Dawn Ramsey

TIME COURSE OF PULMONARY RESPONSE OF RATS TO INHALATION OF CRYSTALLINE SILICA: NF-kappa B ACTIVATION, INFLAMMATION, CYTOKINE PRODUCTION, AND DAMAGE

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.

Enhanced Pulmonary Response to the Inhalation of Freshly Fractured Silica as Compared with Aged Dust Exposure

Abstract 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/m3, 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 pro...

Effect of silica inhalation on the pulmonary clearance of a bacterial pathogen in Fischer 344 rats.

Abstract. Silica inhalation predisposes workers to bacterial infection and impairments in pulmonary defense function. In this study, we evaluated the effect of pre-exposure to silica on lung defense mechanisms by use of a rat pulmonary Listeria monocytogenes infection model. Male Fischer 344 rats were exposed by inhalation to filtered air or silica (15 mg/m3× 6 h/day × 5 days/wk). After 21 or 59 days of silica exposure, the rats were inoculated intratracheally with 5 × 103L. monocytogenes. At 0 (noninfected controls), 3, and 7 days after infection, the left lungs were removed, homogenized, and the number of viable L. monocytogenes was counted after an overnight culture at 37° C. Bronchoalveolar lavage (BAL) was performed on the right lungs. Alveolar macrophages (AM) were collected, and the AM production of chemiluminescence (CL), an index of reactive oxygen species generation, was measured. The number of lavagable neutrophils (PMNs) and acellular BAL lactate dehydrogenase (LDH) activity were determined as indices of inflammation and injury, respectively. Pre-exposure to silica for 59 days caused substantial increases in PMN number and LDH activity compared with the air controls, whereas silica inhalation for both 21 and 59 days significantly enhanced the pulmonary clearance of L. monocytogenes compared with air controls. Dramatic elevations were also observed in zymosan- and phorbol myristate acetate (PMA)–stimulated CL production by lung phagocytes recovered from rats pre-exposed to silica for 59 days. These results demonstrate that short-term exposure to inhaled silica particles activates lung phagocytes, as evidenced by increases in reactive oxygen species. This up-regulation in the production of antimicrobial oxidants is likely responsible for the enhancement in pulmonary clearance of L. monocytogenes observed with short-term silica inhalation.