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Biomedical subjects

L C Chen

Publications and source records attributed to L C Chen.

At least 73 records · Page 4Linked to original sources
PubMed1998

Immunotoxicologic effects of inhaled chromium: role of particle solubility and co-exposure to ozone.

Soluble and insoluble hexavalent chromium (Cr6+) agents are concomitantly released with ozone (O3) during welding. Although pulmonary/immunologic implications from exposure to each agent individually have been investigated, the effects from simultaneous exposure, as occurs under actual working conditions, are unclear. To investigate immunomodulatory effects of inhaled Cr6+, F-344 rats were exposed for 5 h/day, 5 days/week for 2 or 4 weeks to atmospheres containing soluble potassium chromate (K2CrO4) or insoluble barium chromate (BaCrO4), each alone at 360 micrograms Cr/m3 or in combination with 0.3 ppm O3. One day after the final exposure, rats were euthanized, their lungs were lavaged, and pulmonary macrophages (PAM) were recovered for assessment of basal and inducible functions. Rats inhaling K2CrO4-containing atmospheres had greater levels of total recoverable cells, neutrophils, and monocytes in bronchopulmonary lavage compared to rats exposed to insoluble Cr6+ atmospheres, O3 alone, or air; these rats also had a reduced percentage of PAM, although total PAM levels remained unaffected. Although Cr exposure-related changes in PAM functionality were evident, any dependence upon Cr solubility was variable. K2CrO4-containing atmospheres modulated PAM-inducible interleukins-1 and -6, and tumor necrosis factor-alpha production to a greater degree than those containing BaCrO4. Conversely, BaCrO4-containing atmospheres affected PAM basal nitric oxide production and interferon-gamma-primed/zymosan-stimulated reactive oxygen intermediate production to a greater extent than did those containing K2CrO4. In none of the PAM assays did co-inhalation of O3 result in a modulation of the effects obtained with either Cr6+ compound itself. The results indicate that, while immunomodulatory effects of inhaled Cr6+ upon PAM are related to particle solubility, the co-inhalation of O3 apparently does not cause further modifications of the metal-induced effects.

Administration, Inhalation↗
PubMed1998

Sulphasalazine in the treatment of children with chronic arthritis.

The aim of this study was to investigate the efficacy and toxicity of sulphasalazine (SASP) in the treatment of children with chronic arthritis. The medical records of 36 children (25 boys, 11 girls) who received SASP for the treatment of chronic arthritis were reviewed. Twenty-one patients had juvenile spondyloarthropathies (JSA) (eight juvenile ankylosing spondylitis (JAS), 13 undifferentiated JSA (uJSA) and 15 had juvenile rheumatoid arthritis (JRA). The patients received SASP therapy for a mean of 2.5 years (range 3 weeks to 8.1 years). Clinical and laboratory data were reviewed retrospectively to determine the effects of treatment. A clinically significant response occurred in 23 (64%) children: remission in 14 (39%) (JRA 5, JSA 9) and improvement (25% reduction in joint count) in nine (25%) (JRA 4, JSA 5). There was no difference in response rate between JRA and JSA patients (p = 0.11), but the time to remission was shorter in JSA patients (mean 5 months) than in JRA patients (mean 25 months) (p = 0.024). Twelve of the 36 patients discontinued non-steroidal anti-inflammatory drugs, and six of eight patients discontinued prednisolone. A significant fall in erythrocyte sedimentation rate and rise in haemoglobin occurred in SASP-treated patients (p < 0.005) comparing most recent results with pretreatment levels. Side-effects occurred in four of 36 patients (11%); only one patient who had persisting severe diarrhoea required discontinuation of SASP. It was concluded that SASP appears to be effective and safe in the treatment of JRA and JSA patients. As a second-line agent, SASP is the drug of first choice for patients with JSA; for JRA patients SASP may be a useful, possibly less toxic alternative to methotrexate.

Adolescent↗
PubMed1998

Successfully treated sulphasalazine-induced fulminant hepatic failure, thrombocytopenia and erythroid hypoplasia with intravenous immunoglobulin.

We report the simultaneous development of fulminant hepatic failure, thrombocytopenia and erythroid hypoplasia in a child treated with sulphasalazine. A 12-year-old girl with juvenile rheumatoid arthritis developed fulminant hepatic failure, thrombocytopenia and erythroid hypoplasia, which was confirmed by liver histology and bone marrow examination, 2 weeks after initiation of sulphasalazine therapy. The patient recovered after administration of high doses of intravenous immunoglobulin. This is the first reported case of the concurrent development of these complications associated with sulphasalazine hypersensitivity. The use of intravenous immunoglobulin may have helped in the treatment of this rare adverse effect of sulphasalazine.

