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PubMed2006

Src tyrosine kinases mediate crystalline silica-induced NF-kappaB activation through tyrosine phosphorylation of IkappaB-alpha and p65 NF-kappaB in RAW 264.7 macrophages.

Protein tyrosine kinases (PTKs) and mitogen-activated protein kinases (MAPKs) have been demonstrated to play a crucial role in the signaling pathways induced by silica. In the present study, we investigated whether Src family TKs play a role in crystalline silica-induced NF-kappaB activation and whether NF-kappaB activation requires Src TK-dependent MAPK activity in RAW 264.7 cells, a mouse peritoneal macrophage cell line. Selective Src TK inhibitors, damnacanthal or PP1, inhibited silica-induced NF-kappaB activation in a dose-dependent manner. Furthermore, these kinase inhibitors suppressed silica-induced tyrosine phosphorylation of IkappaB-alpha and p65 NF-kappaB. Within a similar time frame, c-Src and Lck were physically associated with IkappaB-alpha and with p65 NF-kappaB. Silica stimulated the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), but not p38 MAPK and c-Jun NH(2)-terminal kinase 1 and 2 (JNK1/2). Damnacanthal or PP1 substantially blocked the silica-induced activation of ERK1/2. Moreover, PD98059, an inhibitor of ERK1/2, or SB203580, an inhibitor of p38 MAPK, failed to inhibit silica-induced NF-kappaB activation. These results suggest that c-Src and Lck act for silica-induced NF-kappaB activation by mediating the tyrosine phosphorylations of IkappaB-alpha and p65 NF-kappaB. However, the Src TK-dependent activation of ERK1/2 may not be involved in the silica signaling pathway leading to NF-kappaB activation.

Animals↗

PubMed2002

Depressant effect of ambroxol on stimulated functional responses and cell death in rat alveolar macrophages exposed to silica in vitro.

The present study examined the effect of ambroxol on free radical production, granule enzyme release, and cell death in silica-activated rat alveolar macrophages. The action of ambroxol was assayed by measuring changes in the activities of protein kinase C (PKC) and tyrosine kinase (PTK) and in the intracellular calcium level. Ambroxol attenuated the production of superoxide, hydrogen peroxide, and nitric oxide and the release of acid phosphatase and lysozyme in macrophages activated by silica. Staurosporine, genistein, EGTA, and trifluoperazine inhibited the silica-induced free radical production and granule enzyme release. Silica induced the increase in PKC and PTK activities and the elevation of intracellular calcium level in macrophages, which was decreased by ambroxol. Silica induced a cell death and increased the caspase-3 activity in macrophages in a concentration-dependent manner. Ambroxol decreased the silica-induced cell viability loss in macrophages. The results show that ambroxol decreases the stimulated responses and cell death in rat alveolar macrophages exposed to silica, which may be accomplished by inhibition of activation processes, protein kinases, and calcium transport. The inhibitory effect of ambroxol on silica-induced cell death appears to provide the protective effect on pulmonary tissues against the toxic action of silica.

Acid Phosphatase↗

PubMed1997

Early increase in expression of surfactant protein A gene in type II cells from silica-treated rats.

Silica is known to cause an increase in lung surfactant and to promote type II cell hypertrophy and hyperplasia. Two populations of type II cells can be isolated from silica-treated rats: type IIA cells that are similar to normal type II cells and type IIB cells that are larger, contain more surfactant phospholipids, and have increased rates of phospholipid biosynthesis. As much less is known about the influence of silica on the amounts of surfactant proteins (SPs) in type II cells, we examined expression of the genes for all four SPs in types IIA and IIB cells isolated from rats 1, 3, and 7 days after a single intratracheal injection of silica. There was a rapid increase in expression of the SP-A gene in type II cells from the silica-treated animals. SP-A mRNA content was 8- to 10-fold greater in types IIA and IIB cells isolated 1 day after silica injection than in type II cells from saline-injected animals. SP-A mRNA levels were also elevated in the cells isolated on days 3 and 7 after silica injection, but the extent of the increase was less than in the cells isolated on day 1 and declined with time after injection. SP-B, SP-C, and SP-D mRNA levels were 2.5- to 4-fold greater in type IIA cells on day 3 after silica injection than in control type II cells. However, those mRNA levels were not significantly increased in the type IIA cells isolated on days 1 and 7 or in type IIB cells at any time point. These data show that silica causes a rapid and substantial increase in expression of the SP-A gene in type II cells.

