asbestos--crocidolite and Disease-Models--Animal

Asbestos causes lung cancer and malignant mesothelioma in humans, but the precise mechanism has not been well understood. MicroRNA (miRNA) is a short non-coding RNA that suppresses gene expression and participates in human diseases including cancer. In this study, we examined the expression levels of miRNA and potential target genes in lung tissues of asbestos-exposed mice by microarray analysis.. We intratracheally administered asbestos (chrysotile and crocidolite, 0.05 or 0.2 mg/instillation) to 6-week-old ICR male mice four times weekly. We extracted total RNA from lung tissues and performed microarray analysis for miRNA and gene expression. We also carried out real-time polymerase chain reaction (PCR), Western blotting, and immunohistochemistry to confirm the results of microarray analysis.. Microarray analysis revealed that the expression levels of 14 miRNAs were significantly changed by chrysotile and/or crocidolite (>2-fold, P < .05). Especially, miR-21, an oncogenic miRNA, was significantly upregulated by both chrysotile and crocidolite. In database analysis, miR-21 was predicted to target tumor suppressor genes programmed cell death 4 (Pdcd4) and reversion-inducing-cysteine-rich protein with kazal motifs (Reck). Although real-time PCR showed that Pdcd4 was not significantly downregulated by asbestos exposure, Western blotting and immunohistochemistry revealed that PDCD4 expression was reduced especially by chrysotile. Reck was significantly downregulated by chrysotile in real-time PCR and immunohistochemistry.. This is the first study demonstrating that miR-21 was upregulated and corresponding tumor suppressor genes were downregulated in lung tissues of asbestos-exposed animals. These molecular events are considered to be an early response to asbestos exposure and may contribute to pulmonary toxicity and carcinogenesis.

Topics: Animals; Apoptosis Regulatory Proteins; Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Disease Models, Animal; Down-Regulation; Gene Expression; GPI-Linked Proteins; Lung; Male; Mice; Mice, Inbred ICR; Microarray Analysis; MicroRNAs; RNA-Binding Proteins; Up-Regulation

Early events in an experimental model of mesothelioma development include increased levels of editing in double-stranded RNA (dsRNA). We hypothesised that expression of endogenous retroviruses (ERV) contributes to dsRNA formation and type-I interferon signaling. ERV and interferon stimulated genes (ISGs) expression were significantly higher in tumor compared to non-tumor samples. 12 tumor specific ERV ("MesoERV1-12") were identified and verified by qPCR in mouse tissues. "MesoERV1-12" expression was lower in mouse embryonic fibroblasts (MEF) compared to mesothelioma cells. "MesoERV1-12" levels were significantly increased by demethylating agent 5-Aza-2'-deoxycytidine treatment and were accompanied by increased levels of dsRNA and ISGs. Basal ISGs expression was higher in mesothelioma cells compared to MEF and was significantly decreased by JAK inhibitor Ruxolitinib, by blocking Ifnar1 and by silencing Mavs. "MesoERV7" promoter was demethylated in asbestos-exposed compared to sham mice tissue as well as in mesothelioma cells and MEF upon 5-Aza-CdR treatment. These observations uncover novel aspects of asbestos-induced mesothelioma whereby ERV expression increases due to promoter demethylation and is paralleled by increased levels of dsRNA and activation of type-I IFN signaling. These features are important for early diagnosis and therapy.

Topics: Animals; Asbestos, Crocidolite; Asbestosis; Cell Line, Tumor; Disease Models, Animal; DNA Methylation; Endogenous Retroviruses; Gene Expression Regulation, Neoplastic; Host-Pathogen Interactions; Interferon Regulatory Factors; Interferon Type I; Mesothelioma; Mice; Promoter Regions, Genetic; RNA Editing; RNA, Double-Stranded; Signal Transduction