Antirheumatic Agents↗
PubMed1998

Pulmonary and cardiovascular effects of acute exposure to concentrated ambient particulate matter in rats.

To examine the biological plausibility of the adverse health effects of ambient particulate matter (PM), we have studied the cardio-pulmonary effects of PM in an animal model of pulmonary hypertension. Normal and monocrotaline-treated rats were exposed, nose-only, for 3 h to filtered air or concentrated ambient PM. At 3 h--but not 24 h--post-exposure, the percentage of neutrophils in peripheral blood was significantly elevated in PM-exposed animals while the percentage of lymphocytes was decreased with no change in white blood cell counts. These changes in white blood cell differential occurred in both normal and monocrotaline-treated animals. Small, but consistent changes in heart rate, but not core temperature, were observed after exposure to concentrated ambient PM. Pulmonary injury, as evidenced by increased protein levels in lavage fluid, occurred only in monocrotaline-treated animals exposed to > 360 microg/m3 PM. The observed pattern of hematological and cardiac changes suggests an activation of the sympathetic stress response.

Air Pollutants↗
PubMed1998

Buffering capacity of coal and its acid-soluble Fe2+ content: possible role in coal workers' pneumoconiosis.

Epidemiological studies have shown that the prevalence of coal workers' pneumoconiosis (CWP) differed remarkably between different coal mine regions despite comparable exposures to respirable dust. In the United States, CWP was found to be most common in Pennsylvania coal miners and least common in miners from Utah. The active component(s) responsible for the regional differences in CWP has not yet been identified. In the present study, we found that coals from Pennsylvania, compared with Utah coals, showed a much lower buffering capacity as determined by the amount of acid consumed in order to reach pH 4.5, which is the pH of the phagolysosomes of macrophages. Moreover, the coals from Pennsylvania released large amounts of Fe2+ in the acidified extract, whereas the coals from Utah released little Fe2+. Using electron spin resonance (ESR), we found that the coals from Pennsylvania, but not from Utah, were effective in oxidizing formate by a radical pathway. Two coals, one from Utah with high buffering capacity and low acid-soluble Fe2+ and the other from Pennsylvania with low buffering capacity and high acid-soluble Fe2+, were then selected for cell treatment. We found that human tracheal epithelial (HTE) cells treated with the coal from Pennsylvania (10 microg/cm2) showed a 36% increase in oxidant formation over the control as detected by dichlorofluorescein assay, whereas the coal from Utah had no effect. An electrophoretic mobility shift assay was used to test the binding affinity of nuclear proteins extracted from the coal-treated HTE cells to an oxidative stress-responsive transcription factor activator protein-1 (AP-1) element. The coal from Pennsylvania with high acid-soluble Fe2+ (1 microg/cm2) activated AP-1 to the same extent as 10 microM H2O2, while the coal from Utah without acid-soluble Fe2+ had no effect. These results support our hypothesis that the prevalence of CWP may be higher in coal workers exposed to coal with high acid-soluble Fe2+ and low buffering capacity than in workers exposed to coal with low acid-soluble Fe2+ and high buffering capacity.

Buffers↗
PubMed1998

Microevolution of a standard strain of Cryptococcus neoformans resulting in differences in virulence and other phenotypes.

Cryptococcus neoformans is a major fungal pathogen for patients with debilitated immune systems. However, no information is available on the stability of virulence or of phenotypes associated with virulence for C. neoformans laboratory strains. A serendipitous observation in our laboratory that one isolate of C. neoformans ATCC 24067 (strain 52D) became attenuated after continuous in vitro culture prompted us to perform a comparative study of nine strain 24067 isolates obtained from six different research laboratories. Each isolate was characterized by DNA typing, virulence for mice, proteinase production, extracellular protein synthesis, melanin synthesis, carbon assimilation pattern, antifungal drug susceptibility, colony morphology, growth rate, agglutination titers, phagocytosis by murine macrophages, capsule size, and capsular polysaccharide structure. All isolates had similar DNA typing patterns consistent with their assignment to the same strain, although minor chromosome size polymorphisms were observed in the electrophoretic karyotypes of two isolates. Several isolates had major differences in phenotypes that may be associated with virulence, including growth rate, capsule size, proteinase production, and melanization. These findings imply that C. neoformans is able to undergo rapid changes in vitro, probably as a result of adaptation to laboratory conditions, and suggest the need for careful attention to storage and maintenance conditions. In summary, our results indicate that C. neoformans (i) can become attenuated by in vitro culture and (ii) is capable of microevolution in vitro with the emergence of variants exhibiting new genotypic and phenotypic characteristics.