Animals↗

PubMed1998

L-arginine uptake and metabolism by lung macrophages and neutrophils following intratracheal instillation of silica in vivo.

Nitric oxide (NO) has been associated with lung inflammation following exposure to silica. L-arginine can be converted to NO and L-citrulline by nitric oxide synthase (NOS), or into urea and L-ornithine by arginase. We tested the hypothesis that after instillation of silica into rat lungs in vivo, lung inflammatory cells increase L-arginine metabolism by both NOS and arginase, which is associated with an increase in L-arginine uptake. We isolated lung inflammatory cells 3 d after silica or saline (control) exposure. The uptake of [3H]L-arginine at 24 h by cells from silica-exposed lungs (73.9 +/- 4.8%) was significantly greater than uptake by control cells (24.7 +/- 2.2%; P < 0.05) and was a saturable process. The greater [3H]L-arginine uptake by cells from silica-exposed lungs was associated with greater NO and urea production than by control cells. The uptake of [3H]L-arginine by cells from control or silica-exposed lungs was blocked in a dose-dependent manner by L-ornithine (an inhibitor of L-arginine transport) and by Nomega-nitro-L-arginine methyl ester (L-NAME) (an NOS inhibitor), but not by L-valine (an arginase inhibitor). The production of NO by cells from silica-exposed lungs was completely blocked by L-NAME. The addition of L-arginine to media resulted in dose-dependent production of NO and urea. The results show that lung inflammatory cells increase L-arginine uptake and metabolism by both NOS and arginase following in vivo silica exposure. The increase in L-arginine uptake may represent a mechanism to maintain an intracellular supply of this amino acid. NO can react to generate peroxynitrite, a potential mediator of lung injury following silica exposure.

Animals↗

PubMed2005

Occupational exposure to crystalline silica dust in the United States, 1988-2003.

The purposes of this study were a) to summarize measurements of airborne (respirable) crystalline silica dust exposure levels among U.S. workers, b) to provide an update of the 1990 Stewart and Rice report on airborne silica exposure levels in high-risk industries and occupations with data for the time period 1988-2003, c) to estimate the number of workers potentially exposed to silica in industries that the Occupational Safety and Health Administration (OSHA) inspected for high exposure levels, and d) to conduct time trend analyses on airborne silica dust exposure levels for time-weighted average (TWA) measurements. Compliance inspection data that were taken from the OSHA Integrated Management Information System (IMIS) for 1988-2003 (n = 7,209) were used to measure the airborne crystalline silica dust exposure levels among U.S. workers. A second-order autoregressive model was applied to assess the change in the mean silica exposure measurements over time. The overall geometric mean of silica exposure levels for 8-hr personal TWA samples collected during programmed inspections was 0.077 mg/m3, well above the applicable American Conference of Governmental Industrial Hygienists threshold limit value of 0.05 mg/m3. Surgical appliances supplies industry [Standard Industrial Classification (SIC) 3842] had the lowest geometric mean silica exposure level of 0.017 mg/m3, compared with the highest level, 0.166 mg/m3, for the metal valves and pipe fitting industry (SIC 3494), for an 8-hr TWA measurement. Although a downward trend in the airborne silica exposure levels was observed during 1988-2003, the results showed that 3.6% of the sampled workers were exposed above the OSHA-calculated permissible exposure limit.

Air Pollutants, Occupational↗

PubMed1990

Evidence of an oxidative mechanism for the hemolytic activity of silica particles.

The formation of reactive oxygen species resulting from the interaction of silica dust particles with red blood cell membranes was investigated; particularly, the effect of surface hydroxyl (silanol) group concentration on the rate of formation of such reactive oxygen species was investigated. The rate of formation was measured indirectly through the effect of catalase, a hemoprotein peroxidase, on silica-induced hemolysis. It was found that the addition of exogenous catalase to erythrocytes markedly reduces the hemolysis caused by silica particles. Furthermore, the amount of catalase required for deactivation of silica per unit area of particle surface is lower for fumed silica particles and calcined crystalline particles than for uncalcined, crystalline silica, suggesting a correlation between the concentration of OH groups at the silica particle surface and its potential for generation of H2O2. The addition of albumin, a copper chelator, also decreases hemolysis. These results suggest that the hemolysis caused by silica particles is at least partly related to the formation of H2O2 at the particle surface and its subsequent reaction with Cu+ ions. The relationship between the concentration of surface silanol groups on the silica surface and the amount of catalase required to decrease hemolysis may also provide a method for testing potential fibrogenicity of respirable dusts.