Malignant mesothelioma (MM) is a rare but socially important neoplasm due to its association with asbestos exposure. Malignant mesothelioma is difficult to diagnose at an early stage, yet there are no particularly effective treatments available at the advanced stage, thus necessitating efficient strategies to prevent MM in individuals already exposed to asbestos. We previously showed that persistent oxidative damage caused by foreign body reaction and affinity of asbestos both to hemoglobin and histones is one of the major pathogeneses. Accordingly, as an effective strategy to prevent asbestos-induced MM, we undertook the use of an iron chelator, deferasirox, which decreased the epithelial-mesenchymal transition in a crocidolite-induced rat MM model. However, this agent may show adverse effects. Here, we studied the effects of iron removal by phlebotomy as a realistic measure on the same rat model. We injected a total of 5 mg crocidolite i.p. to F1 hybrid rats between the Fischer-344 and Brown-Norway strains at the age of 6 weeks. We repeated weekly or biweekly phlebotomy of 6-8 mL/kg/time from 10 to 60 weeks of age. The animals were observed until 120 weeks. In male rats, phlebotomy significantly decreased the weight and nuclear grade of MM, and modestly reduced the associated ascites and the fraction of more malignant sarcomatoid subtype. Weekly phlebotomy prolonged long-term survival. Our results indicate that appropriate phlebotomy may be a practical preventive measure to attenuate the initiation and promotion capacity of asbestos towards MM by reducing iron in individuals exposed to asbestos.

Topics: Animals; Asbestos, Crocidolite; Disease Models, Animal; Iron; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Phlebotomy; Rats; Survival Analysis; Treatment Outcome; Tumor Burden

Malignant mesothelioma (MM), linked to asbestos exposure, is a highly lethal form of thoracic cancer with a long latency period, high mortality and poor treatment options. Chronic inflammation and oxidative tissue damage caused by asbestos fibers are linked to MM development. Flaxseed lignans, enriched in secoisolariciresinol diglucoside (SDG), have antioxidant, anti-inflammatory and cancer chemopreventive properties. As a prelude to chronic chemoprevention studies for MM development, we tested the ability of flaxseed lignan component (FLC) to prevent acute asbestos-induced inflammation in MM-prone Nf2(+/mu) mice. Mice (n = 16-17 per group) were placed on control (CTL) or FLC-supplemented diets initiated 7 days prior to a single intraperitoneal bolus of 400 µg of crocidolite asbestos. Three days post asbestos exposure, mice were evaluated for abdominal inflammation, proinflammatory/profibrogenic cytokine release, WBC gene expression changes and oxidative and nitrosative stress in peritoneal lavage fluid (PLF). Asbestos-exposed mice fed CTL diet developed acute inflammation, with significant (P < 0.0001) elevations in WBCs and proinflammatory/profibrogenic cytokines (IL-1ß, IL-6, TNFα, HMGB1 and active TGFß1) relative to baseline (BL) levels. Alternatively, asbestos-exposed FLC-fed mice had a significant (P < 0.0001) decrease in PLF WBCs and proinflammatory/profibrogenic cytokine levels relative to CTL-fed mice. Importantly, PLF WBC gene expression of cytokines (IL-1ß, IL-6, TNFα, HMGB1 and TGFß1) and cytokine receptors (TNFαR1 and TGFßR1) were also downregulated by FLC. FLC also significantly (P < 0.0001) blunted asbestos-induced nitrosative and oxidative stress. FLC reduces acute asbestos-induced peritoneal inflammation, nitrosative and oxidative stress and may thus prove to be a promising agent in the chemoprevention of MM.

Topics: Animals; Antioxidants; Asbestos, Crocidolite; Butylene Glycols; Chromatography, Liquid; Diet; Dietary Supplements; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Flax; Glucosides; Inflammation; Lignans; Mesothelioma; Mice; Mice, Mutant Strains; Oxidative Stress; Peritoneal Lavage; Peritoneum; Precancerous Conditions; Reverse Transcriptase Polymerase Chain Reaction; Seeds; Tandem Mass Spectrometry; Transcriptome

Chrysotile has been frequently used in the past in manufacturing brakes and continues to be used in brakes in many countries. This study was designed to provide an understanding of the biokinetics and potential toxicology following inhalation of brake dust following short term exposure in rats. The deposition, translocation and pathological response of brake dust derived from brake pads manufactured with chrysotile were evaluated in comparison to the amphibole, crocidolite asbestos. Rats were exposed by inhalation 6 h/day for 5 days to either brake dust obtained by sanding of brake-drums manufactured with chrysotile, a mixture of chrysotile and the brake dust or crocidolite asbestos. No significant pathological response was observed at any time point in either the brake dust or chrysotile/brake dust exposure groups. The long chrysotile fibers (>20 μm) cleared quickly with T(½) estimated as 30 and 33 days, respectively in the brake dust and the chrysotile/brake dust exposure groups. In contrast, the long crocidolite fibers had a T(½)>1000 days and initiated a rapid inflammatory response in the lung following exposure resulting in a 5-fold increase in fibrotic response within 91 days. These results provide support that brake dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung following short term inhalation.