Agglutination Tests↗
PubMed1998

Differential regulation of arginases and inducible nitric oxide synthase in murine macrophage cells.

Activated macrophages avidly consume arginine via the action of inducible nitric oxide synthase (iNOS) and/or arginase. In contrast to our knowledge regarding macrophage iNOS expression, the stimuli and mechanisms that regulate expression of the cytosolic type I (arginase I) or mitochondrial type II (arginase II) isoforms of arginase in macrophages are poorly defined. We show that one or both arginase isoforms may be induced in the RAW 264.7 murine macrophage cell line and that arginase expression is regulated independently of iNOS expression. For example, 8-bromo-cAMP strongly induced both arginase I and II mRNAs but not iNOS. Whereas interferon-gamma induced iNOS but not arginase, 8-bromo-cAMP and interferon-gamma mutually antagonized induction of iNOS and arginase I mRNAs. Dexamethasone, which did not induce either arginase or iNOS, almost completely abolished induction of arginase I mRNA by 8-bromo-cAMP but enhanced induction of arginase II mRNA. Lipopolysaccharide (LPS) induced arginase II mRNA, but 8-bromo-cAMP plus LPS resulted in synergistic induction of both arginase I and II mRNAs. In all cases, increases in arginase mRNAs were sufficient to account for the increases in arginase activity. These complex patterns of expression suggest that the arginase isoforms may play distinct, although partially overlapping, functional roles in macrophage arginine metabolism.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

Two functionally independent pathways for lipopolysaccharide-dependent activation of mouse peritoneal macrophages.

We have investigated the effects of human LPS-binding protein (LBP) and human bactericidal/permeability-increasing protein (BPI) on LPS-dependent activation of mouse thioglycolate-elicited peritoneal macrophages in vitro, in comparison with human PBMCs. Confirming earlier published studies, BPI inhibited, and LBP enhanced, the ability of LPS to stimulate PBMC production of the cytokines TNF-alpha and IL-6. In marked contrast to these results, under identical conditions of in vitro culture, both LBP and BPI suppressed, in a dose-dependent manner, the ability of LPS to stimulate cytokine production in mouse macrophages. Further, while human BPI also suppressed LPS-dependent NO secretion in mouse macrophages, human LBP had no inhibitory effect on NO secretion under conditions that inhibited TNF-alpha secretion. These data provide the first direct evidence that mouse macrophages may utilize two independent pathways in response to LPS, thus leading to different phenotypic responses.

Acute-Phase Proteins↗
PubMed1997

Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors.

Patients with basal cell nevus syndrome have a high incidence of multiple basal cell carcinomas, medulloblastomas, and meningiomas. Because somatic PATCHED (PTCH) mutations have been found in sporadic basal cell carcinomas, we have screened for PTCH mutations in several types of sporadic extracutaneous tumors. We found that 2 of 14 sporadic medulloblastomas bear somatic nonsense mutations in one copy of the gene and also deletion of the other copy. In addition, we identified missense mutations in PTCH in two of seven breast carcinomas, one of nine meningiomas, and one colon cancer cell line. No PTCH gene mutations were detected in 10 primary colon carcinomas and eighteen bladder carcinomas.

Amino Acid Sequence↗
PubMed1997

Formation of intracellular free radicals in guinea pig airway epithelium during in vitro exposure to ozone.

In vivo exposure to ozone (O3) has been shown to cause airway epithelial damage and lipid peroxidation. The oxidation of polyunsaturated fatty acids has been shown to produce hydrogen peroxide and aldehydes with reactive oxygen species (ROS) as intermediates. These products of ozonation may react with other bioorganic molecules and cause cellular damage. To assess the production of ROS, confluent primary cultures of guinea pig airway epithelial cells were grown on Costar membrane with a liquid-air interface and exposed to 0.2, 0.4, and 0.6 ppm O3. The concentrations of intracellular ROS during the exposure were monitored using the fluorescent dye dihydrorhodamine-123. The intracellular concentration of ROS increased immediately upon the commencement of the O3 exposure and persisted until the end of the exposure period (up to 1 hr). The concentration of ROS increased with increasing O3 concentration. To determine the species of ROS produced during O3 exposure, airway epithelial cells were perfused with dimethyl sulfoxide (DMSO), sodium formate (hydroxyl radical scavengers), NaN3 (catalase inhibitor), or diethyl-dithio carbamate (DEDC, superoxide dismutase inhibitor) prior to and during the exposure period and the fluorescent intensity was monitored continuously. While both DMSO and sodium formate decreased the concentration of ROS, DEDC and NaN3 had no effect. We concluded that hydroxyl radicals instead of H2O2 or superoxide anions were produced immediately following the commencement of O3 exposure in guinea pig airway epithelial cells in an exposure concentration-dependent fashion.

