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.

Evidence of non-mean-field-like low-temperature behavior in the Edwards-Anderson spin-glass model.

The three-dimensional Edwards-Anderson and mean-field Sherrington-Kirkpatrick Ising spin glasses are studied via large-scale Monte Carlo simulations at low temperatures, deep within the spin-glass phase. Performing a careful statistical analysis of several thousand independent disorder realizations and using an observable that detects peaks in the overlap distribution, we show that the Sherrington-Kirkpatrick and Edwards-Anderson models have a distinctly different low-temperature behavior. The structure of the spin-glass overlap distribution for the Edwards-Anderson model suggests that its low-temperature phase has only a single pair of pure states.

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.

Serum and BAL cytokine and antioxidant enzyme levels at different stages of pneumoconiosis in coal workers.

Coal workers' pneumoconiosis (CWP) is an occupational pulmonary disease that occurs by chronic inhalation of coal dust. CWP is divided into two stages depending on the extent of the disease, as simple pneumoconiosis (SP) and progressive massive fibrosis (PMF). In the present study, serum and bronchoalveolar lavage (BAL) cytokine (interleukin-1beta [IL-1beta], IL-6, tumor necrosis factor-alpha [TNF-alpha], transforming growth factor-beta [TGF-beta]) and antioxidant enzymes levels, their relation with the disease severity, and whether they can be considered as biological markers were investigated. Serum and BAL levels of IL-1beta, IL-6, and TNF-alpha were higher in SP and PMF patient groups compared with that in active and retired miner groups. Serum and BAL IL-1beta, IL-6, and TNF-alpha levels were also found to be higher in patients with PMF compared with the SP group. BAL superoxide dismutase (SOD), glutathione peroxidase, and catalase levels and serum SOD level were increased in both patient groups compared with the control group. In addition, mean serum and BAL TGF-beta levels were found to be increased in patients with SP compared with PMF group. Based on these results, BAL and serum cytokine and antioxidant enzymes levels were evaluated and discussed as potential biomarkers for different stages of CWP.

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.

Interleukin-6 treatment augments cutaneous wound healing in immunosuppressed mice.

It has been postulated that the inflammatory response that occurs after cutaneous wounding is a prerequisite for healing and that inflammatory cytokines, such as interleukin-6 (IL-6) are involved in this process. We showed previously that IL-6-deficient mice display delayed wound healing, which could be reversed by administration of a murine IL-6 expression plasmid or recombinant murine IL-6 (rMuIL-6). In the present study, we observed that delayed cutaneous wound healing, which occurs as a result of glucocorticoid-induced immunosuppression, can also be reversed by rMuIL-6, as evidenced by epithelialization, granulation tissue formation, and wound closure. In vehicle control mice, rMuIL-6 did not augment healing but rather delayed the process. Immunochemical studies indicated that the expression of matrix metalloproteinase-10 (MMP-10) was increased in dexamethasone-treated mice and that rMuIL-6 treatment reduced its expression, indicating that IL-6 may influence dermal matrix formation and, specifically, collagen synthesis. These results demonstrate that IL-6 can restore abnormal wound repair that occurs in immunodeficiency and suggest its use as a potential therapy.

Role of inflammation in chemical-induced hepatotoxicity.

The liver, which is the major organ responsible for the metabolism of drugs and toxic chemicals, is also the primary target organ for many toxic chemicals. Increasing evidence has indicated that inflammatory processes are intimately involved in chemical-induced hepatotoxic processes, and like other inflammatory diseases, such as autoimmunity, are responsible for producing mediators that can effect liver damage or repair. This review will summarize our current understanding of how inflammatory processes influence hepatic pathology and repair following exposure to established hepatotoxic chemicals including carbon tetrachloride, an industrial chemical, and acetaminophen, a widely used analgesic.

Association of tumor necrosis factor-alpha and interleukin-1 gene polymorphisms with silicosis.