Topics: Animals; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Chemical Phenomena; Disease Models, Animal; Dust; Half-Life; Industry; Inhalation Exposure; Lung; Male; Materials Testing; Motor Vehicles; Occupational Diseases; Protective Devices; Rats; Rats, Wistar; Respiratory Mucosa; Tissue Distribution; Toxicity Tests, Acute

The purpose of this study was to develop an improved method for collagen and protein assessment of fibrotic lungs while decreasing animal use.. 8-10 week old, male C57BL/6 mice were given a single intratracheal instillation of crocidolite asbestos or control titanium dioxide. Lungs were collected on day 14 and dried as whole lung, or homogenized in CHAPS buffer, for hydroxyproline analysis. Insoluble and salt-soluble collagen content was also determined in lung homogenates using a modified Sirius red colorimetric 96-well plate assay.. The hydroxyproline assay showed significant increases in collagen content in the lungs of asbestos-treated mice. Identical results were present between collagen content determined on dried whole lung or whole lung homogenates. The Sirius red plate assay showed a significant increase in collagen content in lung homogenates however, this assay grossly over-estimated the total amount of collagen and underestimated changes between control and fibrotic lungs, conclusions: The proposed method provides accurate quantification of collagen content in whole lungs and additional homogenate samples for biochemical analysis from a single animal. The Sirius-red colorimetric plate assay provides a complementary method for determination of the relative changes in lung collagen but the values tend to overestimate absolute values obtained by the gold standard hydroxyproline assay and underestimate the overall fibrotic injury.

Topics: Analysis of Variance; Animals; Asbestos, Crocidolite; Asbestosis; Azo Compounds; Biomarkers; Collagen; Colorimetry; Coloring Agents; Disease Models, Animal; Hydroxyproline; Lung; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Reproducibility of Results; Severity of Illness Index; Spectrophotometry; Up-Regulation

Oxidative stress is thought to be the pathogenesis of pulmonary fibrosis induced by asbestos, and heme oxygenase-1 (HO-1) protects lung tissue against oxidative stress. We hypothesized that HO-1 is associated with oxidative lung injury caused by exposure to asbestos. This study was conducted to investigate the time course of HO-1 expression of lungs exposed to crocidolite asbestos in vivo. Male Wistar rats were administered 1 mg or 2 mg crocidolite asbestos suspended in saline by a single intratracheal instillation and were sacrificed at 3 d, 1 wk, 1 mo, 3 mo, and 6 mo of recovery time. The expression of HO-1 was observed by Western blot analysis and immunostaining. Protein levels of HO-1 increased at from 3 d to 6 mo following intratracheal instillation of 2 mg crocidolite asbestos. The levels of HO-1 increased at 1 wk and 1 mo following intratracheal instillation of 1 mg crocidolite asbestos. Many HO-1-positive cells were found, particularly in the alveolar macrophages, during immunostaining. These findings suggest that HO-1 may be related to lung disorder induced by dust and therefore can act as a biomarker of lung injury due to dust exposure.

Topics: Animals; Asbestos, Crocidolite; Disease Models, Animal; Gene Expression; Heme Oxygenase-1; Inhalation Exposure; Lung; Male; Pulmonary Fibrosis; Rats; Rats, Wistar

Malignant mesothelioma has been linked to asbestos exposure and generally has a poor prognosis because it is often diagnosed in advanced stages and is refractory to conventional therapy. Human malignant mesotheliomas accumulate multiple somatic genetic alterations, including inactivation of the NF2 and CDKN2A/ARF tumor suppressor genes. To better understand the significance of NF2 inactivation in malignant mesothelioma and identify tumor suppressor gene alterations that cooperate with NF2 loss of function in malignant mesothelioma pathogenesis, we treated Nf2 (+/-) knockout mice with asbestos to induce malignant mesotheliomas. Asbestos-exposed Nf2 (+/-) mice exhibited markedly accelerated malignant mesothelioma tumor formation compared with asbestos-treated wild-type (WT) littermates. Loss of the WT Nf2 allele, leading to biallelic inactivation, was observed in all nine asbestos-induced malignant mesotheliomas from Nf2 (+/-) mice and in 50% of malignant mesotheliomas from asbestos-exposed WT mice. For a detailed comparison with the murine model, DNA analyses were also done on a series of human malignant mesothelioma samples. Remarkably, similar to human malignant mesotheliomas, tumors from Nf2 (+/-) mice showed frequent homologous deletions of the Cdkn2a/Arf locus and adjacent Cdkn2b tumor suppressor gene, as well as reciprocal inactivation of Tp53 in a subset of tumors that retained the Arf locus. As in the human disease counterpart, malignant mesotheliomas from the Nf2 (+/-) mice also showed frequent activation of Akt kinase, which plays a central role in tumorigenesis and therapeutic resistance. Thus, this murine model of environmental carcinogenesis faithfully recapitulates many of the molecular features of human malignant mesothelioma and has significant implications for the further characterization of malignant mesothelioma pathogenesis and preclinical testing of novel therapeutic modalities.

