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2.
Fundam Appl Toxicol ; 24(2): 183-97, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7737430

ABSTRACT

The potential pulmonary toxicity of poorly soluble airborne dusts generated in industrial and environmental settings is often evaluated by inhalation studies in rodents. Studies using intratracheal instillation of particles have been suggested as a less expensive alternative. We conducted a study to compare the inflammatory response of the lung to instilled versus inhaled particles. In one study, female F344/N rats, 11-13 weeks of age, were exposed for 6 hr/day, 5 days/week for 4 weeks by inhalation to 0, 0.1, 1.0, or 10 mg/m3 of either alpha-quartz (toxic particle) or TiO2 (relatively low toxicity particle) and the lung burdens were determined at 1 week after the end of the exposure. The lungs were evaluated by analysis of bronchoalveolar lavage fluid (BALF) at 1, 8, and 24 weeks after the end of the exposure and by histopathology at 24 weeks. In a second study, rats were exposed by instillation to the lung burdens present in the preceding study at 1 week after the inhalation exposure, and the rats were evaluated in the same manner as in the inhalation study. In general, the degree of alveolitis, as evaluated by histopathology and BALF analysis, was similar by the two methods of exposure. With lung burdens up to 750 micrograms/g lung, the TiO2 elicited no changes in BALF parameters at any time by either method of exposure, nor was any histopathology observed. The BALF changes elicited by alpha-quartz were of approximately the same magnitude and followed the same time course by either exposure method with the lowest dose delivered to the lung by either method being a "no-effect" dose. At the highest dose, microgranulomas were observed in bronchial-associated lymphoid tissue (BALT) in both sets of rats. However, the highest inhalation exposure induced pleural granulomatous lesions that were not observed in the animals instilled with alpha-quartz. The results indicate that the relative potentials of the two materials to produce bronchoalveolitis and granulomatous lesions in BALT could be appropriately evaluated using either intratracheal or inhalation exposures.


Subject(s)
Dust/adverse effects , Pneumonia/pathology , Administration, Inhalation , Aerosols , Animals , Body Burden , Bronchi/pathology , Bronchoalveolar Lavage Fluid/cytology , Female , Intubation, Intratracheal , Lung/pathology , Lymphoid Tissue/pathology , Organ Size/physiology , Pneumonia/chemically induced , Quartz/toxicity , Rats , Rats, Inbred F344 , Titanium/toxicity , Water Pollutants, Chemical/toxicity
3.
Toxicol Appl Pharmacol ; 111(2): 201-10, 1991 Nov.
Article in English | MEDLINE | ID: mdl-1659753

ABSTRACT

The pulmonary response to mineral dust inhalation was investigated by characterizing markers of lung injury and inflammation, macrophage activation, dust clearance, and histopathology. Rats were exposed (6 hr/day x 5 days) to air or 50 mg/m3 crystalline silica (SiO2) or titanium dioxide (TiO2). At 7, 14, 28, and 63 days after exposure, bronchoalveolar lavage fluid (BALF) was analyzed for lactate dehydrogenase (LDH), total protein, and N-acetylglucosaminidase, as well as cell number, type, and viability. Alveolar macrophages (AM) obtained in BALF were cultured with or without LPS and release of interleukin-1 (IL-1) and fibronectin was determined. Histopathology was conducted at 28 and 63 days. The exposure protocol resulted in 1.8-1.9 mg of mineral dust being deposited in the pulmonary region. Clearance of SiO2 was significantly less than TiO2. SiO2 increased BALF neutrophils (Days 14, 28, and 63), total protein (Days 28 and 63), and LDH and lymphocytes (Day 63). SiO2 increased AM-derived fibronectin release (Day 63) and LPS-induced IL-1 release (all time points), but not spontaneous release of IL-1. TiO2 did not change BALF biochemical or cellular parameters or AM secretory activity. Histopathology revealed minimal interstitial inflammation with SiO2 and no significant response in control or TiO2 rats. These results demonstrate the pulmonary response to inhaled SiO2 can be differentiated from the relatively innocuous TiO2 by changes in BALF markers of injury and inflammation further supporting the use of BALF analysis to make relative assessments of pulmonary toxicity. The stimulation of macrophage fibronectin release by the fibrogenic dust SiO2 and not TiO2 is consistent with a role for this glycoprotein in lung injury and repair. Last, the early and persistent effect of SiO2 on LPS-induced AM IL-1 release indicates this response may represent a sensitive early marker of dust-induced changes in the AM population.


