Nitric oxide and reactive oxygen species production causes progressive damage in rats after cessation of silica inhalation.
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 is investigated in this model. 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 sacrificed at 0 days postexposure, 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 postexposure period, (2) silica-exposed rats had significant increase in lung NO production which increased in magnitude during the postexposure 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.
Porter
Dale W
DW
National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Morgantown, WV 26505, USA. DPorter@cdc.gov
Millecchia
Lyndell L
LL
Willard
Patsy
P
Robinson
Victor A
VA
Ramsey
Dawn
D
McLaurin
Jeffery
J
Khan
Amir
A
Brumbaugh
Kurt
K
Beighley
Christoper M
CM
Teass
Alexander
A
Castranova
Vincent
V
D000280:Administration, Inhalation; D000395:Air Pollutants, Occupational / Q000633:toxicity*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004195:Disease Models, Animal; D019570:Inhalation Exposure; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012822:Silicon Dioxide / Q000633:toxicity*; D012829:Silicosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors
D000395:Air Pollutants, Occupational; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D012822:Silicon Dioxide; D052247:Nitric Oxide Synthase Type II