Topics: Animals; Asbestos, Crocidolite; Cocarcinogenesis; Disease Models, Animal; Genes, Neurofibromatosis 2; Genes, p53; Genetic Predisposition to Disease; Humans; Mesothelioma; Mice; Mice, Knockout; Tumor Suppressor Protein p14ARF

Asbestos fibers up-regulate the extracellular signal-regulated kinase (ERK1/2) pathway in mesothelial and pulmonary epithelial cells in vitro, but the cell-type expression patterns and intracellular localization of activated, ie, phosphorylated, ERK in the lung after inhalation of asbestos are unclear. C57/BL6 mice were exposed to 7-mg/m(3) air of crocidolite asbestos for 5 and 30 days, the times required for the development of epithelial cell hyperplasia and fibrotic lesions, respectively. Exposure to asbestos caused striking increases in both unphosphorylated and phosphorylated ERK (p-ERK), which were most marked at 30 days and co-localized in bronchiolar and alveolar epithelial cells using an antibody to cytokeratin. Alveolar macrophages, detected with an anti-macrophage antibody, did not express p-ERK. p-ERK was localized at the apical cell surface of bronchiolar and alveolar type II epithelial cells exposed to asbestos fibers, and was most marked in areas of epithelial hyperplasia in association with fibrotic lesions. Because translocation of p-ERK to the nucleus is associated with activation of early response genes and transcription factors, laser scanning cytometry was used to determine the kinetics of activation and nuclear translocation of p-ERK in an alveolar type II epithelial cell line in vitro after exposure to asbestos or the ERK stimuli, epidermal growth factor, or H(2)O(2). Results showed that cytoplasmic to nuclear translocation of p-ERK occurred in a protracted manner in cells exposed to asbestos. The immunolocalization of p-ERK at the membrane surface, a site of initial exposure to asbestos fibers, and the chronic activation of p-ERK in epithelial cells at sites of fibrogenesis are consistent with the concept that epithelial cell signaling through the ERK pathway contributes to remodeling of the lung during the development of pulmonary fibrosis.

Topics: Administration, Inhalation; Animals; Asbestos, Crocidolite; Asbestosis; Disease Models, Animal; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Respiratory Mucosa

Recent studies have suggested that inducible nitric oxide synthase (iNOS) plays a role in the development of asbestos-related pulmonary disorders. The pulmonary reactions of rats and hamsters upon exposure to asbestos fibers are well known to be disparate. In addition, in vitro experiments have indicated that mononuclear phagocytes from hamsters, in contrast to those from rats, lack the iNOS pathway. Therefore, the purpose of this study was to investigate whether rats and hamsters differ in lung iNOS expression in vivo upon exposure to asbestos fibers and whether differences in iNOS induction are associated with differences in the acute pulmonary inflammatory reaction. Body weight, alveolar-arterial oxygen difference, differential cell count in bronchoalveolar lavage fluid, total protein leakage, lung myeloperoxidase activity and lipidperoxidation, wet/dry ratio, iNOS mRNA and protein expression, and nitrotyrosine staining of lung tissue were determined 1 and 7 days after intratracheal instillation of asbestos fibers in CD rats and Syrian golden hamsters. Exposure of rats to asbestos fibers resulted in enhanced pulmonary iNOS expression and nitrotyrosine staining together with an acute inflammation that was characterized by an influx of neutrophils, enhanced myeloperoxidase activity and lipid peroxidation, damage of the alveolar-capillary membrane, edema formation, and impairment of gas exchange. In comparison, instillation of asbestos fibers in hamsters resulted in a significantly milder inflammatory reaction of the lung with no induction of iNOS in pulmonary cells. The data obtained provide important information to understand the underlying mechanisms of species differences in the pulmonary response upon exposure to asbestos fibers.