Subject(s)
Dust/adverse effects , Lung/drug effects , Silicon Dioxide/adverse effects , Titanium/adverse effects , Administration, Inhalation , Animals , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/enzymology , Bronchoalveolar Lavage Fluid/metabolism , Drug Administration Routes , Lung/pathology , Lung/physiology , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/metabolism , Male , Minerals/adverse effects , Pulmonary Fibrosis/chemically induced , Rats , Rats, Inbred F344 , Silicon Dioxide/administration & dosage , Titanium/administration & dosage , Trachea
4.
Fundam Appl Toxicol ; 17(1): 128-35, 1991 Jul.
Article in English | MEDLINE | ID: mdl-1916071

ABSTRACT

Oral feeding studies of a crosslinked, high-molecular-weight polyacrylate polymer (PA) were conducted to (1) characterize the biological effects following exposure to either 0, 300, 1000, or 3000 mg PA/kg/day for 93 days; (2) characterize the fecal and urinary mineral excretion at these same dose levels; and (3) monitor the absorption, distribution, and excretion (ADE) of radiolabeled PA following a single oral exposure. The subchronic study results indicate that dietary intake of up to 3000 mg/kg/day PA had no adverse histopathology, hematology, body weight, or clinical chemistry effects in rats. Dietary exposure to PA did, however, result in an elevation in urinary excretion of sodium and phosphorus, whereas excretion of magnesium, calcium, and potassium was lowered. A more detailed study demonstrated that although the urinary excretion of these minerals was changed, total recovery of the minerals (feces + urine), except for sodium, was not different from that for controls. An increase in sodium excretion was expected since PA was in the form of a sodium salt. The ADE studies following a single oral dose of PA indicate that the majority of dosed PA (91.9%) was excreted in the feces. As expected, a small percentage (approximately 3.5%) was absorbed, possibly metabolized, and excreted. In summary, the oral administration of high levels of PA resulted in (1) no histological, hematological, or clinical chemistry changes; (2) no alteration in the overall mineral excretion (feces + urine) with the exception of sodium; and (3) primarily fecal excretion of orally administered PA.


Subject(s)
Acrylic Resins/toxicity , Acrylic Resins/administration & dosage , Administration, Oral , Animals , Carbon Dioxide/metabolism , Feces/chemistry , Female , Intestinal Absorption , Male , Molecular Weight , Rats , Tissue Distribution , Water-Electrolyte Balance/drug effects
5.
Toxicol Appl Pharmacol ; 106(1): 88-101, 1990 Oct.
Article in English | MEDLINE | ID: mdl-2174581

ABSTRACT

A multidisciplinary approach was used to investigate the responses of the respiratory tract to silica (SiO2) or titanium dioxide (TiO2). Rats were intratracheally instilled with 5-100 mg/kg of dust and bronchoalveolar lavage fluid (BALF) lactate dehydrogenase (LDH) and total protein (TP) and ex vivo alveolar macrophage (AM) fibronectin release assessed on Days 7, 14, and 28 after exposure. Lung dust burdens were determined on Days 1, 7, and 28 after instillation. Both dusts elicited dose-related increases in BALF LDH and TP, a response which was more pronounced and progressive with SiO2. All doses of SiO2 elicited persistent increases in AM fibronectin release. TiO2 stimulated persistent increases in AM fibronectin release at greater than or equal to 50 mg/kg, with transient or no effect at less than or equal to 10 mg/kg. Increased SiO2 retention was observed for all doses and TiO2 retention was increased only at doses greater than or equal to 50 mg/kg. In vitro exposure of naive AM to SiO2 or TiO2 did not stimulate AM fibronectin release. Histopathology demonstrated fibrosis at all SiO2 doses; only TiO2 doses greater than or equal to 50 mg/kg resulted in fibrosis. These results reveal an association between increased dust retention, lung injury, activation of AM fibronectin release, and the development of fibrosis. The magnitude and temporal pattern of responses clearly differentiated SiO2 from TiO2. The correlation of BALF markers of lung injury and increased AM fibronectin release with the development of fibrosis supports the use of these parameters as predictive biomarkers of dust-induced interstitial lung disease.