Albumins↗

PubMed1994

Acute silica toxicity: attenuation by amiodarone-induced pulmonary phospholipidosis.

Exposure to the toxic mineral dust silica has been shown to produce an acute inflammatory response in the lungs of both humans and laboratory animals. Coating silica with phospholipids reduces its toxicity when studied with in vitro systems. The drug amiodarone increases phospholipid within the cells, airways, and alveoli of the lungs. This increase in phospholipid is due to amiodarone's ability to inhibit phospholipase activity within alveolar macrophages (AMs) and whole lung. The purpose of this study was to determine whether the amiodarone-induced increase in pulmonary phospholipid would protect the lungs from acute damage caused by the intratracheal instillation of silica. Treatment of male Fischer 344 rats with amiodarone for 14 days caused an increase in phospholipid content in bronchoalveolar lavage fluid and AMs compared to vehicle-treated controls. The rats were then instilled with silica or saline vehicle. At both 1 and 14 days after silica exposure, pulmonary phospholipidosis was associated with a marked reduction in acute silica-induced pulmonary damage as assessed by biochemical parameters in bronchoalveolar lavage fluid, however, the influx of neutrophils into the airspaces was not reduced. Four times more phospholipid was bound to the silica recovered from amiodarone-treated rats compared to controls. The results of these in vivo experiments indicate that pulmonary phospholipidosis attenuates the acute damage associated with the intratracheal instillation of silica in rats. By using an in vitro cell culture system, we demonstrated that, in contrast to control AMs, phospholipidotic AMs were significantly more resistant to the cytotoxicity of surfactant-coated silica.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1999

Occupational exposure to crystalline silica and autoimmune disease.

Occupational exposure to silica dust has been examined as a possible risk factor with respect to several systemic autoimmune diseases, including scleroderma, rheumatoid arthritis, systemic lupus erythematosus, and some of the small vessel vasculitidies with renal involvement (e.g., Wegener granulomatosis). Crystalline silica, or quartz, is an abundant mineral found in sand, rock, and soil. High-level exposure to respirable silica dust can cause chronic inflammation and fibrosis in the lung and other organs. Studies of specific occupational groups with high-level silica exposure (e.g., miners) have shown increased rates of autoimmune diseases compared to the expected rates in the general population. However, some clinic- and population-based studies have not demonstrated an association between silica exposure and risk of autoimmune diseases. This lack of effect may be due to the limited statistical power of these studies to examine this association or because the lower- or moderate-level exposures that may be more common in the general population were not considered. Experimental studies demonstrate that silica can act as an adjuvant to nonspecifically enhance the immune response. This is one mechanism by which silica might be involved in the development of autoimmune diseases. Given that several different autoimmune diseases may be associated with silica dust exposure, silica dust may act to promote or accelerate disease development, requiring some other factor to break immune tolerance or initiate autoimmunity. The specific manifestation of this effect may depend on underlying differences in genetic susceptibility or other environmental exposures.

Arthritis, Rheumatoid↗

PubMed2001

Silica exposure in anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and lupus nephritis.

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated small-vessel vasculitis (SVV) and systemic lupus erythematosus (SLE) are rare diseases with unknown causes. Silica dust exposure has been suggested to be an environmental factor that may increase the risk of developing these and other autoimmune disorders. This is a report of two case-control studies to determine whether silica dust exposure is independently associated with ANCA-SVV with glomerulonephritis and SLE nephritis. Patients were screened through a collaborative network of 225 private practice and university nephrologists (the Glomerular Disease Collaborative Network). Patients with ANCA-SVV or SLE, all with biopsy-proven renal involvement, were included. Control subjects were patients without ANCA-SVV or SLE who had been referred to the same renal clinics and were matched for gender, race, and age (within 5 yr). Exposures to silica, exposures to other environmental agents, and smoking histories were evaluated using a self-administered questionnaire. Enrollment consisted of 65 patients with ANCA-SVV and 51 patients with SLE nephritis. Silica dust exposure was reported by 46% of patients with ANCA-SVV, compared with 20% of control subjects (P = 0.001). The odds ratio of silica dust exposure was 4.4 times greater for patients with ANCA-SVV, compared with control subjects (95% confidence interval, 1.36 to 13.4; P = 0.013). The odds ratios for silica dust exposure were similar for patients with ANCA-SVV with lung or sinus vasculitis (odds ratio, 4.5; 95% confidence interval, 0.99 to 20.83; P = 0.054) and those without lung or sinus vasculitis (odds ratio, 4.7; 95% confidence interval, 1.34 to 16.24; P = 0.016). Silica dust exposure was reported by 12% of patients with SLE nephritis, compared with 25% of control subjects (P = 0.047). The odds ratio for exposure to silica dust was not statistically different for patients with SLE nephritis, compared with control subjects (odds ratio, 0.001; 95% confidence interval, <0.01 to >100; P = 0.993). Activities and environments known to cause high levels of exposure to silica dust were associated with ANCA-SVV but not with SLE nephritis.

