Inflammatory proteins in nasal lavage of workers exposed to occupational agents.

BACKGROUND: Low-molecular-weight (LMW) and high-molecular-weight (HMW) agents have been recognized as causes of occupational rhinitis (OR). Immunological mechanisms underlying OR differ according to the type of exposure. While HMW agents act mainly through IgE-mediated mechanisms, LMW agents appear to act through both immunological and non-immunological mechanisms. OBJECTIVE: The objective of this study was to identify potential differences in the upper airways inflammatory response after exposure to LMW and HMW agents by specific inhalation challenge test (SIC). METHODS: Nasal lavage (NL) samples from 20 subjects who were exposed to HMW (n = 10, Group I) and LMW (n = 10, Group II) at their workplaces were collected after SIC with control and specific occupational agents. These samples were analysed for 47 inflammatory markers using multiplex bead technology. RESULTS: After exposure to specific agent, Group I exhibited higher concentrations of the following proteins compared to Group II: fibrinogen (median (interquartile range) Group I: 0.09 (0.00) µg/mL, Group II: 0.04 (0.05) µg/mL, P = .05); haptoglobin (Group I: 0.86 (0.01) µg/mL, Group II: 0.14 (0.20) µg/mL, P = .02); vascular cell adhesion molecule-1 (VCAM-1) (Group I: 0.34 (0.67) ng/mL, Group II: 0.11 (0.11) ng/mL, P = .01); vascular endothelial growth factor (VEGF) (Group I: 157.0 (154.0) pg/mL, Group II: 98.0 (20.25) pg/mL, P = .01); and vitamin D (VDBP) (Group I: 0.06 (0.13) µg/mL, Group II: 0.03 (0.03) µg/mL, P = .04). No statistically significant differences in proteins profiles were observed between the groups after exposure to control agent. Also, subjects exposed to HMW agents showed a significant increase in NL levels of C-reactive protein compared to control-day exposure. CONCLUSIONS AND CLINICAL RELEVANCE: Exposure to HMW and LMW agents by SIC induced a differential nasal airway response including acute-phase reactants proteins (fibrinogen, haptoglobin and CRP), cell adhesion molecules (VCAM-1), endothelial growth factors (VEGF) and VDBP.

Inhalation vs. aspiration of single-walled carbon nanotubes in C57BL/6 mice: inflammation, fibrosis, oxidative stress, and mutagenesis.

Nanomaterials are frontier technological products used in different manufactured goods. Because of their unique physicochemical, electrical, mechanical, and thermal properties, single-walled carbon nanotubes (SWCNT) are finding numerous applications in electronics, aerospace devices, computers, and chemical, polymer, and pharmaceutical industries. SWCNT are relatively recently discovered members of the carbon allotropes that are similar in structure to fullerenes and graphite. Previously, we (47) have reported that pharyngeal aspiration of purified SWCNT by C57BL/6 mice caused dose-dependent granulomatous pneumonia, oxidative stress, acute inflammatory/cytokine responses, fibrosis, and decrease in pulmonary function. To avoid potential artifactual effects due to instillation/agglomeration associated with SWCNT, we conducted inhalation exposures using stable and uniform SWCNT dispersions obtained by a newly developed aerosolization technique (2). The inhalation of nonpurified SWCNT (iron content of 17.7% by weight) at 5 mg/m(3), 5 h/day for 4 days was compared with pharyngeal aspiration of varying doses (5-20 microg per mouse) of the same SWCNT. The chain of pathological events in both exposure routes was realized through synergized interactions of early inflammatory response and oxidative stress culminating in the development of multifocal granulomatous pneumonia and interstitial fibrosis. SWCNT inhalation was more effective than aspiration in causing inflammatory response, oxidative stress, collagen deposition, and fibrosis as well as mutations of K-ras gene locus in the lung of C57BL/6 mice.

Genetic susceptibility to progressive massive fibrosis in coal miners.

Progressive massive fibrosis (PMF) is a chronic interstitial lung disease with a complex aetiology that can occur after cumulative dust exposure. A case-control study was conducted to test the hypothesis that single nucleotide polymorphisms (SNPs) within genes involved in inflammatory and fibrotic processes modulate the risk of PMF development. The study population consisted of 648 underground coal miners participating in the National Coal Workers Autopsy Study, of which 304 were diagnosed with PMF. SNPs that influence the regulation of interleukin (IL)-1, IL-6, tumour necrosis factor-alpha, transforming growth factor-beta1, vascular endothelial growth factor (VEGF), epidermal growth factor intercellular cell adhesion molecule (ICAM)-1 and matrix metalloproteinase-2 genes were determined using a 5'-nuclease real-time PCR assay. There were no significant differences in the distribution of any individual SNP or haplotype between the PMF and control groups. However, the polygenotype of VEGF +405/ICAM-1 +241/IL-6 -174 (C-A-G) conferred an increased risk for PMF (odds ratio 3.4, 95% confidence interval 1.3-8.8). The present study suggests that the examined genetic variations that help regulate inflammatory and fibrotic processes are unlikely to strongly influence susceptibility to this interstitial lung disease, although the role of vascular endothelial growth factor, intercellular cell adhesion molecule-1 and interleukin-6 polymorphisms in the development of progressive massive fibrosis may require further investigation.

