title: Vascular and thrombogenic effects of pulmonary exposure to Libby amphibole.
abstract: Exposure to Libby amphibole (LA) asbestos is associated with increased incidences of human autoimmune disease and mortality related to cardiovascular diseases. However, the systemic and vascular impacts are less well examined because of the dominance of pulmonary disease. It was postulated that regardless of the type of exposure scenario, LA exposure might produce systemic and vascular inflammogenic and thrombotic alterations in healthy and cardiovascular compromised rat models. Samples from three independent studies were examined. In the first study, male Wistar Kyoto (WKY), spontaneously hypertensive (SH), and SH heart failure (SHHF) rats were intratracheally instilled once with 0 (vehicle), 0.25, or 1 mg/rat of LA. In the second study, F344 rats were instilled with vehicle or LA at 0.5, 1.5, or 5 mg/rat. In the third study, F344 rats were instilled with the same mass concentrations of LA delivered by biweekly multiple instillations over 3 mo to simulate an episodic subchronic exposure. Complete blood count, platelet aggregation, serum cytokines, and biomarkers of systemic and aortic effects were examined. LA reduced adenosine diphosphate (ADP)-induced platelet aggregation and decreased circulating platelets in WKY (1 mg/rat) and F344 (5 mg/rat) at the 3-mo time point but did not do so in SH or SHHF rats. A decline in circulating lymphocytes with age appeared to be exacerbated by LA exposure in F344 rats but the differences were not significant. Aorta mRNA expression for biomarkers of oxidative stress (HO-1, LOX-1), inflammation (MIP-2), and thrombosis (tPA, PAI-1, vWf) were increased at baseline in SH and SHHF relative to WKY. LA exposure upregulated several of these biomarkers and also those involved in aortic contractility of WKY rats at 3 mo, suggesting thrombogenic, vasocontractile, and oxidative stress-mediated impairments. The aorta changes in F344 rats were less remarkable than changes noted in WKY following LA exposure. In conclusion, exposure to LA decreased circulating platelets and platelet coagulability while increasing the expression of oxidative stress, thrombosis, and vasoconstriction biomarkers in the aorta of healthy rats. These changes were similar to those noted at baseline in SH and SHHF rats, suggesting that LA-induced pulmonary injury might increase the risk of developing cardiovascular disease in healthy individuals.
authors.affiliation: Curriculum in Toxicology, UNC School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Shannahan
authors.forename: M C
authors.initials: MC
authors.lastname: Schladweiler
authors.forename: R F
authors.initials: RF
authors.lastname: Thomas
authors.forename: W O
authors.initials: WO
authors.lastname: Ward
authors.forename: A J
authors.initials: AJ
authors.lastname: Ghio
authors.forename: S H
authors.initials: SH
authors.lastname: Gavett
authors.forename: U P
authors.initials: UP
authors.lastname: Kodavanti
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D017636:Asbestos, Amphibole / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001772:Blood Cell Count; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D007322:Instillation, Drug; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013927:Thrombosis / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism; D059550:Toxicity Tests, Subchronic; D014661:Vasoconstriction
chemical_list: D017636:Asbestos, Amphibole; D015415:Biomarkers; D016207:Cytokines