Adult↗

PubMed1999

Silica increases cytosolic calcium and causes cell injury in renal cell lines.

The purpose of this study was to clarify the effect of silica-induced cytosolic free calcium mobilization and cell injury in immortalized cell lines from transgenic mice kidney harboring SV40 T-antigen gene. The proximal convoluted tubule (S1)- and the inner medullary collecting tubule (IMCT)-originated cell lines were used. Cytosolic free calcium concentration ([Ca2+]i) was measured employing Fura-2 fluorescence and cell injury was evaluated by a vital dye exclusion procedure. Silica increased [Ca2+]i in a concentration-dependent manner in S1 (60 micrograms/ml-600 micrograms/ml) and IMCT (6 micrograms/ml-600 micrograms/ml). Silica caused a biphasic increase in [Ca2+]i which was composed of an initial rapid rise and following sustained phase. Ca2+ removal from the medium resulted in abolishment of initial and sustained phase of silica (600 micrograms/ml)-induced [Ca2+]i in both cell lines. Silica-induced cell injury was increased in a dose-dependent manner. This silica-induced cell injury was attenuated by the pretreatment with EGTA (100 microM) and nifedipine (1 microM). Cellular ATP content ([ATP]i) by silica also decreased in a concentration-dependent manner. The relationship between [Ca2+]i and [ATP]i showed that [ATP]i depletion caused [Ca2+]i to rise. This study suggests that 1) the elevation of [Ca2+]i caused by silica is due mainly to influx through plasma membrane Ca2+ channel and non specific membrane damage (at high concentration) and 2) nephrotoxicity of silica shows site-specificity within the kidney.

Adenosine Triphosphate↗

PubMed1998

Administration of silica sensitizes lipopolysaccharide responsiveness of murine macrophages but inhibits T and B cell priming by inhibition of antigen presenting function.

Macrophages play a key role in natural host defense against infection by a variety of pathogens. In addition, macrophages initiate the development of acquired immunity via antigen processing and presentation. The role of macrophages in resistance to pathogens, the development of autoimmune diseases and the induction of acquired immunity has been studied by treatment of rodents with reagents which are cytotoxic. We have studied the effects of one such reagent, silica, on the function of spleen macrophages and peritoneal exudate cells (PEC). Intraperitoneal administration of silica caused the accumulation of spleen macrophages and neutrophils, reduction in the number of B cells and had a modest effect on T cell abundance. The percentage of CD11b+ PEC was not affected by silica treatment but total PEC recovery was diminished 5-8 fold. Silica treatment did not cause release of TNF-alpha or IL-1-beta but, when stimulated with lipopolysaccharide (LPS) in vitro after silica treatment, PEC or spleen macrophages produced elevated levels of both cytokines compared to controls. In contrast, release of IL-12 from non-LPS treated PEC was stimulated 4-5 fold by silica treatment. In addition, sensitivity to LPS toxicity in vivo was significantly enhanced by silica. The ability of macrophages to present antigen to a T cell clone in vitro was found to be dramatically inhibited by silica treatment, as was the ability to prime antigen-specific T cells and B cells by antigen injection. Collectively these data demonstrate that silica treatment enhances macrophage sensitivity to LPS exposure but inhibits antigen processing and presentation.

Animals↗

PubMed2001

Bronchial epithelial cell matrix production in response to silica and basic fibroblast growth factor.

