Role of inducible nitric oxide-derived nitric oxide in silica-induced pulmonary inflammation and injury.
Zeidler-PC; Hubbs-AF; Castranova-V
Toxicologist 2004 Mar; 78(S-1):143-144
Our lab has demonstrated previously that exposure of rats to silica resulted in induction of inducible nitric oxide synthase (iNOS) in alveolar macrophages (AM) and alveolar type II epithelial cells (TII). The production of nitric oxide (NO) by these pneumocytes and resultant NO-dependent damage (nitrotyrosine residues) have been related temporally and anatomically with silica-induced inflammation and granuloma formation (Am J Physiol Lung Cell Mol Physiol 283:L485, 2002). The objective of the present study was to determine if these associations represent a causal role for NO in silica-induced lung disease. To address this question, the sub-chronic response of C57BL/6J wild type (WT) mice and iNOS knockout (KO) mice to aspiration of silica (40 mg/kg) was compared 42 days post-exposure. Exposure of WT mice to silica was marked by the following sub-chronic responses: pulmonary damage (increased LDH and albumin levels in lung lavage fluid, and increased lung weight), inflammation (increased lung lavage polymorphonuclear leukocytes, TNF-alpha, MIP-2 and TGF-beta, and histological evidence of alveolitis and lipoproteinosis), oxidant stress (increased zymosan-stimulated chemiluminescence from AM, and decreased total antioxidant levels in lung lavage fluid), and fibrosis (increased lung hydroxyproline levels). Absence of the iNOS gene in KO mice resulted in a significant decrease in markers of pulmonary damage, inflammation, oxidant stress and fibrosis 42 days after silica exposure. These data indicate that NO production plays a causal role in the progression of silica-induced lung disease.
Animals; Animal-studies; Exposure-levels; Fibrosis; Injuries; Laboratory-animals; Lung-disease; Lung-disorders; Nitrous-oxides; Oxides; Pulmonary-system-disorders; Respiratory-system-disorders; Silica-dusts; Silicates
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland