Vascular and thrombogenic effects of pulmonary exposure to Libby amphibole

Our plain-English summary of Vascular and thrombogenic effects of pulmonary exposure to Libby amphibole, by J.H. Shannahan, M.C. Schladweiler, R.F. Thomas, et al (Journal of Toxicology and Environmental Health. Part a, 2012).

The study

• Authors: J.H. Shannahan, M.C. Schladweiler, R.F. Thomas, W.O. Ward, A.J. Ghio, S.H. Gavett, U.P. Kodavanti
• Journal: Journal of Toxicology and Environmental Health. Part a
• Published: 2012;75(4):213-31
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This animal experiment tested whether Libby amphibole asbestos, collected near Libby, Montana, affected blood and blood vessels when placed into the lungs of male rats. Wistar Kyoto, spontaneously hypertensive and spontaneously hypertensive heart failure rats received one dose of 0.25 or 1 mg. F344 rats got one dose of up to 5 mg, or the same totals split into seven doses over about three months. In Wistar Kyoto rats, platelet counts rose at 1 day, then fell from 1 week to 3 months. After 1 mg, their platelets clumped more slowly in response to a test chemical (ADP) from 1 week to 3 months, and less overall at 3 months only. At 3 months, aorta genes tied to clotting and vessel narrowing showed changes the authors likened to those in unexposed heart-disease rats. In F344 rats, platelet and lymphocyte counts were lower soon after the last of the highest repeated doses; aorta changes were smaller than in Wistar Kyoto rats. Blood inflammatory markers were mostly undetectable. The authors concluded the exposure may, over time, predispose to a clot-prone, vessel-narrowing state and perhaps increased cardiovascular disease.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (rats given Libby amphibole by intratracheal instillation); samples from three independent studies were examined
• Who was studied: Male rats aged 11–12 weeks from Charles River Laboratories (Raleigh, NC). Study 1: healthy Wistar Kyoto (WKY) rats (n = 12/group), spontaneously hypertensive (SH) rats (n = 6/group) and SH heart failure (SHHF) rats (n = 6/group). Studies 2 and 3: healthy F344 rats (n = 8–24/time point).
• Exposure: Libby amphibole (LA) collected from the Rainy Creek Complex near Libby, Montana, in 2007, size-separated to a rat-respirable fraction (median fiber length 3.59 µm), and instilled into the windpipe. Study 1: one dose of 0, 0.25 or 1 mg/rat in saline; rats examined at 1 day, 1 week, 1 month or 3 months. Study 2: one dose of 0, 0.15, 0.5, 1.5 or 5 mg/rat; examined from 1 day to 24 months. Study 3: the same total doses split into instillations every other week for 13 weeks; examined 1 day, 2 weeks or 24 months after the final dose.
• Main results:
  • In WKY rats (study 1), platelet counts were raised 1 day after LA while remaining unchanged in SH and SHHF rats. From 1 week through 3 months, LA-exposed WKY rats had lower platelet counts than control WKY rats.
  • In WKY rats given 1 mg LA, ADP-induced primary platelet aggregation was reduced at 3 months, and the rate of aggregation was reduced from 1 week through 3 months. Primary aggregation was not changed at other time points or in SH or SHHF rats.
  • In F344 rats given repeated doses (study 3), platelet and lymphocyte counts fell with dose at 1 day and 2 weeks after the final dose. At the 5 mg cumulative dose, platelet counts were 339 ± 11 (1 day) and 323 ± 20 (2 weeks) × 10^6/ml, against 585 ± 17 and 553 ± 13 in controls (Table 1).
  • In F344 rats, platelet aggregation, measured only at 12 and 24 months (study 2) and at 24 months (study 3), showed no LA-related changes in overall aggregation or rate of aggregation.
  • In the aorta of WKY rats 3 months after LA, expression of TIMP-2 rose with dose, eNOS was inhibited after 1 mg, the endothelin receptor ETR-A was induced after 1 mg, and tissue factor (TF) was raised after 0.25 mg.
  • In WKY rats, aortic expression of tPA, PAI-1 and vWF appeared increased after LA, but these trends were not statistically significant. tPA and PAI-1 were elevated at baseline in SH and SHHF rats compared with WKY rats.
  • Serum IL-6 and TNF-alpha were below the limit of detection in most samples, and no significant changes were seen in response to exposure.
  • Aortic gene changes in F344 rats after LA were smaller than those in WKY rats.
• The authors' conclusion: The authors concluded that LA exposure altered systemic vascular endpoints that over time may predispose to a prothrombotic and vasoconstrictive state and perhaps increased cardiovascular disease. Because SH and SHHF rats showed similar aortic changes without exposure, they suggested LA may predispose healthy rats to cardiovascular disease.
• Limitations the authors state:
  • Because tissues came from three independent studies, the doses could not be matched across studies, especially in the two single-instillation studies.
  • The doses used were high.
  • Cytokine changes occurring in the first hours after instillation, before the first sampling time, could not be ruled out.

Mines named here

Asbestos mines this study is about. Each mine's page says who ran it, when it worked, and what it produced.

• Libby vermiculite mine, Montana

All asbestos mines

Topics

Medical terms in this study, explained in our Lexicon: Libby amphiboles, Cytokine, Biomarker, Oxidative Stress, Inflammation.

Related studies

• The role of iron in Libby amphibole-induced acute lung injury and inflammation — J.H. Shannahan, A.J. Ghio, et al. (2011)
• Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure — J.H. Shannahan, O. Alzate, et al. (2012)
• Transcriptional activation of inflammasome components by Libby amphibole and the role of iron — J.H. Shannahan, A.J. Ghio, et al. (2012)
• Pulmonary inflammatory and fibrotic responses in Fischer 344 rats after intratracheal instillation exposure to Libby amphibole — D.J. Padilla-Carlin, M.C. Schladweiler, et al. (2011)
• Long-term response of rats to single intratracheal exposure of Libby amphibole or amosite — J.M. Cyphert, D.J. Padilla-Carlin, et al. (2012)
• Comparative long-term toxicity of Libby amphibole and amosite asbestos in rats after single or multiple intratracheal exposures — J.M. Cyphert, D.J. Carlin, et al. (2015)

Browse more research in Journal of Toxicology and Environmental Health. Part a, or return to medical research.