1 Health Effects Laboratory Division, National
Institute for Occupational Safety and Health, Morgantown, West Virginia
26505; and 2 Division of Applied Research and
Technology, National Institute ...for Occupational Safety and Health,
Cincinnati, Ohio 45226
In previous reports from this study,
measurements of pulmonary inflammation, bronchoalveolar lavage cell
cytokine production and nuclear factor- B activation, cytotoxic
damage, and fibrosis were detailed. In this study, we investigated the
temporal relationship between silica inhalation, nitric oxide (NO), and
reactive oxygen species (ROS) production, and damage mediated by these
radicals in the rat. Rats were exposed to a silica aerosol (15 mg/m 3 silica, 6 h/day, 5 days/wk) for 116 days. We report
time-dependent changes in 1 ) activation of alveolar
macrophages and concomitant production of NO and ROS, 2 )
immunohistochemical localization of inducible NO synthase and the
NO-induced damage product nitrotyrosine, 3 ) bronchoalveolar
lavage fluid NO x and superoxide dismutase concentrations, and 4 ) lung lipid peroxidation levels. The
major observations made in this study are as follows: 1 ) NO
and ROS production and resultant damage increased during silica
exposure, and 2 ) the sites of inducible NO synthase
activation and NO-mediated damage are associated anatomically with
pathological lesions in the lungs.
silicosis; fibrosis; oxidant injury; nitrotyrosine
In vitro studies suggest that silica-induced lung disease may be linked to processes regulated by nuclear factor- κ B (NF- κ B) activation, but this has not been examined in vivo. Rats were exposed ...to a silica aerosol of 15 mg/m 3 (6 h/day, 5 days/wk) for 116 days, and bronchoalveolar lavage (BAL) was conducted at various times during the exposure. Silica-induced pulmonary inflammation and damage were determined by measuring BAL cell differentials and first BAL fluid lactate dehydrogenase (LDH) activity and serum albumin concentrations, respectively. NF- κ B activation and production of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) by BAL cells were also measured. The results demonstrate that NF- κ B activation occurred after 5 days exposure, and continued to increase thereafter. BAL cell production of IL-1 and TNF-α had increased incrementally by 10 and 30 days of exposure, respectively. This elevation continued through 79 days of exposure before further increasing at 116 days of exposure. Pulmonary inflammation and damage in silica-exposed rats were also significantly elevated at 5 days of exposure, further increased at a slow rate through 41 days of exposure, and dramatically increased thereafter. Taken together, the results indicate that the initial molecular response of NF- κ B activation in BAL cells occurs in response to low levels of silica deposition in the lung and increases more rapidly versus exposure duration than silica-induced pulmonary inflammation, cellular damage, and cytokine production by BAL cells. This suggests that NF- κ B activation in BAL cells may play an important role in the initiation and progression of silica-induced pulmonary inflammation, cellular damage, and fibrosis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human epidemiologic studies have found that silicosis may develop or progress even after occupational exposure has ended, suggesting that there is a threshold lung burden above which silica-induced ...pulmonary disease progresses without further exposure. We previously described the time course of rat pulmonary responses to silica inhalation as biphasic, the initial phase characterized by increased but controlled pulmonary inflammation and damage. However, after a threshold lung burden was exceeded, rapid progression of silica-induced pulmonary disease occurred. To test the hypothesis that there is a threshold lung burden above which silica-induced pulmonary disease progresses without further exposure we initiated a study to investigate the relationship between silica exposure, the initiation and progression of silica-induced pulmonary disease, and recovery. Rats were exposed to silica (15 mg/m3, 6 h/day) for either 20, 40, or 60 days. A portion of the rats from each exposure were maintained without further exposure for 36 days to examine recovery. The major findings of this study are: (1) silica-exposed rats were not in pulmonary overload, and lung silica burden decreased with recovery; (2) pulmonary inflammation, damage and lipidosis increased with recovery for rats exposed to silica for 40 and 60 days, but not 20 days; (3) histopathology revealed changes in silica-induced alveolitis, epithelial hypertrophy and hyperplasia, and alveolar lipoproteinosis consistent with bronchoalveolar lavage (BAL) endpoints; and (4) pulmonary fibrosis developed even when exposure was stopped prior to its initial development.