Topics: Animals; Asbestos, Crocidolite; Asbestosis; Body Weight; Bronchoalveolar Lavage Fluid; Cell Count; Cricetinae; Disease Models, Animal; Inhalation Exposure; Intubation, Intratracheal; Lung; Mesocricetus; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxygen; Peroxidase; Rats; RNA, Messenger; Species Specificity; Thiobarbituric Acid Reactive Substances; Tyrosine

The evaluation of the toxicity of mineral fibres has been tried to achieve in experimental animal models. However, the appearance of fibres in the pleural space could not be explained satisfactorily. Histomorphological examinations showed that intratracheal instillation of asbestos fibres leads to parabronchial and intraalveolar granulomatous tissue reactions and bronchial epithelial regenerations. For further elucidation of the pathogenesis of lung cancer and of mesothelioma the localisation and transport of inhaled fibres is of high interest. Thus, a three dimensional visualization of the structure of rat lungs before and after intratracheal instillation of UICC crocidolite fibres was performed by plastic casts to follow the way of asbestos fibres in the lung tissues and the pleura. The casts allowed to demonstrate airway structures with imprints of epithelial cells and blood vessels of normal and treated animals by scanning electron microscopy. Instilled asbestos fibres transformed bronchial structures and resulted in cystic deformations of the pleural surface. The penetration of single fibres through bronchial trunks and the visceral pleura could be shown for the first time in a three-dimensional topography of the affected tissue. Now, there is support for similar results of histomorphological examinations indicating the possibility that asbestos fibres could penetrate the pleura and migrate into the pleural space. The question if the migration of fibres is a mechanical movement or an active transport is still under discussion.

Topics: Animals; Asbestos, Crocidolite; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Lung; Male; Microscopy, Electron, Scanning; Mineral Fibers; Rats; Rats, Sprague-Dawley; Rats, Wistar; Specific Pathogen-Free Organisms; Trachea

Epidemiological reports have indicated that occupational exposure to asbestos and smoking may greatly increase the incidence of lung carcinoma. In this study rats were injected intratracheally with crocidolite or benzo(a)pyrene [B(a)P] only, and crocidolite plus B(a)P in combination. The incidence of lung carcinomas in crocidolite group was 6.4% (3/47), in B(a)P group 10.4% (5/48) and crocidolite plus B(a)P group 46.3% (25/54). Besides, the survival curve and the mean survival time of rats with carcinoma dropped distinctly. Significant difference was shown among the crocidolite plus B(a)P group, crocidolite and B(a)P groups (P < 0.005). The result indicated the synergetic effect of crocidolite and B(a)P on the development of lung carcinoma in rats and the importance of giving up smoking in the people exposed to asbestos. A model of lung carcinoma in rat was successfully prepared for further study in experiment on treatment, prevention and mechanism.

Topics: Animals; Asbestos, Crocidolite; Benzo(a)pyrene; Carcinogens; Cocarcinogenesis; Disease Models, Animal; Lung Neoplasms; Rats; Rats, Wistar; Smoking

This work presents the results of the test performed on rats to evaluate the carcinogenic effect of 4 synthetic amphiboles compared to that of the natural amphibole--crocidolite. The dose of the magnesium amphibole (Na2Mg6Si8(OH)2) administered to the animals contained 240 x 10(6) respirable fibres; the corresponding value for the nickel amphibole (Na2Ni6Si8O22(OH)2) was 339 x 10(6), for the cobalt amphibole (Na2Co6Si8O22(OH)2)--1000 x 16(6) for the geranium amphibole (Na2Mg6Ge8(OH)2)--250 x 10(6), and of the natural crocidolite amphibole (Na2Fe2Fe3Si8O22(OH)2) x 380 x 10(6) respirable fibres. The control animals (rats) received physiological NaCl solution. The number of peritoneal mesotheliomas following single intraperitoneal administration of 20 mg of the dust was adapted to be the measure of the carcinogenic activity of the dust. 3 synthetic (magnesium, cobalt and nickel) amphiboles and crocidolite caused development of malignant peritoneal mesothelioma in 11.1% to 71% rats. The results show that there is a relationship between the chemical composition of the synthetic amphiboles and their carcinogenic effect. Out of 4 investigated synthetic amphiboles, the magnesium amphibole, which contained magnesium and silicon, displayed most severe carcinogenic effect. The synthetic amphiboles containing either silicon and cobalt or silicon and nickel displayed 8.3 and 6.2 times weaker ability to induce peritoneal mesothelioma.

