title: Mechanisms of asbestos-induced nitric oxide production by rat alveolar macrophages in inhalation and in vitro models.
abstract: To evaluate the contribution of reactive nitrogen species to inflammation by asbestos, Fischer 344 rats were exposed to crocidolite or chrysotile asbestos by inhalation to determine whether increases occurred in nitric oxide (NO.) metabolites from alveolar macrophages (AMs). AMs from animals inhaling asbestos showed significant elevations (p < .05) in nitrite/nitrate levels which were ameliorated by NG-monomethyl-L-arginine (NMMA), an inhibitor of inducible nitric oxide synthase (iNOS) activity. Temporal patterns of NO. generation from AMs correlated with neutrophil influx in bronchoalveolar lavage samples after asbestos inhalation or bleomycin instillation, another model of pulmonary fibrosis. To determine the molecular mechanisms and specificity of iNOS promoter activation by asbestos, RAW 264.7 cells, a murine macrophage-like line, and AMs isolated from control rats were exposed to crocidolite asbestos in vitro. These cells showed increases in steady-state levels of iNOS mRNA in response to asbestos and more dramatic increases in both iNOS mRNA and immunoreactive protein after addition of lipopolysaccharide (LPS). After transfection of an iNOS promoter/luciferase reporter construct, RAW 264.7 cells exposed to LPS, crocidolite asbestos and its nonfibrous analog, riebeckite, revealed increases in luciferase activity whereas cristobalite silica had no effects. Studies suggest that NO. generation may be important in cell injury and inflammation by asbestos.
authors.affiliation: Department of Pathology, University of Vermont, Burlington 05405, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Quinlan
authors.forename: K A
authors.initials: KA
authors.lastname: BeruBe
authors.forename: M P
authors.initials: MP
authors.lastname: Hacker
authors.forename: D J
authors.initials: DJ
authors.lastname: Taatjes
authors.forename: C R
authors.initials: CR
authors.lastname: Timblin
authors.forename: J
authors.initials: J
authors.lastname: Goldberg
authors.forename: P
authors.initials: P
authors.lastname: Kimberley
authors.forename: P
authors.initials: P
authors.lastname: O'Shaughnessy
authors.forename: D
authors.initials: D
authors.lastname: Hemenway
authors.forename: J
authors.initials: J
authors.lastname: Torino
authors.forename: L A
authors.initials: LA
authors.lastname: Jimenez
authors.forename: B T
authors.initials: BT
authors.lastname: Mossman
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001194:Asbestos / Q000633:toxicity*; D001761:Bleomycin / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D005609:Free Radicals; D007150:Immunohistochemistry; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D009573:Nitrites / Q000378:metabolism*; D010084:Oxidation-Reduction; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D005609:Free Radicals; D009566:Nitrates; D009573:Nitrites; D001761:Bleomycin; D001194:Asbestos; D009569:Nitric Oxide