BACKGROUND: Previous studies show that macrophages, lung fibroblasts, and their soluble mediators are responsible for the onset and development of pulmonary fibrosis. This study was conducted to determine whether airway epithelial cells are also directly involved in response to fibrogenic agents and consequently in the pathogenesis of lung fibrosis. To verify the hypothesis, we determined whether silica acts directly on human bronchial epithelial cells by stimulating cytokine and growth factor release and by modifying matrix production. MATERIALS AND METHODS: An SV40 large T antigen-transformed human airway epithelial cell line, 16HBE14o (16HBE), was used. The expression profile of some proinflammatory interleukins (ILs), such as IL-1alpha, IL-1beta and IL-6 and their modulation by silica, were evaluated by polymerase chain reaction (PCR) analysis. Transforming growth factor beta (TGFbeta) and basic fibroblast growth factor (bFGF) mRNA levels were tested by Northern blotting in the presence and in the absence of silica. The silica- and/or bFGF-induced effects on matrix components (total proteins, collagen, and fibronectin) were also evaluated using radio-labeled precursors. RESULTS: The results demonstrated 16HBE internalized silica particles. Silica induced a little IL-6 secretion, without affecting IL-1 and TGFbeta isoform production and strongly stimulated bFGF mRNA level and bFGF protein secretion. Silica also induced changes in 16HBE production of total proteins, collagen, and fibronectin production. When added in combination with the growth factor, it strengthened bFGF stimulation of matrix component secretion. CONCLUSIONS: These results support the hypothesis that the changes in matrix components are due to a direct effect of silica on bronchial epithelial cells. Silica-induced over-secretion of bFGF suggests that autocrine and paracrine differentiation loops for bFGF may also be operative and that these mechanisms may be involved in the pathogenesis of pulmonary fibrosis. In the future, cytokine-directed therapeutic strategies might find a place in clinical practice.

Blotting, Northern↗

PubMed2001

Time course of pulmonary response of rats to inhalation of crystalline silica: histological results and biochemical indices of damage, lipidosis, and fibrosis.

Previous studies have determined that alpha-quartz (crystalline silica) can cause pulmonary inflammation, damage, and fibrosis. However, the temporal relationship between silica inhalation and pulmonary inflammation, damage, and fibrosis has not been fully examined. To address this gap in our knowledge of silica-induced pulmonary fibrosis, a chronic inhalation study using rats was designed. Specifically, rats were exposed to a silica aerosol (15 mg/m3 silica, 6 h/d, 5 d/wk, 116 d), and measurements of pulmonary inflammation, damage, and fibrosis were monitored throughout the study. We report (1) data demonstrating that the silica aerosol generation and exposure system produced a consistent silica aerosol of respirable size particles; (2) the time course of silica deposition in the lung; (3) calculations that demonstrate that the rats were not in pulmonary overload; (4) histopathological data demonstrating time-dependent enhancement of silica-induced alveolitis, epithelial hypertrophy and hyperplasia, alveolar lipoproteinosis, and pulmonary fibrosis in the absence of overload; and (5) biochemical data documenting the development of lipidosis, lung damage, and fibrosis.

Administration, Inhalation↗

PubMedDate not supplied

NF-kappaB, a pivotal transcription factor in silica-induced diseases.

Inhalation of silica in a number of occupational settings can result in debilitating and costly lung disease. It is thought that the pathological replacement of functional lung tissue with fibrotic lesions in silica-induced lung disease is the result of chronic inflammation mediated by products of the silica-exposed alveolar macrophage. In particular, inflammatory cytokines, growth factors and reactive oxygen species have been implicated in many acute and chronic inflammatory lung diseases. Pharmacological intervention to modify the production of these mediators has been shown to ameliorate several of these disease processes. Recent studies have demonstrated that the production of these inflammatory mediators is altered as a result of the activation of nuclear factor-kappaB (NF-kappaB). NF-kappaB is a pivotal transcription factor activated by silica in macrophages and other types of lung cells. The understanding of how silica induces NF-kappaB activation and what signaling pathways are involved in this silica-induced NF-kappaB activation is important and should provide valuable new information related to both the etiology and potential treatment of silica-related lung diseases. This review summarizes the molecular mechanisms involved in silica-induced NF-kappaB activation and discusses the importance of NF-kappaB as a critical transcription factor in mediating silica-induced lung diseases.

Animals↗

PubMed2006

[Synthesis and property of nano-fumed silica derivative with quaternary ammonium group].

Nano-fumed silica derivative with quaternary ammonium group was synthesized and the antimicrobial activity was investigated. The nano-fumed silica derivative was investigated by Fourier-transform infrared spectroscopy (FTIR). The zeta potential and the size of the nano-fumed silica derivative were measured. The antimicrobial properties of the nano-fumed silica derivative against selected microorganisms were tested by the quantitative suspension method. The zeta potential showed that the isoelectric points of nano-fumed silica and modified nano-fumed silica are pH=4. 8 and pH =10.5-10.8, respectively, and the shift of the isoelectric point is due to the quaternary ammonium salt. The obtained nano-fumed silica derivative inhibited the growth of Gram-negative (Escherichia coli), Gram-positive bacteria (Staphylococcus aureus), and fungus (Candida albicans). The inhibiting effect of nano-fumed silica derivative on the microorganisms varied with the time of exposure. The bacteriostatic rates were noted to be 99.99%, 99.99% and 94.12% after 15 minutes' exposure, respectively. Thus the results indicate that nano-fumed silica derivative with quaternary ammonium group has significant inhibitory effect on the growth of bacteria.