Silicosis, an interstitial lung disease prevalent among miners, sand blasters, and quarry workers, is manifested as a chronic inflammatory response leading to severe pulmonary fibrotic changes. Proinflammatory cytokines, such as TNFalpha and IL-1, produced in the lung by type II epithelial cells and alveolar macrophages, have been strongly implicated in the formation of these lesions. Recently, a number of single nucleotide polymorphisms (SNPs), which quantitatively affect mRNA synthesis, have been identified in the TNFalpha promoter and IL-1 gene cluster and their frequency is associated with certain chronic inflammatory diseases. To assess the role of these SNPs in silicosis, we examined their frequency in 325 ex-miners with moderate and severe silicosis and 164 miners with no lung disease. The odds ratio of disease for carriers of the minor variant, TNFalpha (-238), was markedly higher for severe silicosis (4.0) and significantly lower for moderate silicosis (0.52). Regardless of disease severity, the odds ratios of disease for carriers of the IL-1RA (+2018) or TNFalpha (-308) variants were elevated. There were no significant consistent differences in the distribution of the IL-1alpha (+4845) or IL-1beta (+3953) variants with respect to disease status. In addition, several significant gene-gene and gene-gene-environment interactions were observed. Different associations between moderate cases and controls versus severe cases and controls were also observed in a number of these multigene comparisons. These studies suggest that gene-environment interactions involving cytokine polymorphisms play a significant role in silicosis by modifying the extent of and susceptibility to disease.

Polymorphisms of the IL-1 gene complex in coal miners with silicosis.

BACKGROUND: Silicosis is characterized by fibrosing nodular lesions that eventually develop into progressive pulmonary fibrosis. Pro-inflammatory cytokines, such as interleukin-1 (IL-1), play a key role in the development of silicosis by regulating mediators which are responsible for lung injury, inflammation, and potentially fibrosis. To study whether functional single nucleotide polymorphisms (SNPs) located in the regulatory elements of genes coding for the IL-1alpha, IL-1beta, and IL-1 receptor antagonist (RA) cytokines are associated with silicosis, we examined 318 Caucasian cases confirmed histopathologically with pulmonary silicosis and 163 controls without any apparent inflammation or other pulmonary disease. METHODS: Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: The proportion of the IL-1RA (+ 2018) allele 2 genotype was increased in miners with silicosis (0.27) compared to controls (0.16). The odds of being a case were 2.15 (CI = 1.4-3.3) times higher for subjects with at least one copy of allele 2. No statistically significant differences in the allelic frequencies or genotype distributions for IL-1alpha (+ 4845) or IL-1beta (+ 3953) were found between the control and disease groups. CONCLUSIONS: This is the first report showing an association between the IL-1RA (+ 2018) polymorphism and silicosis, and suggests that this polymorphism may confer increased risk for the development of the disease.

The role of tumor necrosis factor alpha in chemical-induced hepatotoxicity.

Only recently have toxicologists come to understand the role of inflammation, and TNFalpha specifically, in classical toxicological processes. This relationship appears fairly complex, as inflammation and proliferation may well be only one facet of a time- and dose-dependent continuum of toxicological and repair processes. Not surprisingly, considerable efforts are being undertaken using our newly found understanding of molecular control to develop specific and safe chemical, biological, and molecular regulators of TNFalpha for potential therapeutic use. Their effectiveness in controlling environmental or occupational diseases has yet to be established.

Overview of immunotoxicology and current applications to respiratory diseases.

Immunotoxicology has been defined as the study of adverse effects on the immune system resulting directly from environmental, occupational, or therapeutic exposure to chemicals (including drugs), biological materials and, in certain instances, physiological factors, collectively referred to as agents. It encompasses immunosuppression, allergy, autoimmunity and inflammation.

Immunotoxicology: role of inflammation in chemical-induced hepatotoxicity.

The liver, which is the major organ responsible for the metabolism of drugs and chemicals, is also the primary target organ for many toxic chemicals. Increasing evidence has indicated that inflammatory processes are intimately involved in chemical-induced hepatotoxic processes, and like other inflammatory diseases, such as autoimmunity, are responsible for producing mediators which can effect liver damage or repair. This review will summarize the authors' current understanding of how inflammatory processes influence hepatic pathology and repair following exposure to established hepatotoxic chemicals including carbon tetrachloride (CCl4), an industrial chemical, and acetaminophen (APAP), a widely used analgesic.

Effects of occupational chronic co-exposure to n-hexane, toluen, and methyl ethyl ketone on NK cell activity and some immunoregulatory cytokine levels in shoe workers.