Lack of association between antioxidant gene polymorphisms and progressive massive fibrosis in coal miners.

BACKGROUND: Oxidative stress plays a major role in the pathogenesis of interstitial lung diseases. The antioxidant enzymes glutathione S-transferases (GST) and manganese superoxide dismutase (MnSOD) are important components of lung defence against oxidative stress, and polymorphisms in the genes which regulate their expression may represent important disease modifiers. METHODS: A matched case-control study was conducted to determine the influence of the GSTP1, GSTT1 and MnSOD polymorphisms on susceptibility to progressive massive fibrosis (PMF). Seven hundred ex-coal miners were included in the study; 350 were classified as PMF cases while 350 with a similar underground mining tenure but no clinical or histological evidence of lung disease served as controls. Genotype analysis was performed on genomic DNA, using a 5' nuclease PCR assay. RESULTS: None of the individual investigated polymorphisms and two-way gene-gene interactions had a statistically significant association with PMF. CONCLUSION: The results of this study suggest that polymorphic genotypes within the GST gene cluster and MnSOD do not affect individual susceptibility to PMF.

Gender-dependent immunosuppression following subacute exposure to fumonisin B1.

The effects of fumonisin B1 (FB1), a mycotoxin produced by Fusarium lertcillioides, on the immune system are controversial; FB1 exposure causing immunosuppression in poultry, swine, bovine and rodents species and immunostimulation in rodent species. The current study was conducted to examine the effects of FB1 on the immune system of BALB/c mice and to determine if there is sex specificity. Female and male mice (five per group) received five daily subcutaneous (s.c.) injections of 2.25 mg/kg/day of FB1, on the following day tissues were collected for immunological examinations. FB1 treatment dramatically reduced relative spleen and thymus weights in females, whereas there was no effect on organ weights in males. Exposure to FB1 reduced splenic cellularity and the basal rate of lymphocyte proliferation in females only. In addition, phytohemagglutinin (PHA-P)-induced T-lymphocyte and LPS-induced B-lymphocyte proliferation were reduced in female mice. Splenocytes from female mice exposed to FB1 showed a reduced expression of interleukin-2 mRNA. These changes occurred in the absence of alterations in tumor necrosis factor alpha or interleukin-1beta mRNA expression. Phenotypic analysis indicated that FB treatment caused a relative increase in the T-lymphocyte population in the spleen of female mice only. In contrast, FB1 dramatically reduced the immature CD4+/CD8+ double positive cell population in the thymus of females. No changes were evident in the thymocyte populations of male mice treated with FB1. The results of this study indicate that FB1 is immunosuppressive in mice; the magnitude of FB1-induced immunosuppression is highly dependent on sex, females being more susceptible than males.

The effect of exposure to a commercial 2,4-D herbicide formulation during gestation on urethan-induced lung adenoma formation in CD-1 mice.

Female CD-1 mice were exposed to a commercial amine formulation of 2,4-dichlorophenoxyacetic acid (2,4-D) on days 6-16 of gestation in drinking water at concentrations ranging from 0 to 1.0% of the formulated product, equivalent to approximately 0-650 mg/kg/d expressed as the amine derivative. The effect of 2,4-D on urethan-induced pulmonary adenoma formation was evaluated in female offspring 19 w after birth. Urethan-induced sleeping times observed following ip injection of 1.5 mg urethan/g bw 7 w after birth were not altered by 2,4-D (p = 0.10), indicating that 2,4-D did not affect the rate of urethan elimination. 2,4-D exposure did not affect the number of tumors produced (p = 0.58), but did reduce the mean tumor diameter in the highest dose group (p < 0.01). This minor antineoplastic activity of 2,4-D may be related, in part, to inhibitory effects of 2,4-D on various enzymatic or metabolic pathways, essential for cellular growth and tissue development. Since exposure to 2,4-D during pregnancy had little impact of tumor production, it is unlikely that persistent alteration to developing immune cells involved in the cell-mediated immunosurveillance mechanisms occurred. The subtle alteration in tumor size and the mild impairment of growth in the offspring were observed almost exclusively in the highest treatment group. Since this level of exposure is well in excess of those associated with normal application of 2,4-D, the hazard to non-target mammalian populations appears minimal.

Increased production of proinflammatory cytokines by murine macrophages following oral exposure to sodium selenite but not to seleno-L-methionine.

Selenium (Se) is an essential as well as a toxic trace element in animal and human nutrition. The immune system is a known target of Se intoxication. The objectives of the present study were to determine the effects of oral exposure to inorganic and organic forms of Se on the murine immune system and to compare the relative toxicity of the different chemical forms. Male BALB/c mice, 6-7 weeks of age, were exposed continuously to 0, 1, 3 or 9 ppm of Se as sodium selenite or seleno-L-methionine in the drinking water for 14 days. Following the treatment period mice were euthanized; trunk blood, spleen, thymus, liver and kidney were aseptically collected and organs weighed. Single-cell splenocyte cultures were made from the spleens and used to determine the effects of Se treatment on mitogen-induced lymphocyte blastogenesis and cytokine production. There were no changes in the 0 and 1 ppm Se groups as selenite. The thymus/body weight ratio was significantly reduced at 3 ppm Se as sodium selenite, and all other parameters remained unaffected. Exposure to 9 ppm of Se as sodium selenite resulted in marked decrease in body weight gain and relative organ weights. Treatment of mice with 9 ppm Se as sodium selenite increased erythrocyte counts in peripheral blood, reduced splenic cellularity, but increased the basal rate of splenocyte proliferation and induced a dose-dependent increase in phytohemagglutinin-P-induced lymphocyte proliferation. Sodium selenite at this dose increased the production of proinflammatory cytokines, tumor necrosis factor alpha and interleukin-1 beta, in lipopolysaccharide-stimulated splenic macrophages. Mice exposed to Se as seleno-L-methionine in the drinking water did not display any effects on the parameters examined at the dose range in this study. Results indicated that splenic macrophages and lymphocytes are sensitive to Se intoxication and there is a disparity in the immune system toxicity of inorganic and organic forms of Se administered via the drinking water, inorganic Se being more toxic.

Increase in dopamine metabolites in murine striatum after oral exposure to inorganic but not organic form of selenium.

Selenium (Se) is an essential as well as a toxic trace element. Se intoxication has been reported in both livestock and humans. The central nervous system is sensitive to Se poisoning; exposure to Se causes blind staggers in cattle, poliomyelomalacia in pigs, and nervous system disorders in humans. Differences in neurotoxicity between inorganic and organic Se have been demonstrated. In this study, groups of five male BALB/c mice each were administered sodium selenite or selenomethionine in drinking water ad libitum at 0, 1, 3, and 9 ppm as Se for 14 days. At the end of Se exposure, their brains were removed and dissected into different regions. The concentration of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), and 5-hydroxyindolacetic acid (5-HIAA) were determined in each brain region. Food and water consumption and body weight gain were significantly decreased in the group treated with the highest concentration of sodium selenite. In mice administered sodium selenite at 3 and 9 ppm, DOPAC was significantly higher in the striatum than in the control group. The striatal HVA was also increased in the group treated with 3 ppm Se; the DA showed a similar pattern, but the increase was not statistically significant. No alterations of NE, 5-HT, or 5-HIAA levels were detected in any brain region of mice treated with sodium selenite. No significant differences in any parameter among the groups treated with selenomethionine were observed indicating that inorganic Se was more neurotoxic than organic Se via drinking water. The alterations of DA metabolites by inorganic Se in DA-rich striatum suggested a Se-specific increased neural activity of dopaminergic pathways. Results may be useful in further elucidation of neurotoxicity of Se and in establishing a safe level of intake for this element.

Pre and post-amputation mobility of trans-tibial amputees: correlation to medical problems, age and mortality.

This retrospective study compares pre and post-amputation mobility and the influence of age and associated medical problems. Data from the charts of 120 male patients who underwent unilateral trans-tibial (below-knee) amputation at the Dallas Veteran's Administration Hospital between June, 1983 and October, 1991, were collected and analyzed. Mobility was assessed with a six level scale developed by Volpicelli et al. (1983). The presence of cardiac disease, pulmonary disease (COPD), peripheral vascular disease (PVD), diabetes mellitus, degenerative joint disease, blindness, cerebral vascular accident (CVA), and age are correlated with changes in mobility after amputation. Older patients had more medical problems and lower post-amputation scores Individual medical problems did not influence mobility scores, but the presence of COPD and PVD lowered pre-amputation mobility scores. Cardiac disease and diabetes mellitus influenced post-amputation mobility scores by lowering them, either together or individually. Regardless of age, however, patients with more medical problems were poor ambulators. The cause of amputation per se did not influence mobility scores.