Topics: Animals; Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Cobalt; Disease Models, Animal; Female; Injections, Intraperitoneal; Magnesium; Male; Mesothelioma; Nickel; Peritoneal Neoplasms; Rats; Rats, Wistar

We have studied the effects of in vivo asbestos exposure on the surface immune-associated (Ia) antigen expression and distribution of alveolar macrophage subpopulations defined by continuous iso-osmotic Percoll gradients (density range: 1.006 to 1.123 g/ml) using a rat model of asbestos inhalation. Two groups of rats were exposed by intermittent inhalation (6 hr/day for 5 days/week over 4 weeks) to either amphibole (crocidolite) or serpentine (chrysotile) asbestos. A group of control rats was sham-exposed to clean air only. Alveolar macrophages from rats of three groups were obtained by bronchoalveolar lavage. During exposure, distinct differences appeared within 7 days of asbestos exposure, and some of these findings persisted in the crocidolite-exposed group for as long as 2 to 5 months after the cessation of exposure. Furthermore, relatively greater proportions of Ia-antigen positive cells were detected in several density fractions obtained from both asbestos-exposed groups (especially the crocidolite-exposed group). Multinucleated alveolar macrophages were seen frequently in all Percoll fractions after both types of asbestos inhalation. A significant proportion of multinucleated alveolar macrophages in these fractions expressed surface Ia-antigen positivity. The finding of enriched numbers of higher-density phagocytes in bronchoalveolar lavage cell subpopulations from asbestos-exposed rats may reflect the presence of newly recruited-immature monocytes and/or macrophages at sites of intrapulmonary asbestos deposition. Also, increased proportions of Ia-antigen positive cells suggest that a part of them were functionally activated.

Topics: Administration, Inhalation; Animals; Asbestos; Asbestos, Crocidolite; Asbestos, Serpentine; Asbestosis; Centrifugation, Density Gradient; Disease Models, Animal; Histocompatibility Antigens Class II; Macrophages, Alveolar; Male; Rats; Rats, Inbred F344

Several in vitro studies suggest the involvement of active oxygen metabolites in cell damage caused by asbestos. To determine if lung injury, inflammation, and asbestosis could be inhibited in vivo in a rapid-onset, inhalation model of disease, a novel method of chronic administration of antioxidant enzymes was developed. In brief, Fischer 344 rats were treated with polyethylene glycol-conjugated (PEG-) superoxide dismutase or catalase in osmotic pumps over a 10-day (5 days/wk for 2 wk) or 20-day (5 days/wk for 2 wk) period of exposure to crocidolite asbestos. Control rats included sham-exposed animals and those exposed to asbestos but receiving chemically inactivated enzymes. After 10 days of exposure to asbestos, lactic dehydrogenase (LDH), alkaline phosphatase, and total protein in bronchoalveolar lavage (BAL) were measured in one group of rats. Total and differnetial cell counts in BAL also were assessed. After 20 days of exposure, lungs of an additional group of rats were evaluated by histopathology and by measurement of hydroxyproline. Asbestos-associated elevations in LDH, protein, and total cell numbers in BAL were reduced in rats receiving PEG-catalase. Decreases in numbers of alveolar macrophages, polymorphonuclear leukocytes, and lymphocytes occurred in these animals. Exposure to asbestos for 20 days caused significant increases in both the amount of hydroxyproline in lung and the severity and extent of fibrotic lesions as determined by histopathology. These indicators of asbestosis were inhibited in a dosage-dependent fashion in rats receiving PEG-catalase. Use of inactivated PEG-catalase failed to boost serum levels of catalase and did not inhibit asbestos-induced elevation of hydroxyproline in lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Asbestos; Asbestos, Crocidolite; Asbestosis; Bronchoalveolar Lavage Fluid; Catalase; Disease Models, Animal; Hydroxyproline; Lung; Male; Polyethylene Glycols; Pulmonary Fibrosis; Rats; Rats, Inbred F344; Superoxide Dismutase