1. To evaluate the effects of occupational long-term co-exposure to n-hexane, toluen, and methyl ethyl ketone (MEK) on NK cell activity and serum IL-2, gamma-IFN levels, we studied a group of workers employed in a shoe factory where the jobs include use of glues and adhesives containing mainly n-hexane, and at low concentrations, toluen and MEK. 2. No differences were found in these parameters even in those workers with 3.3-fold higher mean levels of urine, 2,5-Hxdn and approximately twofold higher mean levels of urine hippuric acid as compared to controls. 3. We conclude that chronic co-exposure to n-hexane, toluen, and MEK at these levels is not associated with an impairment on either NK cell activity or serum IL-2 and gamma-IFN levels.

In vitro effects of various metals on natural killer cell activity in cultured human lymphocytes.

Heavy metals have been shown to have a differential effects on various aspects of immune response. Recently natural killer cells have been widely investigated due to their purported role in immune surveillance. To ascertain the immunotoxic effects of lead, cadmium, nickel and chromium on natural killer (NK) cell activity in vitro, peripheral blood lymphocytes from normal donors were examined in the presence of different concentrations (10(-5)-10(-8) M) of four selected metal salts (cadmium sulphate, lead nitrate, chromium nitrate and nickel sulphate). NK cell activity was evaluated in a 4-h chromium release assay against K562 target cells. All of the metal salts were found to exert no effect on NK cell function in the human concentration range.

Investigation of some immunological functions in a group of asphalt workers exposed to polycyclic aromatic hydrocarbons.

To investigate the effects of polycyclic aromatic hydrocarbons (PAHs) on the human immune system, analyses were performed on T-cell subsets (CD4+, CD8+), B-cells (CD19+), serum immunoglobulin levels (IgG, IgM, IgA) and white blood cell percentages of 16 male workers who were employed in road paving operations and compared to 12 unexposed male controls. PAH exposure was assessed using urinary 1-hydroxy-pyrene (1-OHP) levels and was found to be significantly higher in workers than in the controls. While the CD4+ cell percentage and the CD4+/CD8+ ratio were significantly higher in the PAH-exposed group, the percentages of CD8+ and CD19+ cells were unchanged. There was also a significant enhancement in serum IgG levels and the percentage of monocytes in the workers compared to the control group. These data suggest that chronic exposure to PAHs may affect some immune functions in humans.

Proliferative response of peripheral blood lymphocytes and lymphocyte subpopulations in n-Hexane, toluen, and methyl ethyl ketone co-exposed workers.

To estimate the quantitative relation between chronic co-exposure to airborne n-hexane, toluen, methyl ethyl ketone (MEK) and various markers of immune function such as proliferative response of peripheral blood lymphocytes and lymphocyte subpopulations, a group of workers employed in a shoe factory were examined and compared with the unexposed controls. A significant increase was observed in the proliferative response of the peripheral lymphocytes to 2.5 and 5 µg PHA in the exposed group compared with that of the control group. There was no significant change in the percentage of circulating CD3(+), CD4(+), CD8(+), CD19(+), CD16(+) lymphocytes even in those workers with 3.3-fold higher mean levels of urine 2,5-hexanedione (2,5-Hxdn) and approximately twofold higher mean levels of urine hippuric acid (HA) as compared to controls. No difference was also observed between the mean granulocyte, monocyte, lymphocyte percentages of the groups, but a significant increase was observed in mean serum C3 level of the workers. Our results suggest that while lymphocyte subpopulations and leucocyte percentages are not affected, the proliferative response of the peripheral lymphocytes is stimulated after chronic co-exposure to n-hexane, toluen and MEK at the defined levels.

Effects of occupational lead and cadmium exposure on some immunoregulatory cytokine levels in man.

The levels of serum interleukin-1beta (IL-1beta), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-alpha) and gamma-interferon (gamma-IFN) were assessed in the workers who were occupationally exposed to lead and cadmium. The values were compared with the age-matched control group. Blood lead and cadmium levels were significantly raised. Our findings suggest that chronic lead and cadmium exposure in humans resulted in significant suppression of the serum IL-1beta level, but did not alter IL-2 and TNF-alpha levels. The gamma-IFN level was also reduced in lead workers. In contrast, a significant enhancement was observed in the cadmium-exposed group. We conclude from these results that lead and cadmium exposure at chronically high level may affect some cytokine levels in humans.