Anti-Infective Agents↗

PubMed2006

[Synthesis, characterization and antimicrobial activity of nano-fumed silica derivative with quaternary ammonium salts].

Nano-fumed silica reacted with gamma-chlopropyltrimethoxysilane as a coupling agent, and then by quaternization with N,N-dimethyl-n-tetradecylamine, finally the nano-fumed silica derivative with quaternary ammonium salts was obtained. The nano-fumed silica derivative was investigated by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimeter (DSC), and Zeta sizer nano series. The antimicrobial properties of the nano-fumed silica derivative against selected microorganisms were tested by the quantitative suspension method. The results revealed that (1) gamma-chlopropyltrimethoxysilane can be bound to the surface of the nano-fumed silica With increasing the amount of gamma-chlopropyltrimethoxysilane, the amount of surface hydroxyl groups of nano-fumed silica decreases. (2) The Zeta potential showed that the isoelectric point of the nano-fumed silica and the modified nano-fumed silica is pH 4.8 and pH 10.5, respectively. The shift of the isoelectric point is due to the quaternary ammonium groups. (3) The obtained nano-fumed silica derivative has significant inhibition effect on the growth of microorganisms, and the bactericidal rates in 15 min for E. coil (8099), S. aureus (ATCC6538) and C. albicans(ATCC10231) were 99.99%,, 99.99% and 94.12%, respectively.

Anti-Infective Agents↗

PubMed1975

Effects of intravenous silica on immune and non-immune functions of the murine host.

Silica, an agent toxic for macrophages, administered i.v. to DBA/2 mice rapidly depresses the clearance of colloidal carbon by the reticuloendothelial system and reduces the in vitro phagocytic activity of peritoneal macrophages harvested 3 days after silica injection. Silica blocks the humoral immune response to sheep erythrocytes and the cell-mediated immune response to allogeneic fibroblasts when given before antigen. Silica also induces complex alterations in spleen cell responsiveness to concanavalin A involving both local and serum factors. Silica had no significant effect on the induction of interferon by statolon or Newcastle disease virus. No unequivocal evidence was obtained that silica has a direct depressive effect on cells other that macrophages, but indirect effects on lymphocytes were produced most likely by factors released from silica-lysed macrophages. Intravenous silica may prove useful for the separation of interferon induction and immune response stimulation in studies of host resistance to infection and oncogenesis. Considerable variation exists in the immunodepressive effects of different preparations of silica.

Animals↗

PubMedDate not supplied

Role of hydroxyl radical in silica-induced NF-kappa B activation in macrophages.

Nuclear transcription factor kappa B (NF-kappa B) is a multiprotein complex that regulates a variety of genes important for immunity and inflammation. The present study investigates the silica-induced activation of this transcription factor in mouse macrophage cell line RAW 264.7 cells, the role of free radical reactions in the mechanism of the activation, and its possible inhibition. Tetrandrine, a benzylisoquinoline alkaloid, which has been used as an antifibrotic drug to treat the lesions of silicosis and has been characterized as a hydroxyl radical (.OH) scavenger, inhibited the NF-kappa B activation induced by silica, lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate (PMA). Catalase, metal chelator, deferoxamine, and the silanol group (SiOH) blocker, poly(2-vinylpyridine-N-oxide) (PVPNO), also inhibited silica-induced NF-kappa B activation. Electron spin resonance (ESR) spin trapping measurements show that both deferoxamine and PVPNO decreased silica-mediated .OH radical generation from H2O2. It is shown that Fe(II) and not Fe(III) is able to cause NF-kappa B activation. The antioxidant, ascorbate, attenuated the NF-kappa B activation induced by silica but not by LPS. The .OH radical scavenger, sodium formate, inhibited NF-kappa B activation induced by silica but had only a minor effect on NF-kappa B activation induced by LPS. The results indicate that silica-mediated free radical generation via the Fenton or Fenton-like reaction (M(n)+ + H2O2-->M(n + 1)+ + OH- + .OH) and silanol groups on the silica surface play an important role in silica-induced NF-kappa B activation.

Alkaloids↗