subsets of nontelemetered animals in order to assess the impact of HP-12 on biochemical indices of pulmonary inflammation and injury. Immediate dose-related changes in pulmonary function were observed after HP-12 exposure, consisting of decreases in tidal volume (decreasing 12-41%) and increases in breathing frequency (increasing 52-103%), minute ventilation (increasing 12-25%), and enhanced pause (increasing 113-187%). These functional effects were resolved by 7 days post-IT, although some average BALF constituents remained elevated through day 7 for mid- and high-dose groups when compared to those of the saline-treated control group. This study demonstrates significant deficits in pulmonary function, along with significant increases in BALF indices of pulmonary inflammation and injury in SH rats after IT exposure to HP-12.


Subject(s)
Air Pollutants/toxicity , Industrial Oils , Lung/drug effects , Animals , Blood Pressure/drug effects , Body Temperature/drug effects , Bronchoalveolar Lavage Fluid/chemistry , Dose-Response Relationship, Drug , Electrocardiography , Heart Rate/drug effects , Incineration , Lung/physiology , Male , Motor Activity/drug effects , Plethysmography, Whole Body , Rats , Rats, Inbred SHR , Telemetry , Time Factors
7.
Environ Health Perspect ; 109 Suppl 3: 395-403, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11427389

ABSTRACT

Epidemiologic reports by C.A. Pope III et. al. demonstrated that in the Utah Valley, closure of an open-hearth steel mill over the winter of 1987 was associated with reductions in respiratory disease and related hospital admissions in valley residents. To better examine the relationship between plant-associated changes in ambient particulate matter (PM) and respiratory health effects, we obtained total suspended particulate filters originally collected near the steel mill during the winter of 1986 (before closure), 1987 (during closure), and 1988 (after plant reopening). PM subcomponents were water-extracted from these filters and Sprague-Dawley rats were intratracheally instilled with equivalent masses of extract. Data indicated that 24 hr later, rats exposed to 1986 or 1988 extracts developed significant pulmonary injury and neutrophilic inflammation. Additionally, 50% of rats exposed to 1986 or 1988 extracts had increased airway responsiveness to acetylcholine, compared to 17 and 25% of rats exposed to saline or the 1987 extract, respectively. By 96 hr, these effects were largely resolved except for increases in lung lavage fluid neutrophils and lymphocytes in 1986 extract-exposed rats. Analogous effects were observed with lung histologic assessment. Extract analysis using inductively coupled plasma-mass spectroscopy demonstrated in all three extracts nearly 70% of the mass appeared to be sodium-based salts derived from the glass filter matrix. Interestingly, relative to the 1987 extract, the 1986/1988 extracts contained more sulfate, cationic salts (i.e., calcium, potassium, magnesium), and certain metals (i.e., copper, zinc, iron, lead, strontium, arsenic, manganese, nickel). Although total metal content was (3/4) 1% of the extracts by mass, the greater quantity detected in the 1986 and 1988 extracts suggests metals may be important determinants of the pulmonary toxicity observed. In conclusion, the pulmonary effects induced by exposure of rats to water-based extracts of local ambient PM filters were in good accord with the cross-sectional epidemiologic reports of adverse respiratory health effects in Utah Valley residents.


Subject(s)
Air Pollution/adverse effects , Lung/pathology , Respiratory Tract Diseases/etiology , Animals , Epidemiologic Studies , Humans , Industry , Inflammation , Lung/immunology , Male , Particle Size , Public Health , Rats , Rats, Sprague-Dawley , Respiratory Tract Diseases/pathology , Steel
8.
Toxicol Sci ; 61(1): 144-53, 2001 May.
Article in English | MEDLINE | ID: mdl-11294985

ABSTRACT

Inhaled urban particulate matter (PM) often contains metals that appear to contribute to its toxicity. These particles first make contact with a thin layer of epithelial lining fluid in the respiratory tract. Antioxidants present in this fluid and in cells might be important susceptibility factors in PM toxicity. We investigated the role of ascorbic acid (C) and glutathione (GSH) as determinants of susceptibility to inhaled residual oil fly ash (ROFA) in guinea pigs (male, Hartley). Guinea pigs were divided into four groups, +C+GSH, +C-GSH, -C+GSH, and -C-GSH, and exposed to clean air or ROFA (< 2.5 micron diameter, 19--25 mg/m(3) nose-only for 2.0 h). C and/or GSH were lowered by either feeding C-depleted diet (1 microg C/kg diet, 2 weeks) and/or by ip injection of a mixture of buthionine-S,R-sulfoximine (2.7 mmol/kg body weight) and diethylmaleate (1.2 mmol/kg, 2 h prior). Nasal lavage (NL) and bronchoalveolar lavage (BAL) fluid and cells were examined at 0 h and 24 h postexposure to ROFA. The C-deficient diet lowered C concentrations in BAL fluid and cells and in NL fluid by 90%, and the GSH-depletion regimen lowered both GSH and C in the BAL fluid and cells by 50%. ROFA deposition was calculated at time 0 from lung Ni levels to be 46 microg/g wet lung. In unexposed animals, the combined deficiency of C and GSH modified the cellular composition of cells recovered in lavage fluid, i.e., the increased number of eosinophils and macrophages in BAL fluid. ROFA inhalation increased lung injury in the -C-GSH group only (evidenced by increased BAL protein, LDH and neutrophils, and decreased BAL macrophages). ROFA exposure decreased C in BAL and NL at 0 h, and increased BAL C and GSH (2- to 4-fold above normal) at 24 h in nondepleted guinea pigs, but had no effect on C and GSH in depleted guinea pigs. Combined deficiency of C and GSH resulted in the highest macrophage and eosinophil counts of any group. GSH depletion was associated with increased BAL protein and LDH, increased numbers of BAL macrophages and eosinophils, and decreased rectal body temperatures. We conclude that combined deficiency of C and GSH increased susceptibility to inhaled ROFA; caused unusual BAL cellular changes; resulted in lower antioxidant concentrations in BAL than were observed with single deficiencies. Antioxidant deficiency may explain increased susceptibility to PM in elderly or diseased populations and may have important implications for extrapolating animal toxicity data to humans.


Subject(s)
Air Pollutants/toxicity , Antioxidants/metabolism , Ascorbic Acid Deficiency/metabolism , Ascorbic Acid/metabolism , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Carbon/adverse effects , Carbon/pharmacokinetics , Glutathione/deficiency , L-Lactate Dehydrogenase/adverse effects , Lung Diseases/chemically induced , Lung/drug effects , Nasal Lavage Fluid/chemistry , Nasal Lavage Fluid/cytology , Administration, Inhalation , Animals , Ascorbic Acid/analysis , Body Temperature , Carbon/administration & dosage , Cell Count , Coal Ash , Disease Models, Animal , Eosinophils/cytology , Guinea Pigs , L-Lactate Dehydrogenase/analysis , Lung/metabolism , Lung/pathology , Lung Diseases/mortality , Lung Diseases/pathology , Macrophages, Alveolar/cytology , Male , Neutrophils/cytology , Particle Size , Particulate Matter , Survival Rate , Time Factors , Uric Acid/analysis , Uric Acid/metabolism
10.
Toxicol Appl Pharmacol ; 164(3): 250-63, 2000 May 01.
Article in English | MEDLINE | ID: mdl-10799335

ABSTRACT

Cardiovascular disease is considered a probable risk factor of particulate matter (PM)-related mortality and morbidity. It was hypothesized that rats with hereditary systemic hypertension and underlying cardiac disease would be more susceptible than healthy normotensive rats to pulmonary injury from inhaled residual oil fly ash (ROFA) PM. Eight spontaneously hypertensive (SH) and eight normotensive Wistar-Kyoto (WKY) rats (12-13 weeks old) were implanted with radiotelemetry transmitters on Day -10 for measurement of electrocardiographic (ECG) waveforms. These and other nonimplanted rats were exposed to filtered air or ROFA (containing leachable toxic levels of metals) on Day 0 by nose-only inhalation (ROFA, 15 mg/m(3) x 6 h/day x 3 days). ECGs were monitored during both exposure and nonexposure periods. At 0 or 18 h post-ROFA exposure, rats were assessed for airway hyperreactivity, pulmonary and cardiac histological lesions, bronchoalveolar lavage fluid (BALF) markers of lung injury, oxidative stress, and cytokine gene expression. Comparisons were made in two areas: (1) underlying cardiopulmonary complications of control SH rats in comparison to control WKY rats; and (2) ROFA-induced cardiopulmonary injury/inflammation and oxidative burden. With respect to the first area, control air-exposed SH rats had higher lung and left ventricular weights when compared to age-matched WKY rats. SH rats had hyporeactive airways to acetylcholine challenge. Lung histology revealed the presence of activated macrophages, neutrophils, and hemorrhage in control SHrats. Consistently, levels of BALF protein, macrophages, neutrophils, and red blood cells were also higher in SH rats. Thiobarbituric acid-reactive material in the BALF of air-exposed SH rats was significantly higher than that of WKY rats. Lung inflammation and lesions were mirrored in the higher basal levels of pulmonary cytokine mRNA expression. Cardiomyopathy and monocytic cell infiltration were apparent in the left ventricle of SH rats, along with increased cytokine expression. ECG demonstrated a depressed ST segment area in SH rats. With regard to the second area of comparison (ROFA-exposed rats), pulmonary histology indicated a slightly exacerbated pulmonary lesions including inflammatory response to ROFA in SH rats compared to WKY rats and ROFA-induced increases in BALF protein and albumin were significantly higher in SH rats than in WKY rats. In addition, ROFA caused an increase in BALF red blood cells in SH rats, indicating increased hemorrhage in the alveolar parenchyma. The number of alveolar macrophages increased more dramatically in SH rats following ROFA exposure, whereas neutrophils increased similarly in both strains. Despite greater pulmonary injury in SH rats, ROFA-induced increases in BALF GSH, ascorbate, and uric acid were attenuated when compared to WKY rats. ROFA inhalation exposure was associated with similar increases in pulmonary mRNA expression of IL-6, cellular fibronectin, and glucose-6-phosphate dehydrogenase (relative to that of beta-actin) in both rat strains. The expression of MIP-2 was increased in WKY but attenuated in SH rats. Thus, SH rats have underlying cardiac and pulmonary complications. When exposed to ROFA, SH rats exhibited exacerbated pulmonary injury, an attenuated antioxidant response, and acute depression in ST segment area of ECG, which is consistent with a greater susceptibility to adverse health effects of fugitive combustion PM. This study shows that the SH rat is a potentially useful model of genetically determined susceptibility with pulmonary and cardiovascular complications.


Subject(s)
Air Pollutants/toxicity , Carbon/toxicity , Disease Models, Animal , Heart Diseases/etiology , Lung Diseases/etiology , Oxidative Stress , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Coal Ash , Cytokines/genetics , Electrocardiography , Erythrocytes , Lung/pathology , Male , Myocardium/pathology , Organ Size , Particulate Matter , RNA, Messenger/analysis , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Respiratory Function Tests , Thiobarbituric Acid Reactive Substances/analysis
11.
J Toxicol Environ Health A ; 57(8): 543-63, 1999 Aug 27.
Article in English | MEDLINE | ID: mdl-10515573

ABSTRACT

A rat model of monocrotaline (MCT)-induced pulmonary injury/hypertension has been recently used in particulate matter (PM) health effects studies, however, results have been equivocal. Neither the mechanism by which mortality occurs in this model nor the variation in response due to differences in PM exposure protocols (i.e., a bolus dose delivered intratracheally versus a similar cumulative dose inhaled over three days) have been fully investigated. Sprague Dawley rats (SD, 60 d old; 250-300 g) were injected with either saline (healthy) or MCT, 60 mg/kg, i.p. (to induce pulmonary injury/hypertension). Ten days later they were exposed to residual oil fly ash (ROFA), either intratracheally (IT; saline, 0.83 or 3.33 mg/kg) or by nose-only inhalation (15 mg/m3 x 6 h/d x 3 d). Lung histology, pulmonary cytokine gene expression (0 and 18 h postinhalation), and bronchoalveolar lavage fluid (BALF) markers of injury were analyzed (24 and 96 h post-IT; or 18 h post-inhalation). Data comparisons examined three primary aspects, 1) ROFA IT versus inhalation effects in healthy rats; 2) pulmonary injury caused by MCT; and 3) exacerbation of ROFA effects in MCT rats. In the first aspect, pulmonary histological lesions following ROFA inhalation in healthy rats were characterized by edema, inflammatory cell infiltration, and thickening of alveolar walls. Increases in BALF markers of lung injury and inflammation were apparent in ROFA-IT or nose-only exposed healthy rats. Increased IL-6, and MIP-2 expression were also apparent in healthy rats following ROFA inhalation. In regards to the second aspect, MCT rats exposed to saline or air showed perivascular inflammatory cell infiltrates, increased presence of large macrophages, and alveolar thickening. Consistently, BALF protein, and inflammatory markers (macrophage and neutrophil counts) were elevated indicating pulmonary injury. In regards to the third aspect, 58% of MCT rats exposed to ROFA IT died within 96 h regardless of the dose. No mortality was observed using the inhalation protocol. ROFA inhalation in MCT rats caused exacerbation of lung lesions such as increased edema, alveolar wall thickening, and inflammatory cell infiltration. This exacerbation was also evident in terms of additive or more than additive increases in BALF neutrophils, macrophages and eosinophils. IL-6 but not MIP-2 expression was more than additive in MCT rats, and persisted over 18 h following ROFA. IL-10 and cellular fibronectin expression was only increased in MCT rats exposed to ROFA. In summary, only the bolus IT ROFA caused mortality in the rat model of lung injury/hypertension. Exacerbation of histological lesions and cytokine mRNA expression were most reflective of increased ROFA susceptibility in this model.


Subject(s)
Air Pollutants/toxicity , Carbon/toxicity , Hypertension, Pulmonary/chemically induced , Lung Diseases/chemically induced , Lung/drug effects , Monocrotaline/toxicity , Administration, Inhalation , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Carbon/administration & dosage , Coal Ash , Cytokines/genetics , Cytokines/metabolism , DNA, Complementary/analysis , Disease Models, Animal , Intubation, Intratracheal , Lung/metabolism , Lung/pathology , Lung Diseases/mortality , Lung Diseases/pathology , Male , Particulate Matter , RNA/metabolism , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate
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