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.
A study was conducted to investigate the temporal relationship between silica inhalation, nitric oxide, and reactive oxygen species production, and to determine the damage mediated by these radicals ...in the rat.
Fischer 344 rats were exposed to silica at a concentration of 15 mg/m super(3) for 6 h/d, 5 d/week, for a total of 116 exposure days, and effects on pulmonary inflammation, nuclear factor B (NF- B) ...and cytokine production from bronchoalveolar lavage cells, and development of pulmonary damage were examined. Selected rats were euthanized after 5, 10, 16, 20, 30, 41, 79, and 116 d of exposure. Silica-induced inflammation, as indicated by elevated levels of polymorphonuclear leukocytes in bronchoalveolar cells, was observed after 5 d, remaining relatively constant through day 30 and then increasing dramatically. Silica inhalation and deposition in the lung caused not only inflammation in the lung, but also increased the number of blood cells of the type that are recruited to the lung during inflammatory response. In the silica-exposed rats, NF- B was activated in bronchoalveolar lavage cells, with the degree of activation increasing almost linearly throughout exposure. In addition, the production of tumor necrosis factor- alpha and interleukin-1 by bronchoalveolar lavage cells increased upon exposure to silica for 30 and 10 d, respectively. Activation of NF- B in bronchoalveolar lavage cells preceded increases in cytokine production.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We have reported previously that grinding crystalline silica generates radicals on its cleavage planes and that this fresh dust is more cytotoxic in vitro than aged silica. The objective of the ...present study was to determine if freshly fractured silica was also more toxic and inflammatory in vivo than aged silica of the same composition and particle size. Fresh α-quartz was generated using a jet mill, while aged dust was milled and then stored for 2 months before use. Analysis of surface radicals by electron spin resonance spectroscopy verified the enhanced surface activity of this fresh silica compared with aged dust. Male Fischer 344 rats were exposed to fresh or aged α-quartz by inhalation (20 mg/m
3
, 5 hours per day, 5 days per week for 2 weeks) and pulmonary responses were determined 1 to 3 days after exposure. Exposure to aged silica resulted in an increase in total cells, red blood cells, lymphocytes, and granulocytes harvested by bronchoalveolar lavage, and in elevated acellular lavage protein and phospholipid levels. Furthermore, inhalation of aged silica activated alveolar macrophages (measured as zymosan-stimulated chemiluminescence) and resulted in induction of nitric oxide synthase in these cells (determined as L-NAME inhibitable chemiluminescence). In comparison, inhalation of freshly cleaved silica resulted in dramatically greater increases in all these parameters than did aged silica. Histopathologic inflammation, while mild, followed a similar pattern. In conclusion, methods have been successfully developed to expose rats to fresh or aged α-quartz. The results indicate that inhalation of fresh silica causes greater toxic and inflammatory pulmonary reactions than aged silica. These results may be relevant to occupational settings such as sandblasting, rock drilling, and milling, where workers are exposed to freshly fractured silica.
Compositional analyses were undertaken to evaluate the hypothesis that Shivwits Ware pottery found in southern Nevada was not produced in that area but, instead, manufactured on the Shivwits Plateau. ...The evidence supports this hypothesis and indicates that large quantities of Shivwits Ware jars moved through a distribution system linking the upland areas of the western Arizona Strip with the lowlands of southeastern Nevada. This long-distance movement of utilitarian pottery is unusual for precontact North America, in that it occurred in the apparent absence of any centralized distribution mechanisms and between what would have been small, kin-based communities. The nature and the causes for the development of this distribution system are discussed.
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