Subject(s)
Dust/adverse effects , Fibronectins/metabolism , Lung/pathology , Macrophages/metabolism , Pulmonary Alveoli/metabolism , Pulmonary Fibrosis/etiology , Silicon Dioxide/toxicity , Titanium/toxicity , Animals , Body Burden , Bronchoalveolar Lavage Fluid/chemistry , Interleukin-1/metabolism , L-Lactate Dehydrogenase/analysis , Male , Organ Size/drug effects , Proteins/analysis , Rats , Rats, Inbred F344 , Tumor Necrosis Factor-alpha/metabolism
6.
Am J Respir Cell Mol Biol ; 2(4): 381-90, 1990 Apr.
Article in English | MEDLINE | ID: mdl-2157474

ABSTRACT

We investigated the effects of silica (SiO2) and titanium dioxide (TiO2) on the pulmonary recruitment of inflammatory cells and the ability of alveolar macrophages (AMs) to release the pro-inflammatory cytokines, interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF). Rats were intratracheally instilled with 5 to 100 mg/kg of the materials, and bronchoalveolar lavage cell populations and AM cytokine release were characterized on days 1, 7, 14, and 28. Both dusts elicited dose-related increases in neutrophils, lymphocytes, and AMs; however, this response was more pronounced and persistent with SiO2. SiO2 at greater than or equal to 50 mg/kg increased AM release of IL-1 and TNF at all time points; lower SiO2 doses had either a transient or no effect on AM-derived cytokines. TiO2 did not result in AM IL-1 release and increased TNF release transiently at doses greater than or equal to 50 mg/kg. Both dusts primed AMs to release increased levels of IL-1 and TNF upon in vitro stimulation with lipopolysaccharide. Histopathology (day 28) demonstrated dose-related interstitial inflammation associated with SiO2 exposure, an effect that was less severe with TiO2. SiO2 doses of greater than or equal to 50 mg/kg elicited a granulomatous response. Development of granulomatous inflammation only at SiO2 doses for which persistent AM IL-1 release occurred suggests involvement of this cytokine in the formation of SiO2-induced granulomas. The ability of SiO2 to activate AM release of IL-1 and TNF in a more pronounced and persistent manner than TiO2 is likely responsible, at least in part, for the greater inflammation and pneumotoxicity associated with SiO2.


Subject(s)
Interleukin-1/biosynthesis , Macrophages/metabolism , Pulmonary Alveoli/pathology , Pulmonary Fibrosis/pathology , Silicon Dioxide/toxicity , Titanium/toxicity , Tumor Necrosis Factor-alpha/biosynthesis , Animals , Bronchoalveolar Lavage Fluid/cytology , Leukocyte Count , Lipopolysaccharides/pharmacology , Lung/pathology , Lymphocytes/pathology , Macrophages/pathology , Male , Neutrophils/pathology , Pulmonary Fibrosis/chemically induced , Rats , Rats, Inbred F344
7.
Toxicol Appl Pharmacol ; 102(2): 268-81, 1990 Feb.
Article in English | MEDLINE | ID: mdl-2154066

ABSTRACT

Analysis of bronchoalveolar lavage fluid (BALF) appears to be a sensitive approach to characterizing an acute inflammatory response within the lung. More work, however, is needed to determine if analyses of BALF endpoints can predict chronic responses (i.e., fibrosis). The objective of the present study was to compare the dose and temporal pulmonary response of a known fibrogenic agent, silica, and two known nonfibrogenic agents, aluminum oxide and titanium dioxide. Animals were instilled with silica (0, 0.2, 1.0, or 5.0 mg/100 g body wt), titanium dioxide (1.0 or 5 mg/100 g body wt), aluminium oxide (1.0 or 5.0 mg/100 g body wt) or saline. Animals (n = 5/group) were terminated 1, 7, 14, 28, and 63 days following instillation, and the BALF was characterized by biochemical and cellular assays. Histopathological changes were determined at 60 days after exposure. The biochemical results demonstrated BALF levels of lactate dehydrogenase (LDH), beta-glucuronidase (BG), N-acetylglucosaminidase (NAG), and total protein (TP) increased in a dose-related fashion at the earlier time points for all test materials, with the magnitude of change being greatest for silica. The temporal response for these parameters was significantly different for the two classes of materials. With time, the response for the fibrogenic dust steadily increased, while the levels for the nonfibrogenic dusts decreased toward normal values during the 2-month study period. Of the cellular changes, total cell numbers, neutrophils, and lymphocyte numbers were the most sensitive markers of the pulmonary response. As shown with the biochemical parameters, the cellular response to silica increased with time while that of the nuisance dusts did not. It was also found that, similar to inhalation studies, high doses of a nuisance dust may result in toxicity/inflammation. This toxicity at high dose levels emphasizes the importance of choosing relevant doses when comparing potentially fibrogenic and nonfibrogenic dusts. In conclusion, the persistent and progressive changes seen in the biochemical (LDH, TP, BG, NAG) and cellular parameters (total cells, neutrophils and lymphocytes) following silica administration correlated with the fibrotic response which occurred after exposure to this material. The less dramatic and transient changes seen with aluminum oxide and titanium dioxide correlated with the inert nature of these nuisance dusts. The results of this study indicate evaluation of BALF may provide a means to predict the chronic pulmonary response to a material.


Subject(s)
Aluminum Oxide/adverse effects , Aluminum/adverse effects , Bronchoalveolar Lavage Fluid , Dust/adverse effects , Lung Diseases/chemically induced , Silicon Dioxide/adverse effects , Titanium/adverse effects , Acetylglucosaminidase/analysis , Animals , Bronchoalveolar Lavage Fluid/analysis , Bronchoalveolar Lavage Fluid/cytology , Collagen/analysis , Glucuronidase/analysis , L-Lactate Dehydrogenase/analysis , Lung Diseases/metabolism , Lung Diseases/pathology , Lymphocytes/analysis , Macrophages/pathology , Male , Neutrophils/pathology , Organ Size , Proteins/analysis , Pulmonary Alveoli/analysis , Pulmonary Alveoli/pathology , Rats , Rats, Inbred F344
8.
Fundam Appl Toxicol ; 8(4): 474-81, 1987 May.
Article in English | MEDLINE | ID: mdl-3609534

ABSTRACT

Male Fischer 344 rats were given two or four injections of 1,2-dimethylhydrazine (DMH), 40 mg/kg sc, and then fed a diet containing 0.5% butylated hydroxytoluene (BHT). Five months later, the animals treated with two doses of DMH had a significantly higher incidence of colon tumors than the animals fed a BHT-free control diet. In animals treated with four injections of DMH, the increase in colon tumor incidence was statistically not significant, but BHT appeared to produce a shift in tumor distribution. In a second experiment, Fischer 344 rats were treated with 2 X 40 mg/kg of DMH and fed a diet of 0.5 or 0.1% BHT for 6 months; these animals had a significantly increased incidence of small intestinal tumors (duodenum, jejunum, and ileum) compared with animals fed the control diet. In rats treated with DMH and given a diet of 0.5% butylated hydroxyanisole (BHA), overall incidence of gastrointestinal tract tumors was higher than in control animals, although the difference was statistically not significant. Administration of N-nitroso-N-methylurea (NMU; 90 mg/kg given orally) produced stomach and colon tumors; 0.5% BHT in the diet did not modulate tumor incidence. It is concluded that dietary BHT may enhance development of gastrointestinal tumors produced by DMH, but not by NMU, provided exposure to BHT occurs after exposure to the carcinogen.


Subject(s)
Butylated Hydroxyanisole/toxicity , Gastrointestinal Neoplasms/chemically induced , Animals , Butylated Hydroxytoluene/toxicity , Diet , Gastrointestinal Neoplasms/pathology , Male , Methylnitrosourea/toxicity , Rats , Rats, Inbred F344
9.
Fundam Appl Toxicol ; 8(2): 253-62, 1987 Feb.
Article in English | MEDLINE | ID: mdl-3556836

ABSTRACT

Mice were treated with three cytostatic drugs: cyclophosphamide, busulfan, or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The alveolar labeling index was measured following drug administration with a pulse of 3H-labeled thymidine and autoradiography. In cyclophosphamide-treated animals, peak alveolar cell proliferation was seen 5 days after injection of the drug. In animals treated with busulfan or BCNU, proliferation was even more delayed (occurring 2-3 weeks after administration). In contrast, with oleic acid, the highest alveolar cell labeling was found 2 days after intravenous administration. In animals exposed to a cytostatic drug, proliferation of type II alveolar cells was never a prominent feature whereas in animals treated with oleic acid there was an initial burst of type II cell proliferation. It is concluded that the patterns of pulmonary repair vary between chemicals designed to interfere with DNA replication as compared to agents which produce acute lung damage such as oleic acid.


Subject(s)
Busulfan/toxicity , Carmustine/toxicity , Cyclophosphamide/toxicity , Lung/pathology , Animals , Autoradiography , Cell Division/drug effects , DNA Replication/drug effects , Kinetics , Lung/cytology , Lung/drug effects , Male , Mice , Mice, Inbred BALB C , Oleic Acid , Oleic Acids/toxicity , Thymidine/metabolism , Tritium
10.
Carcinogenesis ; 7(9): 1581-6, 1986 Sep.
Article in English | MEDLINE | ID: mdl-3742730

ABSTRACT

The effects of hyperoxia on lung tumor development were examined in mice and rats. In mice, exposure to 70% O2 prevented the development of urethan- or 3-methylcholanthrene-induced lung tumors. Dietary antioxidants [butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA)] were unable to prevent the inhibition of tumor development by oxygen, although BHT retained its capability to enhance tumor development in mouse lung. In visible-size tumors, oxygen did not depress DNA synthesis. Oxygen also reduced the number of pulmonary metastatic nodules after i.v. injection of mammary gland-derived carcinoma cells, but failed to inhibit growth of murine lung carcinoma or murine melanoma-derived cell lines. Rats treated with one single intratracheal instillation of 3-methylcholanthrene developed multiple lung lesions; their growth could be prevented by exposure of the animals to 40 or 70% O2. It is concluded that hyperoxia prevents development of transformed cells in vivo in the lung and may affect adversely the growth of selected cell lines metastatic to the lung.


Subject(s)
Lung Neoplasms/prevention & control , Oxygen/pharmacology , Animals , Butylated Hydroxyanisole/pharmacology , Butylated Hydroxytoluene/pharmacology , Cell Division , DNA/biosynthesis , Dose-Response Relationship, Drug , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Male , Methylcholanthrene , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Rats , Rats, Inbred F344
11.
Toxicol Appl Pharmacol ; 85(1): 69-77, 1986 Aug.
Article in English | MEDLINE | ID: mdl-2425458

ABSTRACT

We examined whether intratracheal instillation (IT) of bleomycin would produce similar or dissimilar lesions when compared to lung damage following intravenous (iv) injection of the drug. BALB/c mice were treated with either 4 U/kg IT or 100 U iv bleomycin and killed at intervals up to 21 days after treatment. Cell proliferation, histopathology, lung lavage, and hydroxyproline content were examined. There was a biphasic response in the cell proliferation in the IT-treated mice, while the iv-treated mice showed a single delayed peak in proliferation. The histopathologic features of interstitial pneumonitis, elevation of lung lavage enzyme activities, and lung hydroxyproline content were qualitatively similar between the two routes of administration, although the IT mice response was always greater in magnitude. Differences exist between the lung reaction to these two routes of administration, but these differences reflect nonspecific inflammatory response and magnitude of initial injury. We conclude that the response to bleomycin administered IT is basically similar to the changes produced by intravenous injection of the drug.


Subject(s)
Bleomycin/toxicity , Lung/drug effects , Animals , Bleomycin/administration & dosage , Cell Division , Hydroxyproline/analysis , Hyperplasia/chemically induced , Hyperplasia/pathology , Injections, Intravenous , Intubation, Intratracheal , Kinetics , Lung/pathology , Male , Mice , Mice, Inbred BALB C , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology
12.
Toxicol Appl Pharmacol ; 84(3): 480-92, 1986 Jul.
Article in English | MEDLINE | ID: mdl-3726871

ABSTRACT

O,S,S,-Trimethyl phosphorodithioate (OSS) is a contaminant of various organophosphorus insecticides which induces delayed damage to rat lung bronchiolar and alveolar epithelial cells. Whether lung damage occurs in mice has not been tested. Changes in DNA synthesis, an index of cell division after the induction of damage, were monitored by measuring thymidine incorporation into pulmonary DNA. Mice, treated with 45 mg/kg OSS, exhibited a significant increase in pulmonary thymidine incorporation on Day 5. Maximal increases occurred on Days 7-10 and were followed by a gradual decline to control levels by Day 15. The labeling index of mouse lung cells, determined following autoradiography, exhibited a similar time course. Differential cell counts indicated that maximal division of type II cells occurred before that of interstitial cells, although interstitial cells were the predominant type labeled at all times. Pulmonary DNA synthesis was significantly increased in rats 2 days after treatment with 90 mg/kg OSS. Maximal thymidine incorporation was measured on Day 3, followed by a decline to control levels on Day 5. Thymidine incorporation into total lung DNA was dose related in both species. Maximal increases appeared after 45 and 90 mg/kg OSS in mice and rats, respectively. The histopathological changes in mouse lung tissue were similar, but somewhat less severe than those seen in rats. Rats exhibited a severe interstitial pneumonitis with type I alveolar cell destruction followed by type II cell proliferation. Mice exhibited a mild to moderate alveolitis with only slight damage to type I cells. Necrosis of bronchiolar Clara cells was evident in both species but was more extensive in rats. SKF 525a and piperonyl butoxide prevented OSS-induced increases in pulmonary DNA synthesis in rat lung suggesting that metabolic activation was necessary to elicit damage. Piperonyl butoxide treatments had no effect, however, on thymidine incorporation after OSS in mouse lung tissue, and the highest dose of SKF 525a had only a moderate inhibitory effect on this parameter while increasing animal mortality. These data indicate that systemic treatment with OSS results in damage to mouse, as well as rat, lung tissue at both the alveolar and bronchiolar levels.


Subject(s)
Lung/drug effects , Organothiophosphorus Compounds/toxicity , Animals , Autoradiography , DNA/biosynthesis , Lethal Dose 50 , Lung/metabolism , Male , Mice , Mice, Inbred BALB C , Organ Size/drug effects , Organothiophosphates , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/pathology , Rats , Rats, Inbred Strains , Species Specificity , Thymidine/metabolism
13.
Cancer Res ; 46(4 Pt 2): 1994-2000, 1986 Apr.
Article in English | MEDLINE | ID: mdl-3948176

ABSTRACT

The hypothesis was tested that continuous hyperoxia would enhance the development of lung tumors in mice. In strain A/J mice treated with a single dose of urethan (1000 mg/kg) and exposed to 70% O2 for 16 wk, an average of 5 tumors per lung developed, whereas in animals kept in air, an average of 20 tumors per lung was found. When the animals were returned to air after oxygen exposure, it was found that a difference of 15 tumors per lung between the two groups persisted up to 1 yr later, indicating that O2 was tumoricidal. The shortest duration of O2 exposure to be effective was 4 wk, and delay of O2 exposure up to 12 wk after urethan still was effective in reducing the number of developing tumors. Histopathology showed that continued exposure to 70% O2 produced some hyperplasia of the bronchiolar epithelium and only very discrete changes in the pulmonary parenchyma. Analysis of cell proliferation patterns with a continuous [3H]thymidine labeling technique showed a persistent high cell labeling in the bronchiolar epithelium and a temporary increase in alveolar wall cell labeling. Chronic hyperoxia failed to alter the activities of pulmonary superoxide dismutase or glucose-6-phosphate dehydrogenase. Ornithine decarboxylase, on the other hand, was increased as long as the animals remained exposed to oxygen. It was concluded that hyperoxia kills developing tumor cells in mouse lung.


Subject(s)
Lung Neoplasms/prevention & control , Oxygen/pharmacology , Animals , Body Weight , Cell Division , Dose-Response Relationship, Drug , Free Radicals , Lung/enzymology , Lung/pathology , Lung Neoplasms/pathology , Male , Mice , Mice, Inbred Strains , Ornithine Decarboxylase/analysis , Thymidine/metabolism , Time Factors , Tritium , Urethane/toxicity
14.
J Biochem Toxicol ; 1(1): 83-91, 1986 Mar.
Article in English | MEDLINE | ID: mdl-2482891

ABSTRACT

Collagen cross-linking was analyzed in lungs of rats, two, four, and ten weeks after intratracheal instillation of 1.5 units of bleomycin. Similar analyses were performed on lungs of mice 18 months after intratracheal instillation of bleomycin with or without subsequent exposure to 70% oxygen (O2) for 72 hours. Lungs were analyzed to determine the content of the reduced difunctional cross-links dihydroxylysinonorleucine (DHLNL) and hydroxylysinonorleucine (HLNL) and of the nonreducible trifunctional cross-link hydroxypyridinium (OHP). Ratios of DHLNL:HLNL were elevated in the rat lungs at two and four weeks, due to increased levels of DHLNL. There were no changes in the difunctional cross-links in any of the mouse lungs. Hydroxypyridinium content was elevated in the rat lungs at ten weeks and in the mouse lungs exposed to bleomycin and oxygen. We conclude that increases in DHLNL may serve as an early indicator that potentially "fibrotic collagen" is being synthesized in lungs acutely exposed to fibrogenic stimuli, while increases in OHP may serve as a permanent marker of a fibrogenic event that could have occurred months to years earlier.


Subject(s)
Bleomycin/pharmacology , Collagen/metabolism , Pulmonary Fibrosis/chemically induced , Animals , Dipeptides/metabolism , Lung/drug effects , Lung/metabolism , Mice , Mice, Inbred BALB C , Pyridines/metabolism , Rats , Rats, Inbred Strains , Time Factors
15.
Toxicol Appl Pharmacol ; 82(2): 344-50, 1986 Feb.
Article in English | MEDLINE | ID: mdl-3945960

ABSTRACT

Beryllium (Be+2), a divalent metal ion, is toxic to both man and animal. Although the molecular basis for its toxicity is unknown, it is well established that micromolar concentrations of beryllium specifically inhibit certain enzymes. Previous in vitro studies have shown that the presence of ferritin, an iron-storage protein, reactivated these enzymes by sequestering beryllium (Price and Joshi, 1984). In the present study we demonstrate in vivo that beryllium and zinc are bound by ferritin in greater amounts than Pb+2, Cu+2, and Cd+2. Beryllium did not induce the synthesis of metallothionein. In animals pretreated with an iron salt (ferric ammonium citrate, 40 mg/kg body wt), liver ferritin was elevated approximately five times and the toxicity of intravenously injected beryllium was significantly attenuated. Excretion and deposition studies suggested that iron salt treatment resulted in a reduction of liver beryllium. Thus the protection against beryllium toxicity by ferric ammonium citrate may be due to increased production of ferritin which binds beryllium and its subsequent elimination in the feces.


Subject(s)
Beryllium/toxicity , Ferritins/metabolism , Animals , Beryllium/metabolism , Ferric Compounds/pharmacology , Liver/metabolism , Male , Metals/metabolism , Protein Binding , Quaternary Ammonium Compounds/pharmacology , Rats , Rats, Inbred F344 , Tissue Distribution
16.
Toxicology ; 38(2): 151-60, 1986 Feb.
Article in English | MEDLINE | ID: mdl-3945967

ABSTRACT

Male and female C3H mice were fed a diet containing 0.5% or 0.05% of the antioxidant butylated hydroxytoluene (BHT). After 10 months, male but not female animals had a significantly increased incidence of liver tumors compared to animals kept on a BHT-free control diet. In a second experiment, male BALB/c mice were treated subcutaneously with the carcinogens dimethylhydrazine (DMH) or intrarectally with methylnitrosourea (MNU). A diet containing 0.5% BHT significantly increased the incidence of colon tumors in DMH treated animals but had no effect in mice given MNU. It is concluded that the effect of BHT on tumor development depends on strain and target organ examined and possibly also on the chemical carcinogen used.


Subject(s)
Butylated Hydroxytoluene/toxicity , Colonic Neoplasms/chemically induced , Liver Neoplasms/chemically induced , 1,2-Dimethylhydrazine , Animals , Body Weight/drug effects , Carcinogens/administration & dosage , Diet , Dimethylhydrazines/administration & dosage , Female , Gastrointestinal Neoplasms/chemically induced , Male , Methylnitrosourea/administration & dosage , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Neoplasms, Multiple Primary/chemically induced , Time Factors
17.
Am Rev Respir Dis ; 133(2): 274-8, 1986 Feb.
Article in English | MEDLINE | ID: mdl-3456218

ABSTRACT

We investigated direct histamine release and its effects in edema formation following paraquat (PQ) injury in a blood-free, perfused rat lung preparation. Under control conditions, perfusate histamine levels from the lung averaged 9.5 +/- 1.4 ng/ml. Lungs perfused with paraquat (1 mM) showed marked increases in pulmonary arterial pressure (133%), airway pressure (74%), alveolarcapillary protein flux (200%), and lung weight (38%). Prior to any detectable lung weight or pressure changes, PQ caused a 300% increase in perfusate histamine. Diphenhydramine (1.0 X 10(-5) M), a specific H1-histamine receptor antagonist, blocked the increased protein flux that followed PQ administration and significantly delayed edema. Furthermore, diphenhydramine attenuated the rise in PGF2 alpha. Conversely, histamine release was partially attenuated by the cyclooxygenase inhibitor, ibuprofen, at 2.4 X 10(-5) M, the same level that we had previously shown to block an early rise in PGF2 alpha and the onset of edema after PQ. These data show that the increased alveolar-capillary protein flux that occurred with PQ injury was attenuated by an H1-receptor antagonist and suggest that histamine is a primary mediator in paraquat-induced injury and that histamine subsequently stimulates prostaglandin release.


Subject(s)
Histamine/physiology , Lung Diseases/chemically induced , Paraquat , Animals , Capillary Permeability , Dinoprost , Diphenhydramine/pharmacology , Histamine/metabolism , In Vitro Techniques , Lung/metabolism , Male , Perfusion , Prostaglandins F/metabolism , Pulmonary Alveoli/blood supply , Rats , Rats, Inbred Strains
18.
Exp Mol Pathol ; 43(3): 348-58, 1985 Dec.
Article in English | MEDLINE | ID: mdl-2415389

ABSTRACT

The concomitant treatment of rats with bleomycin and hyperoxia results in synergistic development of pulmonary injury. We exposed rats to 70% oxygen for 72 hr following an intratracheal instillation of bleomycin (0.2 U/kg body wt). Animals were killed 15, 30, 60 and 90 days after treatment for hydroxyproline, cell kinetics, and histopathologic analysis. A 16% increase in hydroxyproline over controls was seen 15 days after treatment which was manifested by the proliferation phase of diffuse alveolar damage and an increase in cell labeling by tritiated thymidine. Thirty days after treatment the hydroxyproline remained elevated while lung injury appeared to be healing with a residual focal interstitial pneumonitis and a drop in cell labeling. Between 60 and 90 days, there was an additional significant increase in hydroxyproline to 44% over controls. Diffuse interstitial pneumonitis with fibrosis was observed. Cell labeling remained constant between 60 and 90 days. We conclude that the treatment of rats with bleomycin and hyperoxia results in slowly progressive pulmonary fibrosis. The increase in hydroxyproline in the chronic phase was not accompanied by an increase in cell proliferation, and therefore may have resulted from an increase in cellular production of hydroxyproline rather than increased number of cells producing collagen.


Subject(s)
Pulmonary Fibrosis/pathology , Animals , Bleomycin/toxicity , Collagen/biosynthesis , Hydroxyproline/analysis , Male , Oxygen/toxicity , Pulmonary Alveoli/pathology , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/metabolism , Rats , Rats, Inbred Strains , Thymidine/metabolism
19.
Biochem Pharmacol ; 34(24): 4269-73, 1985 Dec 15.
Article in English | MEDLINE | ID: mdl-2416317

ABSTRACT

Cyclic nucleotides have been shown in vitro to regulate fibroblast proliferation and/or collagen production. We have reported previously that propranolol, which decreases the cAMP/cGMP ratio, potentiates the amount of fibrosis produced in a damaged lung. The purpose of this study was to determine if elevations in the cAMP/cGMP ratio may attenuate collagen production by fibroblasts following lung damage. Lung injury was induced in mice by either butylated hydroxytoluene (BHT) (350 or 400 mg/kg intraperitoneally) or bleomycin (4 units/kg intratracheally). The mice were treated with a phosphodiesterase inhibitor, aminophylline (20 mg/kg twice daily), prior to induction of lung injury and for the duration of the study. Cyclic nucleotide changes in the lung were also determined during lung injury, with and without aminophylline. The administration of aminophylline, which increased the cAMP/cGMP ratio, resulted in attenuation of the increase in total lung collagen normally seen after injury, while having no effect on collagen levels in the undamaged lung. The results are compatible with the hypothesis that elevation of whole lung cAMP/cGMP ratio early in the damage and repair process correlates with decreased hydroxyproline deposition.


Subject(s)
Aminophylline/pharmacology , Pulmonary Fibrosis/metabolism , Animals , Bleomycin/toxicity , Butylated Hydroxytoluene/toxicity , Collagen/biosynthesis , Cyclic AMP/analysis , Cyclic GMP/analysis , Hydroxyproline/analysis , Lung/analysis , Male , Mice , Pulmonary Fibrosis/chemically induced , Time Factors
20.
Toxicol Lett ; 26(2-3): 169-73, 1985 Aug.
Article in English | MEDLINE | ID: mdl-2412310

ABSTRACT

Interstitial pulmonary fibrosis is characterized by an abnormal accumulation of fibroblasts with a resultant increase in lung collagen content. Previous research has implied a possible involvement of the T-lymphocyte in this process. We used cyclosporin A (Cy A), a known immunosuppressant, to deplete T-lymphocyte-dependent responses in animals following treatment with agents known to produce fibrosis; butylated hydroxytoluene (BHT), bleomycin and beryllium (Be). BHT-treated mice and bleomycin-treated rats showed significant reduction in total lung hydroxyproline content with Cy A (P less than 0.05). These results suggest a contribution of the T-lymphocyte in the overall process of fibrosis, but do not indicate its role as the sole causative agent.


Subject(s)
Cyclosporins/pharmacology , Pulmonary Fibrosis/immunology , T-Lymphocytes/drug effects , Animals , Beryllium/antagonists & inhibitors , Bleomycin/antagonists & inhibitors , Butylated Hydroxytoluene/antagonists & inhibitors , Hydroxyproline/metabolism , Male , Mice , Mice, Inbred BALB C , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/metabolism , Rats , Rats, Inbred F344
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