ToxSci Advance Access published online on December 9, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj075
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1 National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Morgantown, WV 26505
* To whom correspondence should be addressed. Our laboratory has previously reported results from a rat silica inhalation study which determined that even after silica exposure ended, pulmonary inflammation and damage progressed with subsequent fibrosis development. In the present study, the relationship between silica exposure, nitric oxide (NO) and reactive oxygen species (ROS) production, and the resultant pulmonary damage, are investigated in this model. Rats were exposed to silica (15 mg/m3, 6 hours/day) for either 20, 40 or 60 days. A portion of the rats from each exposure were sacrificed at 0 days post-exposure, while another portion was maintained without further exposure for 36 days to examine recovery or progression. The major findings of this study are: (1) silica-exposed rat lungs were in a state of oxidative stress, the severity of which increased during the post-exposure period, (2) silica-exposed rats had significant increase in lung NO production which increased in magnitude during the post-exposure period, and (3) the presence of silica particle(s) in an alveolar macrophage (AM) was highly associated with inducible nitric oxide synthase (iNOS) protein. These data indicate that even after silica exposure has ended, and despite declining silica lung burden, silica-induced pulmonary NO and ROS production increases, thus producing a more severe oxidative stress. A quantitative association between silica and expression of iNOS protein in AMs was also determined, which adds to our previous observation that iNOS and NO-mediated damage are associated anatomically with silica-induced pathological lesions. Future studies will be needed to determine whether the progressive oxidative stress, and iNOS activation and NO production, is a direct result of silica lung burden or a consequence of silica-induced biochemical mediators. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.
Received September 6, 2005
Accepted November 20, 2005
Respiratory Toxicology
Nitric Oxide and Reactive Oxygen Species Production Causes Progressive Damage in Rats after Cessation of Silica Inhalation
D. W. Porter 1 *,
L. L. Millecchia 1,
P. Willard 1,
V. A. Robinson 1,
D. Ramsey 2,
J. McLaurin 2,
A. Khan 2,
K. Brumbaugh 1,
C. M. Beighley 1,
A. Teass 2,
and
V. Castranova 1
2 National Institute for Occupational Safety and Health, Division of Applied Research and Technology, Cincinnati, OH 45226
D. W. Porter, E-mail: DPorter{at}cdc.gov
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