Animals↗
PubMed1997

Influence of acid aerosol droplet size on structural changes in the rat lung caused by acute exposure to sulfuric acid and ozone.

To investigate whether aerosol droplet size influences structural changes in the lung produced by short-term, concomitant exposure to ozone and sulfuric acid, groups of 10 rats were exposed 4 hr/day for 2 days to filtered air, 0.6 ppm ozone, 0.5 mg/m3 fine (aerosol mass median diameter (MMD) = 0.3 microm) or ultrafine (MMD = 0.06 microm) sulfuric acid, or a mixture of ozone and 0.5 mg/m3 fine or ultrafine sulfuric acid. The volume percentage of total parenchyma containing markedly to severely injured alveolar septae was measured morphometrically. There were no differences between the ultrafine or fine acid exposure groups and the sham group for any of the morphologic endpoints. Volume percentage of markedly to severely injured tissue was increased in the ultrafine, but not fine, mixture animals when compared with the ozone-only group. In addition, a synergistic interaction between ozone and ultrafine, but not fine, sulfuric acid was found for this endpoint. The bromodeoxyuridine cell labeling index in the periacinar region was greater in the rats exposed to the fine sulfuric acid and ozone mixture than that in rats exposed to ozone alone, and a synergistic interaction between ozone and fine sulfuric acid was found for this end point. None of the exposures produced any changes in ventilatory parameters. Thus, acid aerosol droplet size was found to influence the effect of sulfuric acid in modifying ozone-induced structural changes in the rat lung.

Administration, Inhalation↗
PubMed1997

Comparison of inflammatory lung responses in Wistar rats and C57 and DBA mice following acute exposure to cadmium oxide fumes.

Inhalation of cadmium oxide (CdO) is a significant form of human exposure to cadmium (Cd). Furthermore, there is epidemiological and experimental data relating Cd inhalation with lung cancer. Animal studies indicate that rats are more susceptible to Cd-induced lung cancer than mice, but interstrain sensitivity differences to Cd-induced pulmonary inflammation or carcinogenesis have not been addressed in either species. We compared pulmonary inflammatory processes in Wistar Furth (WF) rats with those in C57 and DBA mice exposed to freshly generated CdO fumes in nose-only inhalation chambers. Animals were exposed to 1 mg Cd/m3 for 3 hr and terminated immediately or 1, 3, and 5 days after exposure. Control animals were exposed to air/argon furnace gases. Cd-induced lung injury was assessed by bronchoalveolar lavage fluid (BALF) analyses, histopathology, and immunohistochemical detection of cell proliferation. Inhalation of CdO resulted in pulmonary inflammatory processes that varied widely across species and strains. C57 mice responded with faster and greater influx of neutrophils and proliferation of alveolar macrophages, type II epithelial cells, and bronchiolar epithelial cells compared to DBA mice or WF rats. DBA mice retained a greater percentage of inhaled Cd in the lungs and presented higher levels of BALF protein than C57 mice or rats. In comparison to mice, WF rats responded with a more transient inflammatory response in BALF parameters and higher degree of acute inflammation in lung tissue. The more pronounced proliferation of alveolar and bronchiolar epithelial cells observed in C57 mice might indicate higher susceptibility of this mice strain to Cd-induced lung carcinogenesis compared to DBA mice or WF rats. Furthermore, the present results of fewer inflammatory cells and lower proliferation of epithelial cells in DBA mice in association with our previous observation of higher Cd-induced metallothionein protein in this strain suggest that DBA might be less susceptible to the pulmonary carcinogenic effects of inhaled Cd than C57 mice or WF rats. We conclude that mice might not necessarily be more resistant than rats to the carcinogenic effects of inhaled Cd, since intraspecies susceptibility differences are strongly suggested by the present data. An extrapolation of this conclusion is that genetic variations in the human population may determine individual sensitivity differences to inhaled Cd.

Administration, Inhalation↗
PubMed1997

Metal fume fever: characterization of clinical and plasma IL-6 responses in controlled human exposures to zinc oxide fume at and below the threshold limit value.

Results from animal and preliminary human exposure studies have called into question whether the 5 mg/m3 8-hour time-weighted average threshold limit value (TLV) for zinc oxide fume is sufficient to protect workers against metal fume fever. The objectives of this study were to determine the clinical effects of exposures to low concentrations of zinc oxide and to ascertain whether these exposures elevated circulating levels of specific cytokines, which could account for the symptoms of the metal fume fever syndrome. Thirteen resting naive subjects inhaled, on separate days, air and 2.5 and 5 mg/m3 of furnace-generated zinc oxide fume for 2 hours. Subjects recorded symptoms and temperature and had blood drawn before and after each exposure. The mean (+/- SE) maximum rise in oral temperature at 6 to 12 hours after exposure was 1.4 +/- 0.3 degrees F after 5 mg/m3, compared with 0.6 +/- 0.5 degrees F after air exposure (P < 0.05). Mean temperature was also elevated after exposure to 2.5 mg/m3 zinc oxide (1.2 +/- 0.3 degrees F). In a parallel fashion, plasma levels of interleukin 6 (IL-6), a pyrogen, were significantly elevated after exposure to 5 mg/m3 zinc oxide. Mean IL-6 values (pg/mL) at pre-exposure and at 3 and 6 hours post-exposure were 1.9 (+/- 0.6), 2.8 (+/- 0.7), and 2.9 (+/- 0.6), respectively, on the air day and 1.6 (+/- 0.6), 4.4 (+/- 1.2), and 6.4 (+/- 1.1) on the 5 mg/m3 zinc oxide day. Zinc oxide exposure did not significantly affect plasma levels of tumor necrosis factor. Total symptom scores peaked 9 hours after the 5 mg/m3 zinc oxide exposure. Myalgias, cough, and fatigue were the predominant symptoms reported. Inhalation of zinc oxide for 2 hours at the current TLV of 5 mg/m3 produces fever and symptoms along with elevation in plasma IL-6 levels.

Adult↗
PubMed1997

Extracellular proteins of Cryptococcus neoformans and host antibody response.

Proteins secreted by the fungal pathogen Cryptococcus neoformans may be involved in invasion and could be useful in vaccine design. Despite the medical importance of this fungus, little is known about its extracellular proteins or the immune response to these antigens. To study C. neoformans extracellular proteins, 12 strains were metabolically radiolabeled and protein supernatants were analyzed. Both strain- and growth condition-dependent differences were observed. Enzymatic assays of filtered culture supernatants revealed butyrate esterase and caprylate esterase lipase activity for 11 of 12 strains, as well as acid phosphatase, naphthol-AS-BI-phosphohydrolase, and beta-glucosidase activities in some strains. Serum from infected rodents immunoprecipitated several secreted proteins, consistent with in vivo expression and development of an antibody response. For strain 24067, two immunodominant species, of approximately 75 and 30 kDa, were recognized. The relative intensity of the autoradiographic bands depended on the route of infection for both rats and mice. In summary, our results indicate that (i) there are multiple proteins in C. neoformans culture supernatants, (ii) there are strain differences in supernatant protein profiles, (iii) there are differences in supernatant protein profile depending on the growth conditions, (iv) there are several new extracellular and/or cell-associated enzymatic activities, and (v) antibodies to several supernatant proteins are made in the course of infection.

Acid Phosphatase↗
PubMed1997

Ozone-induced IL-8 expression and transcription factor binding in respiratory epithelial cells.

Ozone, one of the most reactive oxidant gases to which humans are routinely exposed, induces inflammation in the lower airways. The airway epithelium is one of the first targets that inhaled ozone will encounter, but its role in airway inflammation is not well understood. Expression of inducible genes involved in the inflammatory response, such as interleukin (IL)-8, is controlled by transcription factors. Expression of the IL-8 gene is regulated by the transcription factors nuclear factor (NF)-kappaB, NF-IL-6, and possibly activator protein-1 (AP-1). Type II-like epithelial cells (A549) were grown on a collagen-coated membrane and exposed in vitro to 0.1 ppm ozone or air. Exposure to ozone induced DNA-binding activity of NF-kappaB, NF-IL-6, and AP-1. IL-8 mRNA and IL-8 protein levels were also increased after ozone exposure. These results link ozone-induced DNA-binding activity of transcription factors and the production of IL-8 by epithelial cells thus demonstrating a potential cellular cascade resulting in the recruitment of inflammatory cells into the airway lumen.

CCAAT-Enhancer-Binding Proteins↗